Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 years' follow-up.
Sarilumab治疗类风湿关节炎的长期安全性: 长达 7 年随访的综合分析。
- 作者列表："Fleischmann R","Genovese MC","Lin Y","St John G","van der Heijde D","Wang S","Gomez-Reino JJ","Maldonado-Cocco JA","Stanislav M","Kivitz AJ","Burmester GR
OBJECTIVE:Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions. METHODS:Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed. RESULTS:2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time. CONCLUSION:The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling.
目的: Sarilumab是一种阻断IL-6 与膜结合的可溶性IL-6 受体-α 结合的人单克隆抗体。我们评估了sarilumab在来自 8 个临床试验及其开放标签扩展的患者中的长期安全性。 方法: 数据来自接受至少一剂sarilumab联合常规合成改善疾病抗风湿药物的类风湿关节炎患者 (csDMARDs; 联合组) 或作为单药治疗 (单药治疗组)。评估了治疗中出现的不良事件 (AEs) 和特别感兴趣的AEs和实验室值。 结果: 2887 例患者接受sarilumab联合csDMARDs治疗，471 例患者接受sarilumab单药治疗，平均暴露 2.8 年和 1.7 年，最大暴露 7.3 年和 3.5 年，和累积AE观察期分别为 8188 和 812 患者年。联合治疗组和单药治疗组每 100 例患者年的发病率，严重不良事件分别为 9.4 和 6.7，严重感染分别为 3.7 和 1.0，0.6 和 0.5 为带状疱疹 (无病例播散)，0.1 和 0 为胃肠道穿孔，0.5 和 0.2 为主要不良心血管事件，0.7 和 0.6 为恶性肿瘤。分别有 1000 和 13% 的患者记录中性粒细胞绝对计数 <15% 个细胞/mm3。中性粒细胞减少与感染或严重感染风险增加无关。通过 6 个月的间隔分析显示，随着时间的推移，任何AE的速率增加没有信号。 结论: sarilumab的长期安全性特征，无论是与csDMARDs联合使用还是作为单药治疗，都保持稳定，并与抑制IL6 信号的分子的预期特征一致。
METHODS:OBJECTIVE:Patients with immune-mediated inflammatory diseases such as rheumatoid arthritis or systemic lupus erythematosus are at increased risk of cardiovascular disease. However, the cardiovascular risk of patients with primary Sjögren's syndrome (SS) remains poorly studied. We aimed to investigate the association between primary SS and cardiovascular morbidity and mortality. METHODS:We performed a systematic review of articles in Medline and the Cochrane Library and recent abstracts from US and European meetings, searching for reports of randomized controlled studies of cardiovascular morbidity and cardiovascular mortality in primary SS. The relative risk (RR) values for cardiovascular morbidity and mortality associated with primary SS were collected and pooled in a meta-analysis with a random-effects model by using Review Manager (Cochrane collaboration). RESULTS:The literature search revealed 484 articles and abstracts of interest; 14 studies (67,124 patients with primary SS) were included in the meta-analysis. With primary SS versus control populations, the risk was significantly increased for coronary morbidity (RR 1.34 [95% confidence interval (95% CI) 1.06-1.38]; P = 0.01), cerebrovascular morbidity (RR 1.46 [95% CI 1.43-1.49]; P < 0.00001), heart failure rate (odds ratio 2.54 [95% CI 1.30-4.97]; P < 0.007), and thromboembolic morbidity (RR 1.78 [95% CI 1.41-2.25]; P < 0.00001), with no statistically significant increased risk of cardiovascular mortality (RR 1.48 [95% CI 0.77-2.85]; P = 0.24). CONCLUSION:This meta-analysis demonstrates that primary SS is associated with increased cardiovascular morbidity, which suggests that these patients should be screened for cardiovascular comorbidities and considered for preventive interventions, in a multidisciplinary approach with cardiologists.
METHODS:OBJECTIVE:We aimed to evaluate the comparative risk of hospitalized infection among patients with rheumatoid arthritis (RA) who initiated abatacept versus a tumor necrosis factor inhibitor (TNFi). METHODS:Using claims data from Truven MarketScan database (2006-2015), we identified patients with RA ages ≥18 years with ≥2 RA diagnoses who initiated treatment with abatacept or a TNFi. The primary outcome was a composite end point of any hospitalized infection. Secondary outcomes included bacterial infection, herpes zoster, and infections affecting different organ systems. We performed 1:1 propensity score (PS) matching between the groups in order to control for baseline confounders. We estimated incidence rates (IRs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) for hospitalized infection. RESULTS:We identified 11,248 PS-matched pairs of patients who initiated treatment with abatacept and TNFi with a median age of 56 years (83% were women). The IR per 1,000 person-years for any hospitalized infection was 37 among patients who initiated treatment with abatacept and 47 in those who initiated treatment with TNFi. The HR for the risk of any hospitalized infection associated with abatacept versus TNFi was 0.78 (95% CI 0.64-0.95) and remained lower when compared to infliximab (HR 0.63 [95% CI 0.47-0.85]), while no significant difference was seen when compared to adalimumab and etanercept. The risk of secondary outcomes was lower for abatacept for pulmonary infections, and similar to TNFi for the remaining outcomes. CONCLUSION:In this large cohort of patients with RA who initiated treatment with abatacept or TNFi as a first- or second-line biologic agent, we found a lower risk of hospitalized infection after initiating abatacept versus TNFi, which was driven mostly by infliximab.
METHODS:OBJECTIVE:Reducing pain is one of the main health priorities for children and young people with juvenile idiopathic arthritis (JIA); however, some studies indicate that pain is not routinely assessed in this patient group. The aim of this study was to explore health care professionals' (HCPs) beliefs about the role of pain and the prioritization of its assessment in children and young people with JIA. METHODS:Semi-structured interviews were conducted with HCPs who manage children and young people with JIA in the UK (including consultant and trainee pediatric rheumatologists, nurses, physical therapists, and occupational therapists). Data were analyzed qualitatively following a framework analysis approach. RESULTS:Twenty-one HCPs participated. Analyses of the data identified 6 themes, including lack of training and low confidence in pain assessment, reluctance to engage in pain discussions, low prioritization of pain assessment, specific beliefs about the nature of pain in JIA, treatment of pain in JIA, and undervaluing pain reports. Assessment of pain symptoms was regarded as a low priority and some HCPs actively avoided conversations about pain. CONCLUSION:These findings indicate that the assessment of pain in children and young people with JIA may be limited by knowledge, skills, and attitudinal factors. HCPs' accounts of their beliefs about pain in JIA and their low prioritization of pain in clinical practice suggest that a shift in perceptions about pain management may be helpful for professionals managing children and young people with this condition.