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1.
Drugs Today (Barc) ; 56(8): 505-514, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33025946

RESUMO

Peficitinib hydrobromide is a small Janus kinase inhibitor (JAK1, JAK2, JAK3 and TYK2) molecule for the treatment of rheumatoid arthritis (RA). Phase II and phase III clinical trials and extension studies with different doses have been conducted to assess the drug's efficacy and safety with substantially improved outcomes observed in RA. This JAK inhibitor oral drug demonstrated clinical response as once-daily monotherapy in patients with moderate to severe RA, also in combination with methotrexate (MTX), who had an inadequate response to MTX. The findings from studies of this new JAK inhibitor have shown that, both in monotherapy as well as in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), it has efficacy, safety and tolerability in RA patients.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Adamantano/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Janus Quinases/antagonistas & inibidores , Niacinamida/uso terapêutico , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(41): e22504, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031288

RESUMO

In clinical trials of tofacitinib for rheumatoid arthritis (RA), Japanese and Korean patients had higher incidence of herpes zoster (HZ) than subjects from elsewhere; however, post-market data from Asia are lacking. Hence, we investigated the incidence of HZ and its risk factors in Taiwanese RA patients receiving tofacitinib. At a medical center in Taichung, Taiwan, we enrolled patients with active RA treated with tofacitinib between January 4, 2015 and December 9, 2017, following unsuccessful methotrexate therapy and no tofacitinib exposure RA patients as a control group. Demographic characteristics, interferon-gamma levels, and lymphocyte counts were compared. Among 125 tofacitinib-treated RA patients, 7 developed HZ, an incidence rate of 3.6/100 person-years. Patients with HZ had shorter disease duration than those without, but higher frequency of prior HZ. Baseline interferon-gamma levels and HLA-DR activated T cell counts were positively correlated and significantly lower in patients with HZ than without. Strikingly, 5/7 HZ cases occurred within 4 months of starting tofacitinib therapy. Incidence of HZ in tofacitinib-treated Taiwanese RA patients is lower than rates in Japan or Korea, and commensurate with the global average. HZ may occur soon after commencing tofacitinib therapy. The role of interferon-gamma and activated T cells in tofacitinib-related HZ deserves further investigation.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Herpes Zoster/epidemiologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Linfócitos T , Idoso , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Interferon gama/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologia
3.
Medicine (Baltimore) ; 99(35): e21827, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871905

RESUMO

To retrospectively evaluate initial tumor necrosis factor inhibitor (TNFi) failure patients for clinical predictors of response to a 2nd TNFi in our 4282 rheumatoid arthritis (RA) patient database.A cross-sectional retrospective manual chart review of the electronic health record (EHR) was performed on 322 "real world" RA patients who were prescribed 2 TNFis. Response to TNFi was determined by the treating provider who had real time Clinical Disease Activity Index (CDAI) scores to inform treatment decisions. Age, gender, body mass index (BMI), insurance provider, duration of disease, cyclic citrullinated peptide antibody (CCP) and rheumatoid factor (RF) positivity, concomitant disease modifying anti-rheumatic drug therapy, length of time between diagnosis and start of 1st and 2nd TNFi, transient efficacy of 1st TNFi (defined as response to TNFi at 3 months but later lost response), and reason for discontinuation of 1st TNFi were analyzed. A multivariable logistic regression model was used to model response to a 2nd TNFi.Response proportions to the 2nd TNFi were greater in females (161/223, 72.2% response female vs 41/75, 54.7% male, P < .01), those who began their 1st TNFi within 3 months of their RA diagnosis, and in RF+ patients (123/170, 72.4% response seropositive vs 66/110, 60.0% seronegative, P < .03). The higher female response rate was independent of age, BMI, and seropositivity.In RA patients who failed an initial TNFi, female patients and patients with RF+ were more likely to have a clinical response to a 2nd TNFi. In the absence of these predictors, stronger consideration for choosing a biologic with an alternative mechanism of action might be given when the 1st TNFi fails.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fator Reumatoide/sangue , Fatores Sexuais , Tempo para o Tratamento
4.
Isr Med Assoc J ; 9(22): 491-497, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32954695

RESUMO

BACKGROUND: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA. OBJECTIVES: To evaluate SC tocilizumab in a real-life clinical setting. METHODS: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed. RESULTS: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively. CONCLUSIONS: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/fisiopatologia , Quimioterapia Combinada , Feminino , Humanos , Injeções Subcutâneas , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
5.
RMD Open ; 6(2)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32878994

RESUMO

OBJECTIVES: Patients with inflammatory rheumatic diseases (IRD) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be at risk to develop a severe course of COVID-19. The influence of immunomodulating drugs on the course of COVID-19 is unknown. To gather knowledge about SARS-CoV-2 infections in patients with IRD, we established a registry shortly after the beginning of the pandemic in Germany. METHODS: Using an online questionnaire (www.COVID19-rheuma.de), a nationwide database was launched on 30 March 2020, with appropriate ethical and data protection approval to collect data of patients with IRD infected with SARS-CoV-2. In this registry, key clinical and epidemiological parameters-for example, diagnosis of IRD, antirheumatic therapies, comorbidities and course of the infection-are documented. RESULTS: Until 25 April 2020, data from 104 patients with IRD infected with SARS-CoV-2 were reported (40 males; 63 females; 1 diverse). Most of them (45%) were diagnosed with rheumatoid arthritis, 59% had one or more comorbidities and 42% were treated with biological disease-modifying antirheumatic drugs. Hospitalisation was reported in 32% of the patients. Two-thirds of the patients already recovered. Unfortunately, 6 patients had a fatal course. CONCLUSIONS: In a short time, a national registry for SARS-CoV2-infected patients with IRD was established. Within 4 weeks, 104 cases were documented. The registry enables to generate data rapidly in this emerging situation and to gain a better understanding of the course of SARS-CoV2-infection in patients with IRD, with a distinct focus on their immunomodulatory therapies. This knowledge is valuable for timely information of physicians and patients with IRD, and shall also serve for the development of guidance for the management of patients with IRD during this pandemic.


Assuntos
Antirreumáticos/uso terapêutico , Produtos Biológicos/uso terapêutico , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Sistema de Registros , Doenças Reumáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/mortalidade , Feminino , Alemanha , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Hospitalização , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Polimialgia Reumática/complicações , Polimialgia Reumática/tratamento farmacológico , Prognóstico , Doenças Reumáticas/complicações , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Índice de Gravidade de Doença , Espondilite Anquilosante/complicações , Espondilite Anquilosante/tratamento farmacológico , Adulto Jovem
6.
Medicine (Baltimore) ; 99(36): e22011, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899051

RESUMO

BACKGROUND: Rheumatoid arthritis has the characteristics of slow progression, long course, and repeated attacks. At present, western medicine commonly used in clinical practice not only reduces pain and improves symptoms, but also has more adverse reactions, affecting the health, and life of patients. In ancient China, Huangqi Guizhi Wuwu decoction was used by doctors to treat rheumatoid arthritis, with remarkable effect. In recent years, many clinical studies have also shown that Huangqi Guizhi Wuwu decoction has reliable effect in treating rheumatoid arthritis, but there is no evidence of evidence-based medicine. Therefore, this study aims to systematically evaluate the clinical efficacy and safety of Huangqi Guizhi Wuwu decoction in the treatment of rheumatoid arthritis. METHODS: Using computer to retrieve PubMed, The Cochrance Library, Embase, Web of Science, CNKI, VIP and Wanfang database, in addition manually retrieve Google academic and Baidu academic to collect all randomized controlled trials for Huangqi Guizhi Wuwu decoction in the treatment of rheumatoid arthritis, including relevant academic journal and conference papers, dissertations, from the establishment of the database to July 2020. After 2 evaluators independently screened the literature, extracted the data, and evaluated the risk of bias included in the study, RevMan5.3 software was used to analyze the data. RESULTS: This research evaluate the efficacy and safety of Huangqi Guizhi Wuwu decoction in treating Rheumatoid arthritis from the aspects of clinical efficacy rate, visual analog scale (VAS), swollen joint count (SJC), morning stiffness time, Rrythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and adverse reaction incidence. CONCLUSION: This study will provide reliable evidence for the clinical application of Huangqi Guizhi Wuwu decoction in the treatment of rheumatoid arthritis. ETHICS AND DISSEMINATION: The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/RZY3V.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Metanálise como Assunto , Fitoterapia , Revisões Sistemáticas como Assunto
7.
Clin Rheumatol ; 39(11): 3223-3235, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32885345

RESUMO

Cytokine pathways and their signaling disorders can be the cause of onset and pathogenesis of many diseases such as autoimmune diseases and COVID-19 infection. Autoimmune patients may be at higher risk of developing infection due to the impaired immune responses, the use of immunosuppressive drugs, and damage to various organs. Increased secretion of inflammatory cytokines and intolerance of the patient's immune system to COVID-19 infection are the leading causes of hospitalization of these patients. The content used in this paper has been taken from English language articles (2005-2020) retrieved from the PubMed database and Google Scholar search engine using "COVID-19," "Autoimmune disease," "Therapeutic," "Pathogenesis," and "Pathway" keywords. The emergence of COVID-19 and its association with autoimmune disorders is a major challenge in the management of these diseases. The results showed that the use of corticosteroids in the treatment of autoimmune diseases can make diagnosis and treatment of COVID-19 more challenging by preventing the fever. Due to the common pathogenesis of COVID-19 and autoimmune diseases, the use of autoimmune drugs as a possible treatment option could help control the virus. KEY POINTS: • Inflammatory cytokines play an essential role in the pathogenesis of COVID-19 • ACE2 dysfunctions are related to the with COVID-19 and autoimmune diseases • The use autoimmune diseases drugs can be useful in treating COVID-19.


Assuntos
Artrite Reumatoide/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Diabetes Mellitus/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Esclerose Múltipla/imunologia , Pneumonia Viral/imunologia , Artrite Reumatoide/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Esclerose Múltipla/tratamento farmacológico , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico
8.
Clin Rheumatol ; 39(11): 3237-3244, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892311

RESUMO

The outbreak of coronavirus in the world has led to an uncertainty about treatment of patients with autoimmune disorders because of their weakened immune system coupled with immunosuppressive agents they take which predisposes them to a host of infections. Data on COVID-19 patients with underlying rheumatological diseases has been emerging mostly in the form of small case series and one global registry. From these data, it seems like our patients, although immunosuppressed, are not particularly susceptible to the coronavirus infection and if infected, do not have significantly worse outcomes than other patients. In fact, drugs like hydroxychloroquine, dexamethasone, and tocilizumab have been studied for treatment of COVID-19. However, this is only preliminary data, and since a few parts of the world are still grappling with the pandemic at its peak, we need to be equipped on how to protect and manage our immunosuppressed patients. Published evidence to guide treatment decisions are lacking and doubts regarding continuation and initiation of immunosuppressants remain. Rheumatoid arthritis (RA) is the most common immune-mediated disorder in COVID-19 patients, and in this review, we discuss how the commonly used drugs in RA alter the patients' susceptibility to this infection. The review also summarizes the recommendations from the major bodies on how to manage this disease in these times. Key Points • Patients on immunosuppressive medications are not found to be at a greatly increased risk of acquiring COVID-19 infection. • Patients doing well on a stable dose of steroid and/or Disease-Modifying Antirheumatic Drugs (DMARDs) should be allowed to continue the same unless they get infected in which case, temporary stoppage of methotrexate and leflunomide may be considered. • Initiation of high-dose steroids, DMARDs, and biologics, if the clinical situation demands so, can be done. • Maintenance biologic therapy for stable patients should be individualized by the treating physician.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Infecções por Coronavirus , Glucocorticoides/uso terapêutico , Pandemias , Pneumonia Viral , Anti-Inflamatórios não Esteroides/uso terapêutico , Betacoronavirus , Produtos Biológicos/uso terapêutico , Desprescrições , Gerenciamento Clínico , Humanos , Inibidores do Fator de Necrose Tumoral/uso terapêutico
9.
PLoS Med ; 17(9): e1003296, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32960885

RESUMO

BACKGROUND: Based on different genetic and environmental risk factors and histology, it has been proposed that rheumatoid arthritis (RA) consists of 2 types: autoantibody-positive and autoantibody-negative RA. However, until now, this remained hypothetical. To assess this hypothesis, we studied whether the long-term outcomes differed for these 2 groups of RA patients. METHODS AND FINDINGS: In the Leiden Early Arthritis Clinic cohort, 1,285 consecutive RA patients were included between 1993 and 2016 and followed yearly. Treatment protocols in routine care improved over time, irrespective of autoantibody status, and 5 inclusion periods were used as instrumental variables: 1993-1996, delayed mild disease-modifying antirheumatic drug (DMARD) initiation (reference period); 1997-2000, early mild DMARDs; 2001-2005, early methotrexate; 2006-2010, early methotrexate followed by treat-to-target adjustments; 2011-2016, similar to 2006-2010 plus additional efforts for very early referral. Three long-term outcomes were studied: sustained DMARD-free remission (SDFR) (persistent absence of clinical synovitis after DMARD cessation), mortality, and functional disability measured by yearly Health Assessment Questionnaire (HAQ). Treatment response in the short term (disease activity) was measured by Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR). Linear mixed models and Cox regression were used, stratified for autoantibody positivity, defined as IgG anti-CCP2 and/or IgM rheumatoid factor positivity. In total, 823 patients had autoantibody-positive RA (mean age 55 years, 67% female); 462 patients had autoantibody-negative RA (age 60 years, 64% female). Age, gender, and percentage of autoantibody-positive patients were stable throughout the inclusion periods. Disease activity significantly decreased over time within both groups. SDFR rates increased after introduction of treat-to-target (hazard ratio [HR] 2006-2010 relative to 1993-1996: 3.35 [95% CI 1.46 to 7.72; p = 0.004]; HR 2011-2016: 4.57 [95% CI 1.80 to 11.6; p = 0.001]) in autoantibody-positive RA, but not in autoantibody-negative RA. In autoantibody-positive RA, mortality decreased significantly after the introduction of treat-to-target treatment adjustments (HR 2006-2010: 0.56 [95% CI 0.34 to 0.92; p = 0.023]; HR 2011-2016: 0.33 [95% CI 0.14 to 0.77; p = 0.010]), but not in autoantibody-negative RA (HR 2006-2010: 0.79 [95% CI 0.40 to 1.56; p = 0.50]; HR 2011-2016: 0.36 [95% CI 0.10 to 1.34; p = 0.13]). Similarly, functional disability improved in autoantibody-positive RA for the periods after 2000 relative to 1993-1996 (range -0.16 [95% CI -0.29 to -0.03; p = 0.043] to -0.32 [95% CI -0.44 to -0.20; p < 0.001] units of improvement), but not in autoantibody-negative RA (range 0.10 [95% CI -0.12 to 0.31; p = 0.38] to -0.13 [95% CI -0.34 to 0.07; p = 0.20] units of improvement). Limitations to note were that treatment was not randomized-but it was protocolized and instrumental variable analysis was used to obtain comparable groups-and that a limited spread of ethnicities was included. CONCLUSIONS: Although disease activity has improved in both autoantibody-positive and autoantibody-negative RA in recent decades, the response in long-term outcomes differed. We propose that it is time to subdivide RA into autoantibody-positive RA (type 1) and autoantibody-negative RA (type 2), in the hope that this leads to stratified treatment in RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Adulto , Idoso , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Autoanticorpos/genética , Autoanticorpos/imunologia , Biomarcadores Farmacológicos/sangue , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Índice de Gravidade de Doença
10.
Medicine (Baltimore) ; 99(39): e22264, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991425

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease, which can lead to joint destruction, dysfunction, finally deformity. Currently, Western medicine treats it with disease-modifying antireheumatic drugs, NSAIDs, glucocorticoid, biological agents, etc, which can induce adverse drug reactions. And now, as an important mean of treating RA, Zhuang medicine has been widely used in clinics, and has achieved significant efficacy. METHODS AND ANALYSIS: The following databases will be searched for relevant information before July 2020: PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure. MAJOR RESULTS: levels of C-reactive protein, erythrocyte sedimentation rate, Rheumatoid factor. Secondary results: morning stiffness time, range of motion, arthralgia, joint tenderness index, joint swelling index, total effective rate, adverse event. Data will be collected independently by 2 researchers, and the risk of bias in meta analysis will be evaluated according to "Cochrane Handbook for Systematic Reviews of Interventions". All data analysis will be conducted using Review Manager V.5.3. and Stata V.12.0. RESULTS: The curative effect and safety of traditional therapies of Zhuang Medicine treatment for RA patients will be evaluated systematically. CONCLUSION: The systematic review of this study will summarize the currently published evidence of traditional therapies of Zhuang Medicine treatment for RA to further guide its promotion and application.Open Science Framework (OSF) registration number: https://osf.io/c4xv3/.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Dor/tratamento farmacológico , Adulto , Artralgia , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Artropatias/tratamento farmacológico , Artropatias/fisiopatologia , Masculino , Medicina Tradicional Chinesa/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Amplitude de Movimento Articular/efeitos dos fármacos , Segurança , Resultado do Tratamento
12.
Medicine (Baltimore) ; 99(30): e21151, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791688

RESUMO

BACKGROUND: The introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) into clinical practice has dramatically improve the clinical outcomes of individuals with rheumatoid arthritis (RA). However, bDMARDs are associated with high costs, which has resulted in restricted treatment access and a burden on medical insurance finances. Although biosimilars offer cost-saving, their effectiveness and safety must be established in Post-Marketing Surveillance (PMS). Infliximab (IFX), a chimeric monoclonal antibody to TNF-alpha, is the first bDMARD; its biosimilar, CT-P13, is the first biosimilar DMARD approved for RA treatment in Japan. We will evaluate whether switching from originator IFX to CT-P13 is not inferior for maintaining non-clinical relapse to continued treatment with originator IFX in RA patients achieving clinical remission. METHODS/DESIGN: This study is an interventional, multicenter, open-label, single-arm against historical control and noninferiority clinical trial with a 24-week follow-up. Eighty RA patients who are treated by originator IFX for ≥24 weeks and are achieving clinical remission will be included. Patients will be switched to CT-P13 with the unchanged dosing regimen. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the ratio of patients who experience a nonclinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of many biomarkers such as cytokines and chemokines. DISCUSSION: The study results are expected to show the noninferiority of switching to CT-P13 over the continuation of originator IFX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices but also MSUS to accurately and objectively evaluate disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will explore whether parameters at baseline can predict a nonclinical relapse after switching from originator IFX to CT-P13 by integrating multilateral assessments, i.e., clinical disease activity indices, MSUS findings, and serum biomarkers. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on October 11, 2019 as jRCTs071190030.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Quimiocinas/sangue , Infliximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Biomarcadores/sangue , Substituição de Medicamentos , Estudos de Equivalência como Asunto , Humanos , Japão , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Índice de Gravidade de Doença , Ultrassonografia , Adulto Jovem
13.
Medicine (Baltimore) ; 99(32): e21480, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769882

RESUMO

BACKGROUND: The introduction of biological disease-modifying anti-rheumatic drugs into clinical practice has dramatically improved the clinical outcomes of individuals with rheumatoid arthritis (RA). We are conducting the IFX-SIRIUS STUDY I that evaluates whether switching from originator infliximab (IFX) to its biosimilar, CT-P13, is not inferior in maintaining nonclinical relapse to continue treatment with originator IFX in patients with RA achieving clinical remission. It is the next great issue whether disease activity can be maintained in good condition after discontinuation of CT-P13 because no evidence is available regarding the clinical value of discontinuing biosimilars in patients with RA. Thus, we will evaluate whether a condition without clinical relapse will be maintained after discontinuation of CT-P13 in patients with RA, achieving clinical remission or low disease activity during the IFX-SIRIUS STUDY I. METHODS/DESIGN: This study is an interventional, multicenter, open-label, single-arm clinical trial with a 48-week follow-up. Patients with RA who are treated with CT-P13 and sustained nonclinical relapse during the IFX-SIRIUS STUDY I will be included. Patients will discontinue CT-P13 after the study period of the IFX-SIRIUS STUDY I. We will evaluate disease activity by clinical disease activity indices and musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who do not have clinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of multiple biomarkers, such as cytokines and chemokines. In addition, if a clinical relapse occurs in patients after the discontinuation of CT-P13, we will evaluate the effectiveness and safety of restarting CT-P13. DISCUSSION: The study results are expected to show the clinical benefit of the discontinuation of CT-P13 and effectiveness and safety of restarting CT-P13 after clinical relapse. The strength of this study is to prospectively evaluate the therapeutic effectiveness by not only clinical disease activity indices but also standardized MSUS findings in multiple centers. We will explore whether parameters at baseline can predict a nonclinical relapse after the discontinuation of CT-P13 by integrating multilateral assessments, that is, patient's characteristics, clinical disease activity indices, MSUS findings, and serum biomarkers. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on April 20, 2020 as jRCTs071200007.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/patologia , Medicamentos Biossimilares/administração & dosagem , Substituição de Medicamentos , Infliximab/administração & dosagem , Adulto , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/análise , Estudos de Equivalência como Asunto , Feminino , Humanos , Quimioterapia de Indução , Japão , Masculino , Recidiva , Resultado do Tratamento , Ultrassonografia
14.
Life Sci ; 258: 118164, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739467

RESUMO

High mobility group box-1 (HMGB1) protein is a diverse, single polypeptide moiety, present in mammalian eukaryotic cells. In response to stimuli, this nuclear protein is actively secreted in to the extracellular compartment or passively released by the necrotic cells, in order to mediate inflammatory responses, by forming complexes with IL-1α, IL-1ß, LPS and other moieties, and binding to RAGE, TLR and other receptor ligands, initiating downstream, signaling processes. This molecule acts as a proinflammatory cytokine and contributes to the progression of diseases like, acute lung injury, autoimmune liver damage, graft rejection immune response and arthritis. Small concentrations of HMGB1 are released during apoptosis, which facilitates oxidative regulation on Cys106, and propagates immune inactivating tolerogenic signals in the body. The review portrays the role of HMGB1 in rheumatoid arthritis, evidently supported by pre-clinical and clinical investigations, demonstrating extensive HMGB1 expression in synovial tissue and fluid as well as serum, excessive expression of transduction receptor signaling molecules, bone remodeling and uncontrolled expression of bone destroying osteoclastogenesis, resulting in destruction of articular cartilage, bone deformation and synovial proliferation, alleviating the pathogenesis in RA disease. Moreover, the review highlights the therapeutic regime targeting HMGB1, facilitating inhibition of its actions and release into the extracellular compartment, to ameliorate the destructive events that prevail in rheumatoid arthritis.


Assuntos
Artrite Reumatoide/patologia , Proteína HMGB1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/fisiopatologia , Remodelação Óssea/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Cartilagem Articular/fisiopatologia , Proteína HMGB1/análise , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Terapia de Alvo Molecular , Osteogênese/efeitos dos fármacos
15.
Rheumatol Int ; 40(10): 1593-1598, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32794113

RESUMO

OBJECTIVE: To describe clinical characteristics of patients with rheumatic and musculoskeletal diseases (RMDs) and immunosuppressive therapies with Coronavirus disease 2019 (COVID-19) at an academic rheumatology center in Madrid and to identify baseline variables associated with a severe infection requiring hospitalization. METHODS: We identified SARS-CoV-2 positive cases by polymerase chain reaction performed at our center within an updated RMDs database in our clinic. Additional RMDs patients were identified when they contacted the clinic because of a positive infection. Data extraction included diagnosis, demographics, immunosuppressive treatment, comorbidities, and laboratory tests. Comparisons between patients with or without hospitalization were performed. Multivariate logistic regression was used to analyze associations between baseline variables and need for hospitalization. RESULTS: A total of 62 patients with COVID-19 and underlying RMDs were identified by April 24, 2020. Median age was 60.9 years, and 42% men. Forty-two patients required hospitalization; these were more frequently men, older and with comorbidities. There were no statistically significant between-group differences for rheumatologic diagnosis and for baseline use of immunosuppressive therapy except for glucocorticoids that were more frequent in hospitalized patients. Total deaths were 10 (16%) patients. In multivariate analysis, male sex (odds ratio [OR], 8.63; p = 0.018), previous lung disease (OR, 27.47; p = 0.042), and glucocorticoids use (> 5 mg/day) (OR, 9.95; p = 0.019) were significantly associated to hospitalization. CONCLUSION: Neither specific RMD diagnoses or exposures to DMARDs were associated with increased odds of hospitalization. Being male, previous lung disease and exposure to glucocorticoids were associated with higher odds of hospitalization in RMDs patients.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Glucocorticoides/uso terapêutico , Hospitalização/estatística & dados numéricos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Idoso , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Artrite Psoriásica/complicações , Artrite Psoriásica/epidemiologia , Artrite Reumatoide/complicações , Artrite Reumatoide/epidemiologia , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/epidemiologia , Azitromicina/uso terapêutico , Betacoronavirus , Comorbidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Modelos Logísticos , Lopinavir/uso terapêutico , Pneumopatias/epidemiologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Estudos Retrospectivos , Ritonavir/uso terapêutico , Índice de Gravidade de Doença , Fatores Sexuais , Espanha/epidemiologia
16.
Cells ; 9(8)2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32796683

RESUMO

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Animais , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/imunologia , Citocinas/metabolismo , Quimioterapia Combinada , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
18.
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
19.
Arthritis Care Res (Hoboken) ; 72(9): 1248-1256, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32754989

RESUMO

OBJECTIVE: To examine the risk of incident type 2 diabetes mellitus (DM) among patients with rheumatoid arthritis (RA) versus the risk among 4 different comparison cohorts. METHODS: Using a large US commercial insurance database, Optum Clinformatics Data Mart (2005-2017), we identified patients with RA based on ≥2 diagnoses for RA and use of ≥1 disease-modifying antirheumatic drug. We selected 4 comparison cohorts with ≥2 disease-specific diagnoses and ≥1 dispensing of disease-specific drugs: 1) general non-RA patients, 2) patients with hypertension, 3) patients with osteoarthritis (OA), and 4) patients with psoriatic arthritis (PsA). The index date was the disease-specific drug dispensing date. Patients with RA were matched to the comparator cohorts (except PsA) for age as of the index date, sex, and index date. The primary outcome was incident type 2 DM, defined as a new diagnosis of type 2 DM plus a new dispensing of antidiabetic drugs. A multivariable Cox proportional hazards model estimated hazard ratios of incident type 2 DM among RA versus each of the comparison cohorts, accounting for >40 baseline covariates. RESULTS: A total of 449,327 RA, general non-RA, hypertension, OA, or PsA patients were selected. During the median of 1.6 (range 0.6-3.3) years of follow-up, the incidence rate of type 2 DM was the lowest in the RA cohort (7.0 per 1,000 person-years) and highest (12.3 per 1,000 person-years) in the hypertension cohort. After adjusting for >40 baseline covariates, we found that RA was associated with a 24-35% lower risk of incident type 2 DM compared to 4 comparison groups. CONCLUSION: In this large population-based cohort study, patients with RA had a lower rate of incident type 2 DM compared to the general non-RA, hypertension, OA, and PsA cohorts.


Assuntos
Artrite Reumatoide/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Estudos de Coortes , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Estudos Retrospectivos , Risco
20.
Scand J Rheumatol ; 49(4): 267-270, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32757727

RESUMO

OBJECTIVES: Substantial changes in the handling of patients with inflammatory arthritis have occurred during the past half century. Polyarticular psoriatic arthritis (PsA) has been treated with the same synthetic disease-modifying anti-rheumatic drugs (DMARDs) as rheumatoid arthritis (RA), but for PsA there is less documentation regarding their effect. For biologic DMARDs, evidence of effect is more convincing. We have previously investigated the risk of orthopaedic surgery in patients with RA and PsA to see whether the change in treatment over time has improved the long-term outcome of inflammatory arthritis. For RA, patients diagnosed from 1999 onwards had a lower risk of surgery than patients diagnosed in earlier years. For PsA, the risk of surgery did not change similarly. We wished to compare RA patients to PsA patients with regard to medical and surgical treatment. METHOD: We compared a historic cohort of 1010 RA patients diagnosed in 1972-2009 to a historic cohort of 590 PsA patients diagnosed in 1954-2011. RESULTS: PsA patients received significantly less medical treatment both in the first year of disease and during the disease course. Risk of surgery during the disease course was lower for PsA than for RA (20% vs 31%). The risk of surgery in RA patients diagnosed from 1999 onwards was similar to that of PsA patients. CONCLUSIONS: PsA patients received less intensive treatment than RA patients. Their prognosis, regarding orthopaedic surgery, was also less severe. Contrary to RA, the change in treatment did not have beneficial effects regarding the risk of orthopaedic surgery.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/cirurgia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/cirurgia , Procedimentos Ortopédicos/estatística & dados numéricos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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