Certolizumab pegol: a new biologic targeting rheumatoid arthritis

The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis. This is mostly due to targeted biologic agents that have changed the outcome of this disease. Certolizumab pegol (Cimzia^®, UCB Inc., GA, USA), which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn’s disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy. This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease-modifying antirheumatic drugs and other biologic agents. Treatment recommendations are beyond the scope of this review; however, with many options available, there will be annotations on current trends in the care of this chronic disease.     

赛妥珠单抗治疗类风湿性关节炎疗效及不良反应的荟萃分析

目的: 探究赛妥珠单抗治疗类风湿性关节炎的有效性及安全性。方法: 计算机检索Pubmed、Medline、Embase、The Cochrane Library、万方数据库(WANFANG)、中国期刊全文数据库(CNKI)、中国生物医学文献数据库中关于赛妥珠单抗与安慰剂治疗类风湿性关节炎的随机对照研究(Randomized controlled trials,RCTs),检索时限均为建库至2015 年3 月。采用RevMan5.3 软件进行统计分析。结果:共纳入10 篇文献、8 项研究,纳入文献质量均较高,本meta 分析结果显示CZP 在改善类风湿患者病情的疗效(ACR20、ACR50、ACR70),关节疾病活动性评分,患者对疾病活动性评价指标(HAQ-DI、关节疼痛、疲劳)方面优于安慰剂组。在轻度、中度、重度不良反应方面两组差异无统计学意义,CZP 并未增加不良反应的发生率。结论:CZP 能减缓患者关节炎症进展,改善患者关节功能,提高患者生活质量,短期安全性较高,CZP 长期疗效及安全性有待于进一步研究证实。     

不同剂量赛妥珠单抗治疗类风湿性关节炎有效性和安全性的系统评价

目的:探究不同剂量赛妥珠单抗治疗类风湿性关节炎的有效性及安全性。方法:计算机检索Pubmed、Medline、Embase、The Cochrane Library、万方数据库(WANFANG)、中国期刊全文数据库(CNKI)、中国生物医学文献数据库中关于不同剂量赛妥珠单抗治疗类风湿性关节炎的随机对照研究(Randomized controlled trials,RCTs),检索时限均为建库至2015年3 月。采用RevMan5郾3 软件进行统计分析。结果:共纳入6 篇文献、4 项研究,纳入文献质量均较高,本meta 分析结果显示不同剂量CZP 在改善类风湿患者病情的疗效(ACR20、ACR50、ACR70),关节疾病活动性评分,患者对疾病活动性评价指标(HAQ-DI、关节疼痛、疲劳),轻度、中度、重度不良反应方面差异无统计学意义。结论:不同剂量CZP 治疗RA 具有相同的治疗效果,短期安全性相似,不同剂量CZP 长期疗效及安全性有待于进一步研究证实。     

Certolizumab pegol in axial spondyloarthritis

The axial spondyloarthritis (SpA) classification criteria cover both patients with ankylosing spondylitis and non-radiographic axial SpA. After failure of NSAIDs TNF-α-inhibitors (TNF-blockers) can be given to patients with active axial SpA. Until recently, the TNF-blockers infliximab, adalimumab, etanercept and golimumab are labeled for the treatment of active ankylosing spondylitis while for active nr-axSpA only adalimumab has been approved in Europe. The TNF-blocker certolizumab pegol has recently been evaluated in the RAPID-axSpA trial which is the first placebo-controlled randomized-controlled trial in the entire group of axial SpA. An elevated C-reactive protein and/ or evidence of bone marrow edema on MRI of the sacroiliac joints were required for inclusion in RAPID-axSpA, and patients could have been preexposed to TNF-blockers. The interesting data of this important trial in the context of the emerging therapeutic field of non-radiographic axial SpA therapy is discussed in this review.     

Certolizumab pegol for the treatment of psoriatic arthritis and plaque psoriasis

ABSTRACT

Introduction: Certolizumab pegol (CZP) is an Fc-free PEGylated TNF-α inhibitor approved for the treatment of psoriatic arthritis (PsA) and plaque psoriasis in many countries. It demonstrated favorable results in PsA in terms of improvement in peripheral arthritis, dactylitis, and enthesitis in a phase III trial (RAPID-PSA) and in real-life experiences. Recently, three phase III randomized clinical trials (CIMPASI-1, CIMPASI-2, CIMPACT) showed significant and sustained improvements in signs and symptoms of moderate-to-severe plaque psoriasis as well as in quality of life parameters as compared to placebo and etanercept.

Areas covered: We reviewed the structure and the mechanism of action of CZP, and critically analyzed data from clinical trials and real-life, concerning its efficacy and safety in all aspects of the psoriatic disease. We designed a comprehensive literature search on this topic, by a review of published articles in indexed international journals up until 31 July 2019.

Expert opinion: CZP demonstrated positive results in several domains of psoriatic disease, also in patients previously exposed to other TNF-α inhibitors and in patients receiving re-treatment after treatment interruption. The peculiar chemical structure, along with its well-established efficacy and safety, support CZP as the drug of choice in specific subgroups of patients with psoriatic disease, in particular patients with comorbidities and pregnant or breastfeeding female patients.     

RAPID and FAST4WARD trials: certolizumab pegol for rheumatoid arthritis

In the last decade, biological therapies have dramatically changed the treatment for rheumatoid arthritis (RA) in such a way that remission is currently an achievable goal. The armamentarium of therapeutic options for RA has recently been enriched with another approved anti-TNF-α agent, certolizumab pegol (CZP). This article reviews the trials conducted with CZP in RA, the Rheumatoid Arthritis PreventIon of structural Damage (RAPID 1 and 2) and the EFficAcy and Safety of cerTolizumab pegol – 4 Weekly dosAge in RheumatoiD arthritis (FAST4WARD). These trials have demonstrated that this new biological agent significantly improves the clinical signs and symptoms of RA, inhibits progression of structural damage, and improves physical function and quality of life in patients with active RA who have failed treatment with methotrexate. The safety profile of CZP is acceptable and similar to that of other anti-TNF-α agents.     

Emerging biologic drugs for the treatment of rheumatoid arthritis

This article reviews the role of emerging biologic drugs for the treatment of rheumatoid arthritis (RA). Besides anti-tumor necrosis factor (TNF)-alpha and anti-interleukin (IL)-1 agents (Infliximab, Adalimumab, Etanercept and Anakinra) whose clinical efficacy is now established, new drugs have been proposed for the therapy of rheumatoid arthritis patients not responding to conventional treatments. These approaches include the blockade of B-cell activity with anti-CD20 monoclonal antibody (Rituximab) and the inhibition of T-cell activation with fusion protein CTLA4Ig. Moreover, promising results have been obtained in animal models utilizing suppressors of cytokine signaling (SOCS) and dominant-negative TNF variants to inactivate TNF signaling.     

Artemether: a new therapeutic strategy in experimental rheumatoid arthritis

The current research was designed to determine the effect of artemether in treatment of experimental rheumatoid arthritis. Collagen-induced arthritis was induced in Lewis rats. The intramusculary administration of artemether (ART) and intraperitoneally injection of methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was taken intermittently. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay.The biocompatibility of ART and MTX were assessed using fibrosarcoma cell line. Data showed that i.m. injection of ART to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed a reduced inflammatory cell infiltrate in joints of treated rats; tissue edema, and bone erosion in the paws were markedly reduced following ART therapy. Furthermore, our radiography results paralleled our histological findings. Cytotoxicity analysis of ART showed greater tolerability compared with MTX. Treatment with ART significantly diminished NO formation in treated rats compared with nontreated controls. Our data shed light on the therapeutic efficacy of artemether in experimental rheumatoid arthritis compared with a choice drug (methotrexate), and it may be offered as a second-line drug in treatment of rheumatoid arthritis.     

The perioperative use of biologic agents in patients with rheumatoid arthritis

Biologic drugs have gained an important place in the treatment of rheumatic diseases. These medications may, however, pose a higher risk of infections in rheumatic patients who a priori are prone to infections. The potential consequences of the immunosuppressive effects of the biologics raise concern about their safety in the perioperative setting. This article reviews the scientific literature that examines the influence of biologic drugs on post-surgical complications. According to these studies, it is apparently safe to use tumor necrosis factor-α blockers and the IL-6 receptor blocker, although a few study limitations, such as small sample size, retrospective design and differences in the comparison groups weaken the conclusions. In addition, the recommendations for some of the biologic drugs are based solely on pharmacological parameters due to the absence of trials, and larger randomized controlled studies are needed to establish the safety of their use by patients with rheumatic diseases.     

甲氨蝶呤治疗类风湿关节炎的新思考

甲氨蝶呤(MTX)为目前治疗类风湿关节炎(RA)首选的改善病情抗风湿药(DMARDs)。MTX在减轻症状和体征、减少致残及延缓影像学结构破坏等方面优于其他DMARDs。在生物制剂和MTX等传统DMARDs之间进行选择时,需充分考虑成本效益因素以保障患者的依从性和病情缓解。预测MTX治疗反应性或安全性的生物或基因标记物可指导临床医生制定最佳的RA治疗方案。     

Methotrexate is a new consideration in treatment of rheumatoid arthritis

甲氨蝶呤(MTX)为目前治疗类风湿关节炎(RA)首选的改善病情抗风湿药(DMARDs).MTX在减轻症状和体征、减少致残及延缓影像学结构破坏等方面优于其他DMARDs.在生物制剂和MTX等传统DMARDs之间进行选择时,需充分考虑成本效益因素以保障患者的依从性和病情缓解.预测MTX治疗反应性或安全性的生物或基因标记物可指导临床医生制定最佳的RA治疗方案.     

The management of first-line biologic therapy failures in rheumatoid arthritis: Current practice and future perspectives

The introduction of biologic disease–modifying anti-rheumatic drugs (bDMARDs) has dramatically changed the management of rheumatoid arthritis (RA). However, in a real-life setting about 30–40% of bDMARD treated patients experience drug discontinuation because of either inefficacy or adverse events. According to international recommendations, to date the best strategy for managing first-line bDMARD failures has not been defined yet and available data (especially on TNF inhibitors [TNFis]) seem to drive toward a personalized approach for the individual patient. Some TNFi partial responders may benefit from optimization of concomitant methotrexate therapy or from switching to a different concomitant sDMARD such as leflunomide. Conversely, apart from infliximab, TNFi dose escalation seems to be poor efficacious and poor cost-effective compared with alternative strategies. Albeit counterintuitive, the use of a second TNFi after the failure of the first-one (cycling strategy) is supported by clear evidences and has become widespread in the 2000s as the result of the limited alternative options till the introduction of bDMARDs with a mechanism of action other than TNF blockade. Nowadays, the use of abatacept, rituximab, tocilizumab, or JAK inhibitors as second-line agent (swapping strategy) is strongly supported by RCTs and real-life experiences. In the absence of head-to-head trials directly comparing these two strategies, meta-analyses of separated RCTs failed to find significant differences in favor of one or another choice. However, results from most observational studies, including well designed prospective pragmatic randomised analyses, demonstrated the superiority of swapping over cycling approach, whereas only few studies reported a comparable effectiveness. In this review, we aimed to critically analyze all the potential therapeutic options for the treatment of first-line bDMARD failures in order to provide a comprehensive overview of available strategies to be applied in clinical practice.     

The role and therapeutic targeting of IL-6 in rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is an autoimmune chronic disease with joint and systemic inflammation and it has been found that interleukin-6 (IL-6) plays a key role in RA. Indeed, various clinical studies have proved that the first-in-class IL-6 inhibitor, tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed outstanding efficacy in RA.

Areas covered: We review here the role of IL-6 in the inflammatory conditions and how IL-6 contributes to pathogenesis of RA, what induces IL-6 and how IL-6 expression is regulated. Furthermore, clinical studies of tocilizumab for RA are summarized,

Expert commentary: We review and discuss the prospects for future applications of IL-6 targeting therapy and new therapeutic strategies targeting IL-6. Finally, we discuss relevant issues with regard to the clinical management of IL-6 blockade in RA.     

A new strategy for the early diagnosis of rheumatoid arthritis: a combined approach

Rheumatoid arthritis [RA] is one of the most common and severe autoimmune rheumatic diseases, diagnosed primarily according to clinical manifestations and radiological reports. For many years, laboratory diagnosis of rheumatoid arthritis has relied on the detection of rheumatoid factor [RF], as established by the ACR criteria. A recent test to detect antibodies towards citrullinated peptides, called the anti-CCP assay, showed a similar sensitivity but a more elevated specificity than the RF test. Our intention was the recognition of an optimal diagnostic strategy that exhibits the highest sensitivity and specificity for RA detection. To this purpose, we examine the usefulness of autoantibodies in RA testing, evaluating the diagnostic performance of conventional and innovative assays for RF detection, and ELISA anti-CCP test, for anti-CCP antibodies detection, by a prospective study. Multiplex cytofluorimetric test appeared to be more sensitive and specific than nephelometric assay for RF detection. Hence, a novel combined approach, significantly increasing the diagnostic sensitivity for RA, was planned, employing the multiplex RF test in combination with the anti-CCP test.     

Treating rheumatoid arthritis with new disease modifying drugs

Rheumatoid arthritis (RA) is a serious illness that can only be controlled by the appropriate use of disease modifying anti-rheumatic drugs (DMARDs). In spite of the successful use of such substances, and of methotrexate in particular, a large number of patients still experience disease progression. Leflunomide and the two anti-TNF agents, infliximab and etanercept, were therefore warmly greeted as very welcome additions to the rheumatologist's armamentarium. These successful newcomers, their strengths and problems are the focus of the present review.     

The effect of antidrug antibodies on the sustainable efficacy of biologic therapies in rheumatoid arthritis: practical consequences

Biologic therapies, predominantly TNF-α inhibitors, have revolutionized the treatment of rheumatoid arthritis (RA). However, their clinical utility can be limited by the development of antidrug antibodies (ADAs). Immunogenicity is a complex phenomenon related to various drug, disease, and patient characteristics, and may be more common with the monoclonal antibodies than with etanercept, a soluble TNF receptor-Fc immunoglobulin fusion protein. Neutralizing antibodies – those that hinder bioactivity by preventing drug molecules from binding to TNF – are correlated with reduced serum drug concentrations, loss of therapeutic response, adverse events, and treatment discontinuation. Cost-effective use of these agents will depend on further research into drug and ADA assays, and how they should guide dose reduction or switching strategies.     

Microparticles and autophagy: a new frontier in the understanding of atherosclerosis in rheumatoid arthritis

Microparticles (MPs) are small membrane vesicles released by many cell types under physiological and pathological conditions. In the last years, these particles were considered as inert cell debris, but recently many studies have demonstrated they could have a role in intercellular communication. Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, and autoimmune diseases, such as rheumatoid arthritis (RA). RA is an autoimmune systemic inflammatory disease characterized by chronic synovial inflammation, resulting in cartilage and bone damage with accelerated atherosclerosis increasing mortality. According to the literature data, also MPs could have a role in endothelial dysfunction, contributing to atherosclerosis in RA patients. Moreover many researchers have shown that a dysregulated autophagy seems to be involved in endothelial dysfunction. Autophagy is a reparative process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. It has been shown in many works that basal autophagy is essential to proper vascular function. Taking into account these considerations, we hypothesized that in RA patients MPs could contribute to atherosclerosis process by dysregulation of endothelial autophagy process.