Etanercept for the treatment of non-radiographic axial spondyloarthritis

Presently, tumor necrosis factor α antagonist therapy is the only effective alternative treatment to nonsteroidal anti-inflammatory drugs for the entire spectrum of axial spondyloarthritis, including non-radiographic and radiographic (=ankylosing spondylitis) forms. Recently, etanercept has been approved by the European Medicines Agency for the treatment of non-radiographic axial spondyloarthritis, increasing the number of available treatment options for this indication. The latest data on etanercept concerning clinical efficacy and safety in short-term and long-term treatment of patients with non-radiographic axial spondyloarthritis who do not respond to the first-line therapy with non-steroidal anti-inflammatory drugs suggests good efficacy and safety profiles similar to that observed previously in ankylosing spondylitis. This article reviews recent data on the efficacy and safety of etanercept and is focused on the treatment of non-radiographic axial spondyloarthritis. This article will also discuss the role of etanercept in the context of current and developing treatment options.     

Radiographic progression in non-radiographic axial spondyloarthritis

Introduction: Non-radiographic axial spondyloarthritis (nr-axSpA) represents a subtype of axial spondyloarthritis (axSpA) with no significant structural damage in sacroiliac joints and spine. In addition, patients with nr-axSpA demonstrate a substantial burden of illness, and a considerable share of them might progress to radiographic axSpA (r-axSpA) over time. The amount and quality of published data allows crude estimation of progression rate and factors related to a higher risk of progression.

Areas covered: This review discusses the available data reporting the rates and predictors of radiographic progression in the sacroiliac joints and in the spine in patients with nr-axSpA as well as predisposing factors for such a progression.

Expert commentary: Most of the studies report about 10–40% of patients with nr-axSpA to progress to r-axSpA over a period of 2–10 years. Multiple risk factors for the radiographic sacroiliitis progression are outlined and explored. There are not enough data to presume that any treatment modality may influence progression from nr-axSpA to r-axSpA, with TNFi showing some promising results. Radiographic progression in the spine is in general low in nr-axSpA; thus, long-term studies are required to investigate the natural course of the progression and possible treatment effects.     

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.     

An update on the use of tumor necrosis factor alpha inhibitors in the treatment of ankylosing spondylitis

Introduction: Ankylosing spondylitis is a chronic immune-mediated disease affecting the sacroiliac joints and the spine manifesting with new bone formation and osteopenia. Over the past decade, tumour necrosis factor alpha (TNF-α) inhibitors (TNFi) have become the cornerstone for therapy in improving functional outcomes, and decreasing disease activity in patients with a marginal benefit from non-steroidal anti-inflammatory (NSAID) therapy. At this time, it remains to be determined whether these agents decrease new bone formation, although some studies have recently suggested that.

Areas covered: In this review we discuss the factors that favour a good response to these agents both initially and during maintenance, and some of the more recent studies outlining strategies for dose reduction.

Expert commentary: Finally, we discuss the importance of using more objective tools for disease activity, such as magnetic resonance imaging, as a complementary tool for clinical assessments in both predicting responses to treatment but also in selecting patients most suited for targeted therapy.     

Golimumab in the treatment of psoriatic arthritis

ABSTRACT

Introduction: Psoriatic arthritis (PsA) is an inflammatory arthritis that can be aggressive and destructive, resulting in significant morbidity. While many new agents have been approved for the treatment of PsA over the past decade, TNF inhibitors (TNFi)remain an anchor treatment, in part based on extensive clinical experience. Recently, the TNFi golimumab was approved for intravenous use in PsA.

Areas covered: This expert review presents an overview of the currently available treatment options for PsA with a focus on the evidence from clinical trials supporting the use of golimumab in PsA. This information is placed in context with recent advances in the understanding of PsA pathogenesis and treatment.

Expert commentary: The rapid growth of treatment options available for PsA has brought the prospect of personalized treatment selection closer to reality but improved understanding of the domains of PsA and new biomarkers may be needed before such changes reach the clinic. Until patients who are most likely to benefit from a given agent can be identified and then treated accordingly, TNFi will likely remain a central option and their further development, such as the introduction of an intravenous form of golimumab, remains an important part of treatment improvement.     

Inflammatory pathways in spondyloarthritis

Spondyloarthritis is the second most common form of chronic inflammatory arthritis and a unique hallmark of the disease is pathologic new bone formation. Several cytokine pathways have been genetically associated with ankylosing spondylitis (AS), the prototypic subtype of SpA, and additional evidence from human and animal studies support a role of these pathways in the disease. TNF has a key role in SpA as blockade significantly reduces inflammation and destruction, however the treatment does not halt new bone formation. New insights into the TNF pathway were recently obtained from an animal model specifically overexpressing the transmembrane form of TNF. This model leads to axial and peripheral new bone formation which is not seen in soluble TNF overexpression models, indicating different pathogenic roles of soluble and transmembrane TNF in arthritis development. Besides TNF, the IL-23/IL-17 axis is emerging as an important inflammatory pathway in SpA, as a SNP in the IL-23R locus has been associated with developing AS, mice overexpressing IL-23 develop SpA-like features and IL-17 blockade has been shown to be efficacious for AS patients in a phase II trial. In this review, we focus on the cytokine pathways that have recently been genetically associated with SpA, i.e. TNF, IL-1, IL-6 and IL-23/IL-17. We review the current genetic, experimental and human in vivo data available and discuss how these different pathways are involved in the pathophysiology of SpA. Additionally, we discuss how these pathways relate to the pathogenic new bone formation in SpA.     

Cellular and molecular diversity in spondyloarthritis

The spondyloarthritides are a cluster of inflammatory rheumatic diseases characterized by different diagnostic entities with heterogeneous phenotypes. The current classification system groups spondyloarthritis patients in two main categories, axial and peripheral spondyloarthritis, providing a framework wherein the clinical picture guides the treatment. However, the heterogeneity of the clinical manifestations of the pathologies, even when residing in the same group, highlights the importance of analyzing the smallest features of each entity to understand how different cellular subsets evolve, what the underlying mechanisms are and what biological markers can be identified and validated to evaluate the stage of disease and the corresponding efficacy of treatments. In this review, we will focus mostly on axial spondyloarthritis, report current knowledge concerning the cellular populations involved in its pathophysiology, and their molecular diversity. We will discuss the implications of such a diversity, and their meaning in terms of patients’ stratification.     

脊柱关节炎的发病机制与治疗新进展

脊柱关节炎（SpA）是指包括强直性脊柱炎（AS）、反应性关节炎,赖特综合征、银屑病关节炎、与炎性肠病相关的关节炎、幼年脊柱关节炎以及分类未定脊柱关节炎在内的一组互相关联的、与HLA-B27（简称B27）有不同程度关联的炎性关节疾病。已知遗传与环境因素均参与发病,但确切的病因与发病机制尚不明了。本文介绍遗传因子B27如何参与SpA发病的最新研究结果,如游离的B27重链的作用、调控细胞对细菌入侵的反应方式、B27可能改变早期的细胞信号转导以及末折叠蛋白反应理论等;还介绍近4年来在国外广泛应用的抗肿瘤坏死因子（TNF）-α疗法。有证据显示,抗TNF治疗不仅可明显控制活动性或SpA对抗炎药、病情缓解药治疗无效的SpA患者的症状。改善关节功能,而且可以延缓疾病的放射学进展。     

Treating to target in axial spondyloarthritis: defining the target and the arrow

The treat-to-target concept is currently proposed in axial spondyloarthritis and aims for remission to be reached and maintained. Consensual definitions of remission and flare of the disease are currently lacking but are needed to validate this strategy and to confirm the window of opportunity hypothesis. The discovery of new therapeutic targets, such as IL-23 and IL-17, will enable and enlarge the possibility of targeted therapies in axial spondyloarthritis.     

Association study of LMP gene polymorphisms in Mexican patients with spondyloarthritis

To evaluate the role of LMP (low molecular weight protein) genes as susceptibility markers for spondyloarthritis (SpA), LMP gene polymorphisms were analyzed in 223 Mexican patients with SpA (81 undifferentiated SpA [U-SpA], 117 with ankylosing spondylitis [AS], 25 with reactive arthritis) and in 139 ethnically matched healthy individuals. LMP genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The LMP2 and LMP7 allele frequencies were similar in patients and healthy controls. Genotype analysis revealed an increased frequency of LMP2 R/R genotype in the whole group of SpA (pC = 0.003, OR = 2.06, 95%CI = 1.3–3.25) and in the clinical subgroups of AS (pC = 0.039, OR = 1.88, 95%CI = 1.1–3.22) and U-SpA (pC = 0.003, OR = 2.56, 95%CI = 1.37–4.8) compared with healthy controls. Analysis in the LMP7 did not reveal significant differences in patients and healthy controls. The HLA-B27-negative AS subgroup also showed an increased frequency of LMP2 R/R genotype (pC = 0.027, OR = 4.81, 95%CI = 1.21–22.13). The LMP2-R/R AS patients were younger than LMP2-H/R and H/H patients at onset of the disease (16.0 ± 6.8 years for R/R, 22.0 ± 11.2 years for H/R and 28.6 ± 10.9 years for H/H) (p < 0.05). The data suggest that, besides HLA-B27, LMP2 genotypes are also involved in the genetic susceptibility to develop AS in Mexicans. Furthermore, the age at onset of this disease might also be influenced by genotypes of this gene.     

Plasma levels of H- and L-ficolin are increased in axial spondyloarthritis: improvement of disease identification

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that primarily affects the axial skeleton. A predominance of innate versus adaptive immune responses have been reported in axSpA, indicating a prominent autoinflammatory component of the disease. Little is known about the lectin pathway proteins (LPPs) of the complement system in relation to axSpA. We have investigated LPPs in patients with axSpA and control individuals. Plasma samples were obtained from a cross-sectional cohort of 120 patients with a clinical diagnosis of axSpA and from 144 age- and gender-matched controls. The plasma concentrations of 11 LPPs were measured, using sandwich-type time-resolved immunofluorometric assays in patients and controls, and related to clinical diagnosis and disease activity. Three LPPs [H-ficolin (ficolin-3), L-ficolin (ficolin-2) and collectin liver 1 (CL-L1)] were significantly higher in axSpA patients than in controls (P < 0·0001) and one LPP, collectin kidney 1 (CL-K1), was significantly lower (P < 0·0001). Further, combining H- or L-ficolin concentrations above the 75th percentile of the respective H- or L-ficolin concentration measured in controls with human leucocyte antigen (HLA)-B27 positivity yielded axSpA diagnostic specificities of 99/99% and positive likelihood ratios of 68/62, respectively. H-ficolin and L-ficolin plasma concentrations were found to be elevated in axSpA patients regardless of time since diagnosis. H-ficolin and L-ficolin may represent diagnostic biomarkers for patients with axSpA and should be further evaluated. Our results showed no association between disease activity and the measured LPP concentrations. This result might be due to the cross-sectional design, and should be further investigated.     

肿瘤坏死因子-α 5 旁侧基因多态性与强直性脊柱炎相关性

目的探讨肿瘤坏死因子α基因多态性与强直性脊柱炎(AS)发生的易感关系。方法采用序列特异引物PCR方法(SSP-PCR)检测了136例AS患者和127例正常人的TNF-α5旁侧-857C/T,-863C/A和-1031T/C三个基因多态性位点,并比较了部分不同地区人群之间的基因型与等位基因频率。结果AS患者TNF-α-857基因型(CC,TC和TT)分布频率分别是64.0%,35.3%和0.7%;TNF-α-863基因型(CC,CA和AA)分布频率分别是68.4%,30.0%和1.5%;TNF-α-1031基因型(TT,TC和CC)分布频率分别是66.2%,32.4%和1.5%;TNF-α-857等位基因频率C和T分别是81.6%和18.8%;TNF-α-863等位基因频率C和A分别是83.5%和16.5%;TNF-α-1031等位基因频率T和C分别是:82.4%和17.6%;正常对照者TNF-α-857基因型(CC,TC和TT)分布频率分别是70.9%,27.6%和1.6%;TNF-α-863基因型(CC,CA和AA)分布频率分别是68.5%,29.9%和1.6%;TNF-α-1031基因型(TT,TC和CC)分布频率分别是69.3%,29.1%和1.6%;TNF-α-857等位基因频率C和T分别是84.6%和15.4%;TNF-α-863等位基因频率C和A分别是83.5%和16.5%;TNF-α-1031等位基因频率T和C分别是:83.9%和16.1%;AS患者和正常对照者之间的基因型分布和等位基因频率比较差异无显著性,(P>0.05);本文中国汉族人TNF-α-857(C/T),-863(C/A),-1031(T/C)位点基因多态性分布同亚洲的日本、韩国人群基本一致,差异无显著性;-863(C/A),-1031(T/C)位点基因多态性分布同欧洲的英国、荷兰、瑞典人群比较差异也无显著性,但欧洲人群的TNF-α-857T的等位基因频率明显高于亚洲人群,差异有显著性(P<0.05)。结论TNF-α-857,-863和-1031三个基因多态性位点可能不是中国人患AS的主要易感位点基因。     

Ixekizumab for the treatment of ankylosing spondylitis

ABSTRACT

Introduction

Ixekizumab (IXE) is a high affinity IgG4 approved for the treatment of ankylosing spondylitis (AS). Recently, two phase III randomized clinical trials (COAST-V, COAST-W) showed significant and sustained improvements in signs and symptoms of AS as evaluated by ASAS40 response. Areas covered: The authors performed a comprehensive literature search on this topic, by a review of published articles to date. The authors introduced the structure and the mechanism of action of IXE, and critically reviewed data from clinical trials, concerning its efficacy and safety in AS.Expert opinion: IXE proved dramatic efficacy and tolerable safety in patients with AS, in particular, patients with intolerance or insufficient response to TNFi, which provides an alternative and breakthrough for the treatment options of AS. IXE might not work in AS with IBD and uveitis involvement. Patients treated with IXE should be aware of candida infection in long term application.     

Expression of activation-induced cytidine deaminase splicing variants in patients with ankylosing spondylitis

To investigate the expression patterns of activation-induced cytidine deaminase (AID) variants in peripheral blood mononuclear cells (PBMCs) of patients with ankylosing spondylitis (AS) and examine their clinical implications, we isolated PBMCs from healthy controls (HC, n?=?33) and patients with AS (n?=?62), and measured mRNA expression of AID variants and translesion synthesis (TLS) polymerases using quantitative real-time polymerase chain reaction. The proportion of patients with AS in whom AID splicing variant (sv) 2 was expressed was significantly higher than that of HC (p?=?.031). 80.7% of AS patients were treated with tumour necrosis factor inhibitor (TNFi). Significantly higher proportion of the TNFi-treated group expressed sv2 compared to the TNF-naïve group (p?=?.037). And we compared the level of AID variants expression between the TNFi-treated group and the TNF-naïve group. The expression levels of AID full-length (FL) and sv1 were significantly lower in the TNFi-treated group than the TNF-naïve group (FL: p?=?.002, sv1: p?=?.045). In addition, we investigated mRNA expression levels of translesion synthesis (TLS) polymerases in PBMCs from patients with AS and HC. The expression level of TLS pol ι was significantly lower in patients with AS than in HC (p?=?.007). In conclusion, AS patients expressed significantly higher levels of sv2 than HC. TNFi treatment restored the gene expression of the AID variants (FL, sv1, and sv2) in patients with AS. A clear understanding of the underlying cellular and molecular mechanisms will help to identify the pathogenesis of AS better and to develop novel therapeutic targets.     

Adalimumab for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease occurring in 6–39% of patients with psoriasis. Standard therapy of PsA includes nonsteroidal anti-inflammatory drugs, intra-articular steroids and disease-modifying antirheumatic drugs. Failure of standard therapy is an indication for anti-TNF-α therapy. Adalimumab – a fully human monoclonal antibody against TNF-α – is an effective and generally reasonably well-tolerated drug for treating signs and symptoms of PsA. In placebo-controlled clinical trials, adalimumab showed American College of Rheumatology (ACR)20 response rates of 39–58% and ACR50 response rates of 25–39% in patients with active PsA who had failed previous standard therapy. Significant improvement of psoriatic skin changes and disease-related quality of life were also noted. The response of joints and skin and quality of life improvement was sustained over 2 years of therapy. In addition, adalimumab suppressed structural joint damage and retards radiographic progression of PsA.     

ELIspot法观察中药红曲对强直性脊柱炎外周血单个核细胞分泌TNF-α的影响

目的 使用ELIspot法观察中药红曲对强直性脊柱炎(ankylosing spondylitis)患者外周血单个核细胞分泌TNF-α的影响.方法 采集强直性脊柱炎病情活动期患者(均符合1984年美国风湿病协会关于强直性脊柱炎的诊断)的外周血,分离外周血单个核细胞(peripheral blood mononuclear cells,PBMCs),制成细胞悬液,以每孔2.5 ×105个细胞种植到包被有抗肿瘤坏死因子α(tumor necrosis factor α,TNF-α)抗体的96孔酶联免疫(enzyme-linked immunospot,ELIspot)板上.分为正常对照组、阴性对照组(TNF-α抑制剂组)、阳性对照组[脂多糖(lipopolysaccharide,LPS)刺激]、红曲高浓度组(0.5mg/mL)、红曲中浓度组(0.25mg/mL、红曲低浓度组(0.125 mg/mL),细胞种植的同时给予阴性药物、阳性药物和红曲高中低三种浓度药物刺激,24后检测TNF-α分泌情况.结果 红曲高中低浓度组的ELIspot检测,斑点计数均少于正常组,其中红曲高、中浓度组与正常对照组比较差异有统计学意义(P＜0.05).结论 ELIspot检测是一种较好的用于观察药物对细胞作用效果的方法;红曲能减少强直性脊柱炎患者外周血单个核细胞TNF-α的分泌.     

The profiling of axial spondyloarthritis patient candidate to a biologic therapy: Consensus from a Delphi-panel of Italian experts

Objective

The project aimed to collect expert consensus statements for the profiling of patients with axial spondyloarthritis (axSpA) candidate to biologic agents (bDMARDs) treatment, in order to better define the drivers for the best treatment choice.

Adalimumab for the treatment of uveitis

Introduction: Adalimumab, an inhibitor of tumor necrosis factor-alpha (TNFα), is the only systemic non-corticosteroid agent which has been approved by the US Food and Drug Administration (FDA) for the treatment of non-infectious uveitis.

Areas covered: The aim of this review is to summarize the research which demonstrated the effectiveness of adalimumab in the treatment of intraocular inflammation and helped to establish its side effect profile, ultimately leading to its FDA approval.

Expert commentary: Adalimumab is a useful second-line agent in the treatment of non-infectious uveitis. While it is only approved in the United States for use in intermediate, posterior, and panuveitis in adults, I find it to be effective in off-label treatment of pediatric uveitis and scleritis as well.     

单节段经椎弓根椎体截骨术治疗强直性脊柱炎

目的总结单节段经椎弓根椎体截骨术治疗强直性脊柱后凸畸形的临床疗效。方法 2005~2010采取单节段经椎弓根椎体截骨术治疗20例强直性脊柱炎后凸畸形患者。术前、术后均行胸腰椎X线检查,评定胸腰段Cobb角矫正情况、植骨愈合情况、临床疗效、内固定位置及手术并发症。结果无术中死亡及术后感染,术中2例患者硬膜破裂,术后1例患者麻痹性肠梗阻,2例出现短暂不全瘫。随访15~60个月,后凸畸形均获明显矫正,胸腰段Cobb角平均矫正35.6°,矫正前后有显著性差异﹙<0.05﹚。末次随访无内固定断裂、脱出,均达骨性融合。结论单节段经椎弓根椎体截骨术治疗强直性脊柱脊柱后凸畸形,矫形效果及临床疗效满意。