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1.
Clin Exp Rheumatol ; 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32662413

RESUMO

OBJECTIVES: We aimed to measure long-term effectiveness and safety of tocilizumab in patients with rheumatoid arthritis in daily German practice. METHODS: ICHIBAN was a prospective, multi-centre, non-interventional study (ML22928) that enrolled adult patients with active moderate to severe rheumatoid arthritis. Patients were to be treated according to tocilizumab label and observed for up to two years. Effectiveness outcomes included DAS28-ESR remission, EULAR response, CDAI and HAQ. RESULTS: Overall, 3164 patients received at least one dose of tocilizumab. Patient mean age was 55.5±13.1 years (74.8% female). At baseline, 72.1% of patients had at least one comorbidity. Approximately 50.9% of patients received concomitant csDMARDs, mostly methotrexate, and 80.7% received concomitant glucocorticoids (GCs). In patients receiving GCs at baseline, the mean dose decreased from 9.32±16.36 mg/d to 4.60±4.48 mg/d at week 104. In the effectiveness population with no prior TCZ (n=2902), 61.4% of patients achieved the primary outcome, DAS28-ESR remission. Improvements were seen as early as week 4. At week 104, 77.9% of patients had DAS28-ESR low disease activity, 89.6% achieved good or moderate EULAR response, and 29.5% achieved a CDAI-based remission. Effectiveness outcomes were similar in all previous therapy subgroups. The incidence of serious infections was similar to the rates in former studies involving tocilizumab. Patients receiving GC at baseline experienced slightly higher rates of treatment-related serious adverse events, mainly infections. No new safety signals were observed. CONCLUSIONS: Long-term effectiveness and safety in ICHIBAN were in line with previously reported tocilizumab efficacy and safety studies.

2.
RMD Open ; 6(1)2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32371430

RESUMO

BACKGROUND/OBJECTIVE: FKB327 is a biosimilar of the antitumour necrosis factor adalimumab reference product (RP). A randomised, double-blind (DB) phase 3 study compared the efficacy of FKB327 with the RP in patients with active rheumatoid arthritis (RA) inadequately controlled with methotrexate (MTX). A subsequent randomised open-label extension (OLE) study with treatment switching assessed long-term safety, efficacy, pharmacokinetics and immunogenicity of FKB327 compared with the RP. METHODS: Patients with moderate-to-severe, active RA on a stable dose of MTX were randomised 1:1 to receive FKB327 or the RP (40 mg subcutaneously every other week) for 24 weeks. Patients who completed the DB study were enrolled in the OLE and rerandomised 2:1 to receive FKB327 or the RP; two-thirds continued on the same treatment and one-third switched for 30 weeks. All patients received FKB327 through Week 76. Long-term efficacy, safety and immunogenicity were assessed. RESULTS: Of 728 patients in the DB study, 645 were enrolled in the FKB327-OLE study. The American College of Rheumatology (ACR)20 response rates for all treatment groups at Week 30 in the OLE ranged from 83.2% to 85.9%. ACR20 response rates remained stable for all patients regardless of single- or double-switching treatment and were similar for all treatment sequences through Week 76. The safety profile and incidence of antidrug antibodies were comparable across sequences. CONCLUSION: Efficacy, safety and immunogenicity were similar among patients with RA treated with FKB327 or the RP for up to 2 years, and were not affected by single- or double-switching treatment.

3.
Arthritis Res Ther ; 21(1): 281, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831079

RESUMO

OBJECTIVE: To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA). METHODS: Patients were randomized 1:1 in a double-blind study (NCT02260791), received 40 mg of FKB327 or RP by subcutaneous injection every other week for 24 weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ± 13% and - 12% to + 15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54. RESULTS: A total of 730 patients were randomized in Period I (n = 367 FKB327, n = 363 RP), and 645 transitioned to Period II (n = 216 FKB327-FKB327, n = 108 FKB327-RP, n = 108 RP-FKB327, n = 213 RP-RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were - 7.9 to 4.7% and - 7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II. CONCLUSION: FKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02260791, Registered 29 July 2014. ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.


Assuntos
Adalimumab/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Metotrexato/uso terapêutico , Adalimumab/administração & dosagem , Adulto , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/patologia , Medicamentos Biossimilares/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Injeções Subcutâneas , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
4.
Orthopade ; 48(11): 936-941, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31686154

RESUMO

BACKGROUND: Gastroenterological and rheumatological diseases often have a systemic character, with disease manifestations beyond the area affected by the disease. Common disease-relevant pathophysiological pathways, e.g. chronic inflammation, may present primarily as rheumatological or gastroenterological disease. Knowledge of disease-specific symptoms and signs beyond one's own area of expertise my lead to an earlier and more precise diagnosis, with the chance of a more focused therapy. AIM: The aim of this overview is to sensitize orthopedists as well as rheumatologists to gastroenterological signs and symptoms and give them a clinical guide to approaching an interdisciplinary patient. Targeted, clinically relevant questions are discussed and common disease entities are presented.


Assuntos
Doenças do Sistema Digestório , Gastroenterologia , Inflamação , Doenças Reumáticas , Reumatologia , Humanos
5.
Clin Exp Rheumatol ; 37(6): 937-945, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31025930

RESUMO

OBJECTIVES: To evaluate early and late responses in biological-naïve patients with rheumatoid arthritis (RA) initiating tocilizumab and early tocilizumab non-responders who switched to rituximab. METHODS: In this open-label, non-randomised phase 3 study, RA patients with inadequate response to conventional synthetic DMARDs received tocilizumab 8 mg/kg intravenously at study begin and weeks 4, 8 and 12. After evaluation at week 16, early responders (Disease Activity Score based on 28 joints-erythrocyte sedimentation rate [DAS28-ESR] <2.6) completed the study; partial responders (DAS28-ESR decrease >1.2 or DAS28-ESR ≥2.6-≤3.2) were to continue tocilizumab through week 28; non-responders (DAS28-ESR decrease ≤1.2) switched to rituximab (1000 mg, weeks 16 and 18) with safety follow-up through week 66. RESULTS: Of 519 patients, 222 (42.8%) achieved early DAS28-ESR remission at week 16; 240 patients continued treatment, 213 (41.0%) received tocilizumab, and 27 (5.2%) switched to rituximab. At week 32 DAS28-ESR remission was achieved by 117/213 patients (54.9%) who continued tocilizumab and 4/27 patients (14.8%) who switched to rituximab; good EULAR response was achieved by 66.7% and 25.9% and CDAI remission by 19.2% and 14.8% of patients, respectively. Serious adverse events occurred through week 32 in 45/490 patients (9.2%) who received tocilizumab (serious infections, 2.7%) and through week 66 in 8/27 patients (29.6%) who switched to rituximab. CONCLUSIONS: Early response to tocilizumab was observed in 42.8% of patients. Half of early partial responders benefitted from continuing tocilizumab. Switching non-responders to rituximab seems feasible. No new safety signals were observed in patients treated with tocilizumab or switched to rituximab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos , Artrite Reumatoide , Rituximab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Método Duplo-Cego , Humanos , Indução de Remissão , Resultado do Tratamento
6.
Ann Rheum Dis ; 78(6): 754-760, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30902820

RESUMO

OBJECTIVE: To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR). METHODS: In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug. RESULTS: At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40-CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity. CONCLUSION: Although blockade of the CD40-CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study. TRIAL REGISTRATION NUMBER: NCT01751776.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Autoanticorpos/sangue , Subpopulações de Linfócitos B/efeitos dos fármacos , Biomarcadores/sangue , Remodelação Óssea/efeitos dos fármacos , Ligante de CD40/antagonistas & inibidores , Método Duplo-Cego , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Injeções Subcutâneas , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
7.
Eur Radiol ; 27(9): 3662-3668, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28116513

RESUMO

OBJECTIVES: To determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant K trans , in a multicentre trial setting. METHODS: DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated. RESULTS: At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. K trans intra-subject coefficient of variation (N = 14) was 30%. K trans change demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks. CONCLUSION: This demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials. KEY POINTS: • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre.


Assuntos
Adalimumab/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imagem por Ressonância Magnética/métodos , Oxazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/metabolismo , Biomarcadores/análise , Feminino , Mãos/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Articulação do Punho/diagnóstico por imagem
8.
Ann Rheum Dis ; 75(2): 408-12, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26248638

RESUMO

INTRODUCTION: A 28-week study suggested efficacy of the anti-interleukin-17A monoclonal antibody secukinumab in active ankylosing spondylitis (AS). MRI-assessed inflammation was reduced at weeks 6, 28. OBJECTIVE: To analyse the longer-term effects of secukinumab on MRI inflammatory and non-inflammatory spinal lesions in relation to its clinical efficacy in subjects with active AS. METHODS: Spinal MRI results (baseline, week 94) for 13 subjects with AS initially treated with secukinumab 2×10 mg/kg intravenously (n=10) or placebo (n=3) and receiving a secukinumab maintenance dose of 3 mg/kg IV every 4 weeks up to week 94 were evaluated by the Berlin score; inflammatory/non-inflammatory (fatty) changes were assessed at vertebral edges (VEs). Results were compared with clinical outcomes. RESULTS: Most of the 13 subjects assessed at week 94 had sustained clinical responses: 8 (62%) achieved Assessment of SpondyloArthritis international Society 20% (ASAS20), including 6 (46%) achieving ASAS40 responses, corresponding to 75% and 83% reductions in the Berlin score, respectively. In the 10 subjects treated with secukinumab throughout the study period, 79/91 (87%) inflammatory VEs at baseline resolved by week 94; new fatty lesions occurred in 39/796 (4.9%) of VEs; 87/124 (70%) VEs with fatty lesions at baseline remained unchanged; 30% were no longer visible. CONCLUSIONS: In this pilot study, secukinumab treatment up to 2 years yielded sustained clinical improvement accompanied by regression of spinal inflammation. The impact of secukinumab on the development of fatty changes and bone formation in AS will be assessed in larger trials. TRIAL REGISTRATION NUMBER: This study is registered with ClinicalTrials.gov, number NCT00809159.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Espondilite Anquilosante/tratamento farmacológico , Administração Intravenosa , Adulto , Anticorpos Monoclonais Humanizados , Berlim , Esquema de Medicação , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Índice de Gravidade de Doença , Espondilite Anquilosante/patologia , Tempo , Resultado do Tratamento
9.
Curr Med Res Opin ; 30(11): 2139-49, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25050591

RESUMO

OBJECTIVE: Evaluate efficacy of infliximab with response-driven dosing in patients with active RA. RESEARCH DESIGN AND METHODS: Patients (n = 203) with active RA despite methotrexate + etanercept/adalimumab, participated in this active-infliximab-switch study. Infliximab 3 mg/kg was infused at Weeks 0, 2, 6, 14, and 22 with escalation to 5 or 7 mg/kg depending on EULAR response at Weeks 14 and 22. The primary endpoint was EULAR response at Week 10. Safety was assessed through Week 30. Infliximab levels and antibodies to infliximab (ATI) were measured at Weeks 0, 6, 14, and 26. CLINICAL TRIAL REGISTRATION: NCT 00714493, EudraCT 2007-003288-36. RESULTS: Of 197 evaluable patients, 120/77 previously received etanercept/adalimumab. Baseline mean (SD) swollen and tender joint counts were 17.3 (10.54) and 30.2 (16.89), respectively; mean DAS28-ESR was 6.19 (0.981). At Week 10, 98 (49.7%; 95% CI: 42.6%, 56.9%) patients achieved EULAR response, with a significantly improved DAS28-ESR score (mean [SD] change -1.1 [1.15]; p < 0.001). EULAR response was achieved by 41.7%/62.3% of patients previously receiving etanercept/adalimumab (p = 0.006). At Week 26, 51.8% (95% CI: 44.6%, 58.9%) of patients achieved or maintained EULAR response. Infliximab dose was escalated in 100 patients, 52% of whom achieved EULAR response at Week 26. Median serum concentration levels at Week 26 showed that dose escalation helped EULAR non-responders achieve levels similar to or higher than the levels seen in responders. ATI were associated with lower serum concentrations of infliximab, consistent with lower efficacy rates among ATI-positive patients. CONCLUSION: Infliximab, in treat-to-target settings with individual dose escalation, demonstrated significant efficacy at Weeks 10 and 26 in patients switched to infliximab after inadequate response to etanercept/adalimumab. The observed efficacy indicated that the switch to infliximab and ability to increase dose in a targeted fashion were beneficial. KEY LIMITATIONS: Given the relatively short duration of study follow-up, these safety findings require confirmation in a longer-term study.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Substituição de Medicamentos , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab , Adulto , Idoso , Relação Dose-Resposta a Droga , Esquema de Medicação , Etanercepte , Feminino , Humanos , Infliximab , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento
11.
J Rheumatol ; 41(3): 414-21, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24429175

RESUMO

OBJECTIVE: To evaluate the longer-term safety and efficacy of secukinumab, a fully human monoclonal antiinterleukin-17A antibody, in patients with rheumatoid arthritis. METHODS: In this 52-week, double-blind, placebo-controlled (up to Week 20) study (NCT00928512), patients responding inadequately to disease-modifying antirheumatic drugs (DMARD) or biologics were randomized to receive monthly subcutaneous injections of secukinumab (25, 75, 150, or 300 mg), or placebo. The efficacy and safety results up to Week 20 have been reported previously. Here, efficacy results from Week 20 to 52 and safety results from Week 20 to 60 are presented. RESULTS: Of 237 patients randomized, 174 (73.4%) completed the study. Patients with improved American College of Rheumatology (ACR) and 28-joint Disease Activity Score (DAS28) C-reactive protein (CRP) responses at Week 16 sustained their responses through Week 52. In patients taking 150 mg of secukinumab, responses were improved through Week 52 (ACR50: Week 16 = 45%, Week 52 = 55%; DAS28-CRP ≤ 2.6: Week 16 = 25%, Week 52 = 40%). The rate of adverse events (AE) from weeks 20 to 60 was 64.8%, with most AE being mild to moderate in severity. The overall rate of infections was 31.9%, most being mild. The most predominant infection was nasopharyngitis, and was not associated with dose or concurrent neutropenia. Serious AE were reported in 21 patients (8.9%). There were 3 reports of malignancies (ovarian, lung, basal cell), and no deaths between weeks 20 and 60. CONCLUSION: Patients with active RA who failed to respond to DMARD and other biologics showed an improvement after longterm treatment with 150 mg of secukinumab. The frequency of AE remained stable over time and secukinumab had a consistent safety profile over 60 weeks.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Método Duplo-Cego , Humanos , Injeções Subcutâneas , Resultado do Tratamento
12.
Rheumatol Int ; 34(1): 1-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23942828

RESUMO

The German Society of Rheumatology approved new German guidelines for the sequential medical treatment of rheumatoid arthritis (RA) based on the European League Against Rheumatism (EULAR) recommendations for the management of RA published in 2010. An update of the EULAR systematic literature research was performed in Medline, Embase, and Cochrane databases. Meta-analyses, controlled trials, cohort studies, and registry data addressing traditional and biologic disease-modifying antirheumatic drugs, glucocorticoids, and treatment strategies published between January 2009 and August 2011 were included. Two reviewers independently evaluated and compared the additional data that had been published after the time limit set by the EULAR recommendations. A national guideline working group developed an adapted set of recommendations. The new German guidelines were accepted by vote using an informal Delphi approach. Twelve recommendations and the resulting updated treatment algorithm were developed and approved as a practical orientation for rheumatologists. These recommendations are based on a successive treatment with traditional and biologic disease-modifying drugs depending on the individual progress of the disease and distinct patient characteristics. The German guidelines have been developed on the basis of the internationally well-recognized EULAR recommendations. In addition, more recent evidence from a systematic literature research was considered. They have been developed and approved by a group of national experts aiming at guidance for rheumatologists to reach best medical practice.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/administração & dosagem , Reumatologia/normas , Algoritmos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Produtos Biológicos/efeitos adversos , Consenso , Procedimentos Clínicos/normas , Técnica Delfos , Esquema de Medicação , Substituição de Medicamentos , Quimioterapia Combinada , Medicina Baseada em Evidências/normas , Alemanha , Humanos , Fatores de Tempo , Resultado do Tratamento
13.
Open Rheumatol J ; 7: 96-100, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24358067

RESUMO

OBJECTIVE: Compare effectiveness of celecoxib versus diclofenac plus omeprazole in improving arthritis signs and symptoms in patients at high gastrointestinal (GI) risk who were enrolled in the CONDOR (Celecoxib vs Omeprazole and Diclofenac in Patients With Osteoarthritis and Rheumatoid Arthritis) trial. METHODS: CONDOR was a 6-month, prospective, double-blind, triple-dummy, parallel-group, randomized, multicenter trial comparing celecoxib 200 mg twice daily versus diclofenac slow release (SR) 75 mg twice daily plus omeprazole 20 mg daily. Patients were Helicobacter pylori negative, had osteoarthritis (OA) or rheumatoid arthritis (RA), were aged ≥60 years, were with or without a history of gastroduodenal ulceration, or were ≥18 years with previous gastroduodenal ulceration. Patients' Global Assessment of Arthritis was determined at each study visit. RESULTS: A total of 4484 patients were randomized to treatment (2238 celecoxib, 2246 diclofenac SR) and included in the intention-to-treat analyses. Least squares mean (LSM) (standard error [SE]) for Patients' Global Assessment of Arthritis was 3.219 (0.017) and 3.221 (0.017) at baseline for celecoxib and diclofenac SR (p=0.90). Improvement in both groups was similar in months 2, 4, and 6; at month 1 the LSM (SE) was 2.647 (0.017) and 2.586 (0.017) for celecoxib and diclofenac (p=0.0025). LSM difference (SE) from baseline to final visit demonstrated an improvement of 0.75 (0.02) in celecoxib-treated patients and 0.77 (0.02) in diclofenac SR-treated patients (p=0.42). CONCLUSIONS: Celecoxib and diclofenac plus omeprazole were shown to have similar efficacy in patients with OA and/or RA at increased GI risk who were enrolled in the CONDOR trial. TRIAL REGISTRY: Trial was registered under ClinicalTrials.gov identifier NCT00141102.

14.
BMC Musculoskelet Disord ; 14: 358, 2013 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-24351026

RESUMO

BACKGROUND: To evaluate the utility of the recently introduced SOLAR score (sonography of large joints in Rheumatology), which has been validated in RA patients, in a cohort of patients with Psoriatic Arthritis (PsA) and Ankylosing Spondylitis (AS) presenting with involvement of large peripheral joints. METHODS: The recently established SOLAR score has been designed to determine the degree of inflammation in the shoulder, the elbow, the hip and the knee joint in patients suffering from RA. Since large joints are frequently involved in PsA and AS, synovitis and synovial vascularity were scored semiquantitatively (grade 0-3) by grey scale (GSUS) and power Doppler ultrasound (PDUS) utilizing the validated scoring system. Each joint was scanned from different angles, the knee joint for example was divided into four areas to score for synovitis: the suprapatellar longitudinal, the medial longitudinal, the lateral longitudinal, and the posterior region. Each area was scored from 0-3, so a maximum score of 12 could be achieved. PsA and AS patients presenting with peripheral joint disease involving large joints were examined at baseline, 3 and 6 months after initiation of local or systemic therapy (DMARDs/Biologics). For evaluation of the inflammatory status, the erythrocyte sedimentation rate (ESR) was determined. RESULTS: A cohort of 126 patients were enclosed, and 83 of these were followed for 6 months. At baseline before modification of the therapy, patients received DMARDs (n = 83), DMARDs plus biologics (n = 30), or biologic monotherapy (n = 29). Following intervention, all US scores demonstrated a marked improvement. The GSUS and the PDUS scores for all joint areas, except the PDUS score of the hip, exhibited a significant improvement (p < 0.05), while the GSUS of the knee showed even a highly significant (p < 0.001) change. The ESR displayed a significant decrease from 27 to 19 mm (p < 0.002) representing good treatment response. CONCLUSION: The SOLAR score, which has been recently introduced for RA patients, is a very suitable instrument for the qualitative and quantitative evaluation of large joint involvement in PsA and AS patients and allows for treatment monitoring.


Assuntos
Artrite Psoriásica/diagnóstico por imagem , Articulações/diagnóstico por imagem , Espondilite Anquilosante/diagnóstico por imagem , Adulto , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Espondilite Anquilosante/tratamento farmacológico , Ultrassonografia
16.
Lancet ; 382(9906): 1705-13, 2013 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-24035250

RESUMO

BACKGROUND: Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. METHODS: We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159. FINDINGS: 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group. INTERPRETATION: Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial. FUNDING: Novartis.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Espondilite Anquilosante/tratamento farmacológico , Abscesso/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Biomarcadores/metabolismo , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/complicações , Infecções Cutâneas Estafilocócicas/induzido quimicamente , Staphylococcus aureus , Resultado do Tratamento , Adulto Jovem
17.
Ther Adv Musculoskelet Dis ; 5(3): 141-52, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23858337

RESUMO

Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.

18.
Eur Radiol ; 23(7): 1773-84, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23494493

RESUMO

OBJECTIVES: Multifocal musculoskeletal inflammation is common in ankylosing spondylitis (AS) and is effectively treated by expensive anti-TNF (tumour necrosis factor) therapy. This study evaluated assessment of response by whole-body (WB) MRI compared with clinical assessment in AS patients during etanercept therapy. METHODS: Ten patients with AS underwent a 12-month therapy with etanercept. Clinical markers were monitored [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP)] and patients underwent WBMRI (1.5 T, STIR and T1-weighted) at three different time points (0, 26 and 52 weeks). WBMRI was evaluated and correlated with clinical scores. RESULTS: The BASDAI index decreased under therapy from 5.5 ± 0.5 (week 0) to 1.7 ± 0.5 (week 52, P < 0.05). CRP declined from 15.7 ± 2.2 mg/dl (week 0) to 0.9 ± 0.9 mg/dl (week 52, P < 0.05). In WBMRI, the sum of all lesions showed a significant decrease from week 0 (38.9 ± 3.4) to week 52 (2.2 ± 0.9, 94.3 % reduction). WBMRI detected more areas of synovitis and enthesitis than clinical examination alone. CONCLUSIONS: AS activity significantly decreased under etanercept therapy, which was proven by clinical examination and WBMRI. WBMRI detected more inflammatory lesions than clinical examination alone. The results suggest that WBMRI improves the detection of inflammatory changes and the assessment of their course under therapy. KEY POINTS: • Multifocal musculoskeletal inflammation in AS is effectively treated by anti-TNF therapy. • Inflammatory lesions can be assessed by clinical examination and whole-body MRI. • AS activity significantly decreased under therapy as shown by WBMRI/clinical examination. • WBMRI detected more inflammatory lesions than clinical examination alone. • WBMRI improves detection of inflammatory changes and may help evaluation of therapy.


Assuntos
Imagem por Ressonância Magnética/métodos , Espondilite Anquilosante/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Proteína C-Reativa/metabolismo , Etanercepte , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Fatores Imunológicos/uso terapêutico , Inflamação , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/administração & dosagem , Sinovite/diagnóstico , Fatores de Tempo , Resultado do Tratamento , Imagem Corporal Total/métodos
19.
Ann Rheum Dis ; 72(6): 863-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22730366

RESUMO

OBJECTIVE: To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA). METHODS: Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16. RESULTS: Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one). CONCLUSIONS: ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
Ann Rheum Dis ; 72(7): 1163-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22956596

RESUMO

PURPOSE: To determine the sensitivity to change of the US7 score among RA patients under various therapies and to analyze the effect of each therapeutic option over 1 year. To estimate predictors for development of destructive bone changes. METHODS: Musculoskeletal ultrasound (US7 score), DAS28, CRP and ESR were performed in 432 RA patients at baseline and after 3, 6 and 12 months. The cohort was divided into four sub-groups: first-line DMARDs (Group 1; 27.3%), therapy switch: DMARDs to second DMARDs (Group 2; 25.0%), first-line biologic after DMARDs therapy (Group 3; 35.4%) and therapy change from biologic to second biologic (Group 4; 12.3%). RESULTS: The US7 synovitis and tenosynovitis sum scores in grey-scale (GSUS) and power Doppler ultrasound (PDUS) as well as ESR, CRP decreased significantly (p<0.05) after 12 months in group 1 to 3. Group 1+2 also illustrated a significant change of DAS28 after 1 year (p<0.001). Only in Group 4, the US7 erosion sum score decreased significantly from 4.3 to 3.6 (p=0.008) after 1 year. Predictors capable of forecasting US erosions after one year were: higher score of US7 synovitis (p<0.001), of US7 erosions in GSUS (p<0.001), as well as of DAS28 (p<0.001) at baseline. CONCLUSIONS: The comparable developments of the US7 score with clinical and laboratory data illustrates its potential to reflect therapeutic response. Therefore, the novel US7 score is sensitive to change. Patients who switched from one biologic to another exhibited a significant decline in erosions after 12 months, while the erosions scores in the other groups were stable.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Sinovite/diagnóstico por imagem , Tenossinovite/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Estudos de Coortes , Feminino , Articulações do Pé/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Sinovite/etiologia , Tenossinovite/etiologia , Resultado do Tratamento , Ultrassonografia Doppler em Cores , Adulto Jovem
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