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Ann Rheum Dis ; 79(6): 685-699, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31969328


OBJECTIVES: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. METHODS: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. RESULTS: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. CONCLUSIONS: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.

Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Sociedades Médicas , Medicamentos Sintéticos/uso terapêutico , Antirreumáticos/economia , Produtos Biológicos/economia , Consenso , Quimioterapia Combinada , Europa (Continente) , Humanos , Inibidores de Janus Quinases/uso terapêutico , Medicamentos Sintéticos/economia , Revisões Sistemáticas como Assunto , Fator de Necrose Tumoral alfa/antagonistas & inibidores
Ann Rheum Dis ; 75(1): 68-74, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26056119


OBJECTIVES: To evaluate the long-term efficacy and safety of subcutaneous (SC) tocilizumab (TCZ) versus intravenous (IV) TCZ, including switching formulations, in patients with rheumatoid arthritis (RA) and inadequate response to disease-modifying antirheumatic drugs (DMARDs). METHODS: Patients (n=1262) were randomised 1:1 to receive TCZ-SC 162 mg weekly (qw)+placebo-IV every four weeks (q4w) or TCZ-IV 8 mg/kg q4w+placebo-SC qw in combination with DMARD(s). After a 24-week double-blind period, patients receiving TCZ-SC were re-randomised 11:1 to TCZ-SC (n=521) or TCZ-IV (TCZ-SC-IV, n=48), and patients receiving TCZ-IV were re-randomised 2:1 to TCZ-IV (n=372) or TCZ-SC (TCZ-IV-SC; n=186). Maintenance of clinical responses and safety through week 97 were assessed. RESULTS: The proportions of patients who achieved American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints remission and improvement from baseline in Health Assessment Questionnaire Disability Index ≥0.3 were sustained through week 97 and comparable across arms. TCZ-SC had a comparable safety profile to TCZ-IV through week 97, except that injection site reactions (ISRs) were more common with TCZ-SC. Safety profiles in patients who switched were similar to those in patients who received continuous TCZ-SC or TCZ-IV treatment. The proportion of patients who developed anti-TCZ antibodies remained low across treatment arms. No association between anti-TCZ antibody development and clinical response or adverse events was observed. CONCLUSIONS: The long-term efficacy and safety of TCZ-SC was maintained and comparable to that of TCZ-IV, except for ISRs. Profiles in patients who switched formulations were comparable to those in patients who received TCZ-IV or TCZ-SC. TCZ-SC provides additional treatment options for patients with RA. TRIAL REGISTRATION NUMBER: NCT01194414.

Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Método Duplo-Cego , Vias de Administração de Medicamentos , Quimioterapia Combinada , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
Ann Rheum Dis ; 73(1): 69-74, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23904473


OBJECTIVES: This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS: Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. RESULTS: At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups -4.0%, 95% CI -9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks. CONCLUSIONS: Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.

Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Imunossupressores/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
Arthritis Rheum ; 65(9): 2368-79, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23740801


OBJECTIVE: To investigate the efficacy and safety of ocrelizumab in patients with class III/IV lupus nephritis (LN). METHODS: Patients were randomized 1:1:1 to receive placebo, 400 mg ocrelizumab, or 1,000 mg ocrelizumab given as an intravenous infusion on days 1 and 15, followed by a single infusion at week 16 and every 16 weeks thereafter, accompanied by background glucocorticoids plus either mycophenolate mofetil (MMF) or the Euro-Lupus Nephritis Trial (ELNT) regimen (cyclophosphamide followed by azathioprine). The study was terminated early due to an imbalance in serious infections in ocrelizumab-treated patients versus placebo-treated patients. We report week 48 efficacy data for patients receiving ≥32 weeks of treatment (n = 223) and safety results for all treated patients (n = 378). RESULTS: The overall renal response rate was 54.7%, 66.7%, 67.1%, and 66.9% in the placebo-treated, 400 mg ocrelizumab-treated, 1,000 mg ocrelizumab-treated, and combined ocrelizumab-treated groups, respectively. The associated treatment difference versus placebo for the combined ocrelizumab-treated groups was 12.7% (95% confidence interval [95% CI] -0.8, 26.1) (P = 0.065), with similar differences observed for both ocrelizumab-treated groups. Ocrelizumab versus placebo treatment differences were apparent in patients receiving the background ELNT regimen, but not in those receiving background MMF. A numerically greater proportion of ocrelizumab-treated patients had a ≥50% reduction in the urinary protein:urinary creatinine ratio at 48 weeks compared with placebo-treated patients (placebo-treated patients, 58.7%; 400 mg ocrelizumab-treated patients, 70.7%; 1,000 mg ocrelizumab-treated patients, 68.5%). Serious adverse events occurred in 27.2% of placebo-treated patients, 35.7% of 400 mg ocrelizumab-treated patients, and 22.0% of 1,000 mg ocrelizumab-treated patients. Corresponding serious infection rates (events/100 patient-years) were 18.7 (95% CI 12.2, 28.7), 28.8 (95% CI 20.6, 40.3), and 25.1 (95% CI 17.4, 36.1), respectively. The imbalance in serious infections with ocrelizumab occurred with background MMF but not with the background ELNT regimen. CONCLUSION: In patients with active LN, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo. Ocrelizumab treatment was associated with a higher rate of serious infections in the subgroup receiving background MMF.

Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Azatioprina/administração & dosagem , Azatioprina/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Resultado do Tratamento
Arthritis Rheum ; 58(10): 2968-80, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18821691


OBJECTIVE: To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA). METHODS: A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks. RESULTS: At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported. CONCLUSION: Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.

Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Receptores de Interleucina-6/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença