抗CD20单克隆抗体研究进展

抗CD20单克隆抗体是一类治疗B细胞淋巴瘤的靶向药物。迄今,主要有三代抗CD20单克隆抗体药物:以利妥昔单抗为代表的第一代抗CD20单抗,ofatumumab、veltuzumab、ocrelizumab等第二代抗CD20单抗,以及obinutu-zumab、ocaratuzumab等第三代抗CD20单抗。我们就抗CD20治疗性单克隆抗体研究的新进展进行简要综述。     

B淋巴细胞活化因子抗体在自身免疫性疾病治疗中的研究进展北大核心CSCD

近几十年来,自身免疫性疾病的治疗已从使用激素和常规免疫抑制药物转向使用生物制剂。B淋巴细胞的增殖及成熟对自身免疫性疾病的发病起到至关重要的作用。其中,肿瘤坏死因子超家族B淋巴细胞活化因子(B cell activating factor,BAFF)及其受体通过调控信号通路介导B淋巴细胞存活,因此BAFF及其受体是自身免疫性疾病的重要治疗靶点。文中阐述了BAFF及其受体在人体免疫系统中的作用机制,同时介绍了BAFF通路的过度活化如何促进系统性红斑狼疮、干燥综合征和类风湿关节炎等自身免疫疾病发展的最新观点。针对以上3种疾病,文中以3种主要的靶向BAFF抗体药物Belimumab、Tabalumab和Atacicept为例,介绍和讨论了其最新的临床试验及临床应用现状。最后提出靶向BAFF通路开发新型治疗自身免疫性疾病的方案和策略。     

B 细胞膜CD20 抗原的分布与单分子力谱探测

CD20抗原分子在B细胞上表达下降是慢性B淋巴细胞白血病 (B-CLL) 的标志性特征。采用激光扫描共聚焦显微镜 (LSCM) 和量子点标记相结合的方法对正常和B-CLL外周血CD20+B淋巴细胞膜表面CD20抗原分子的表达及分布进行了荧光成像。同时,采用原子力显微镜 (AFM) 对CD20+B细胞的形貌及超微结构特征进行了表征,并且将AFM针尖用生物素化的单克隆抗体进行修饰,对CD20+B细胞表面的CD20抗原-抗体之间的单分子力谱进行了探测。LSCM荧光图像显示,B-CLL CD20+B淋巴细胞上CD20分子的表达量比正常CD20+B淋巴细胞显著降低。AFM结果显示,B-CLL CD20+B淋巴细胞超微结构比正常的粗糙。力谱结果显示,CD20抗原-抗体的相互作用力大约是非特异性黏附力的5倍,CD20分子在正常CD20+B淋巴细胞膜上分布比较均匀,小部分有聚集现象,反之,在B-CLL CD20+B淋巴细胞膜表面分布稀疏。利用以上两种方法能进一步观察到B-CLL外周血B淋巴细胞的异常,并在一定程度上解释临床上B-CLL病人对利妥昔的低反应现象,为针对抗原CD20的治疗用药选择提供参考。     

抗CD20单克隆抗体治疗B 细胞淋巴瘤的效应机制

B细胞淋巴瘤是一种主要的非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL),95%以上的B细胞淋巴瘤均表达B细胞分化抗原CD20。尽管目前CD20在B细胞分化发育过程中的具体功能尚未阐明,但其特有的表达方式和在细胞膜上的分布特点决定了其成为B细胞淋巴瘤靶向治疗的主要靶点。近十年来,随着抗CD20单克隆抗体的不断发展和进步,联合传统的CHOP化疗方案,在NHL的治疗中显示出良好的效果。虽然,近年来抗CD20单抗逐渐被用于B细胞相关的自身免疫病的治疗,但相关作用机制尚不明确。在针对NHL的临床治疗中,抗CD20单抗的疗效被认为依赖于效应器机制,主要有ADCC、CDC和细胞凋亡。虽然抗CD20在淋巴瘤的治疗中具有显著的免疫疗效,但部分瘤荷较大的病人出现了耐药和复发,循环中大量B细胞由于单抗的结合而被机体的单核巨噬细胞吞噬或NK细胞杀伤,机体出现成熟B细胞空缺期,同时单核巨噬细胞、NK细胞和补体大量消耗,造成机体免疫效应功能饱和和效应器耗竭。本文就抗CD20单克隆抗体在治疗淋巴瘤中的具体作用机制及可能造成的机体效应器耗竭问题做一简要的概述。     

CD154在活动期SLE的改变

目的探讨CD154在系统性红斑狼疮(SLE)中的异常表达及其在狼疮发病中的作用机制。方法31例活动期SLE及20例正常健康人,分离外周血CD19阳性B细胞,以流式细胞仪荧光抗体标记检测其CD154的表达,并体外观察抗CD154抗体对外周血B细胞的增生及IgG分泌的影响。结果(1)活动期SLE外周血B淋巴细胞中CD154阳性率(35±14)%及表达强度(312±108)均显著高于正常健康人,后者分别为(9±7)%、(98±41)(P均<0.001);(2)体外单独培养,活动期SLE外周血B淋巴细胞自身即可异常增生并分泌IgG,[3H]-TdR掺入及体外培养上清液IgG浓度与正常人相比,差异有显著性(P值分别<0.0001和0.001)。抗CD154抗体可显著抑制活动期SLE外周血B淋巴细胞的异常增生及IgG的异常分泌,[3H]-TdR掺入及体外培养上清液IgG浓度与对照抗体组相比,差异有显著性(P值分别为0.01和0.05)。结论CD154在活动期SLE的B淋巴细胞中有异常表达,其异常调控可能是导致分泌自身抗体B细胞克隆增生的主要原因。     

冻存前后人脐带间充质干细胞对T和B淋巴细胞免疫抑制能力的差异比较

目的 探讨冻存前和复苏后人脐带间充质干细胞(hUCMSCs)对T和B淋巴细胞免疫抑制能力的差异.方法 分离健康人外周血单个核细胞,使用Anti-CD3和Anti-CD28单克隆抗体体外激活T淋巴细胞,使用ODN2395,hCD40L,羊抗人IgM抗体和白介素2体外刺激经过分选的B淋巴细胞,通过冻存前后hUCMSCs进行...     

抗人B淋巴细胞单克隆抗体清除中国恒河猴体内B淋巴细胞效果观察

目的用抗人B淋巴细胞单克隆抗体（利妥昔单抗注射液,Rituximab）通过静脉滴注的方法敲除中国恒河猴体内B淋巴细胞,并观察其敲除效果,为建立B淋巴细胞缺失的恒河猴动物模型提供基础的实验数据。方法选取健康的中国恒河猴两只,静脉滴注抗人B淋巴细胞单克隆抗体,定期采集外周血、腹股沟淋巴结和十二指肠黏膜组织,制备淋巴细胞悬液,应用流式细胞术的方法系统性测定B淋巴细胞及T淋巴细胞亚群的变化。结果静脉滴注利妥昔单抗注射液后24 h,中国恒河猴外周血中B淋巴细胞的缺失即能达到100%,持续约14 d;腹股沟淋巴结中B淋巴细胞在静注后7 d缺失100%;十二指肠黏膜组织中B淋巴细胞在静脉滴注后7 d缺失达到90%,维持28 d。并且在成功敲除B淋巴细胞的情况下,CD4＋T及CD8＋T淋巴细胞无明显波动,维持在一个稳定的水平。结论利妥昔单抗注射液能有效去除中国恒河猴体内B淋巴细胞,为建立B淋巴细胞缺失动物模型奠定基础。     

针对CD33分子的抗体偶联药物的研究进展

单克隆抗体因具有分子量小、毒副作用低、靶向性好等优点,近年来已成为肿瘤治疗用药的主要方式。CD33分子是免疫球蛋白超家族成员,同时也是唾液酸依赖的免疫球蛋白样凝集素家族的成员,在免疫调节过程中具有重要作用。CD33分子特异表达于白血病细胞表面而在造血干细胞中不表达,因而成为白血病免疫治疗的理想靶点。以CD33为靶点的抗体药物主要有CMA676、HUMl95、AVE9633、WM537LHIM3-4等,目前大多处于临床试验阶段。该实验室也在进行抗CD33全人源抗体的研究,利用噬菌体展示技术筛选与CD33胞外区特异性结合的单链抗体,并构建免疫毒素和抗体偶联药物以研究其体内外抗肿瘤作用。该文针对CD33分子及其抗体偶联药物的现状及趋势作一综述。     

共刺激分子对全身炎症反应综合征中细胞因子的影响

目的:探讨全身炎症反应综合征(SIRS)中相关共刺激分子的表达及其调控因素,并对共刺激分子在全身炎症反应综合征发展及治疗中的作用及机制进行初步探究.方法:腹腔注射脂多糖(LPS)建立全身炎症反应综合征的小鼠动物模型后,将BALB/c模型小鼠随机分为生理盐水(NS)、LPS、CD28+LPS三组,进行脾淋巴细胞的分离,通过RT-PCR、ELISA等方法检测共刺激分子在不同组别中的表达.结果:经CD28活化型单克隆抗体(CD28mAb)刺激后的BALB/c小鼠组中共刺激分子CD40配体(CD40L)、杀伤性T细胞相关抗原-4(CTLA-4)的表达量较生理盐水组明显增高.结论:共刺激分子CD28对于全身炎症反应综合征有促进的作用.     

调节性B细胞及其在类风湿关节炎中的研究进展

调节性B细胞(regulatory B cells, Bregs)是一类具有免疫抑制功能的B细胞亚群,可通过表达分化抗原1d(cluster of differentiation 1d, CD1d)、凋亡相关因子配体(factor related apoptosis ligand, FasL)、程序性死亡配体-1(programmed death ligand-1, PD-L1)等膜结合因子,分泌白细胞介素-10(interleukin-10, IL-10)、IL-35、转化生长因子-β(transforming growth factor-β, TGF-β)、颗粒酶B和腺苷等多种机制发挥其免疫抑制功能。近年研究发现,Bregs在类风湿关节炎(rheumatoid arthritis, RA)发病机制中起到重要作用,且有可能成为治疗RA等自身免疫性疾病的新靶点。现就Bregs及其在RA中的研究进展作一概述。     

Current and future management approaches for rheumatoid arthritis

With the introduction of new disease-modifying antirheumatic drugs (DMARDs) and other therapeutic agents, the management of rheumatoid arthritis (RA) has shifted toward earlier, more aggressive therapy. The ultimate goal is to prevent structural joint damage that leads to pain and functional disability. Early diagnosis of RA is therefore essential, and early DMARD treatment combined with nonsteroidal anti-inflammatory drugs is recommended. Combination DMARD regimens and new biologic agents (anti-tumor necrosis factor [TNF] therapies [infliximab, etanercept] and the interleukin [IL]-1 antagonist [anakinra]) have emerged as viable options for early treatment of RA patients. These new biologic agents and future nonbiologic agents that target proteins in signaling cascades are likely to change the landscape of RA treatments.     

B cell targeted therapies

Although the precise pathogenesis of rheumatoid arthritis (RA) remains unclear, many cell populations, including monocytes, macrophages, endothelial cells, fibroblasts and B cells, participate in the inflammatory process. Ongoing research continues to evaluate the critical roles played by B cells in sustaining the chronic inflammatory process of RA. These findings have contributed to the development of targeted therapies that deplete B cells, such as rituximab, as well as inhibitors of B lymphocyte stimulation, such as belimumab. In a phase I trial, belimumab treatment significantly reduced CD20+ levels in patients with systemic lupus erythematosus. Phase I and phase II trials of rituximab found that rituximab plus methotrexate achieved significantly better American College of Rheumatology 50% responses for patients with RA than those patients receiving monotherapy with methotrexate. These clinical trial data present promising evidence for B cell targeted therapies as future therapeutic options for RA.     

The disease formerly known as rheumatoid arthritis

Rheumatoid arthritis is a complex disease where predetermined and stochastic factors conspire to confer disease susceptibility. In light of the diverse responses to targeted therapies, rheumatoid arthritis might represent a final common clinical phenotype that reflects many pathogenic pathways. Therefore, it might be appropriate to begin thinking about rheumatoid arthritis as a syndrome rather than a disease. Use of genetics, epigenetics, microbiomics, and other unbiased technologies will probably permit stratification of patients based on mechanisms of disease rather than by clinical phenotype.Observer la nature, et suivez la route qu’elle vous trace.JJ Rousseau, quoted in [1].Over 150 years ago, Garrod coined the term ‘rheumatoid arthritis’ (RA) to distinguish it from other forms of arthritis, most notably gout and acute rheumatism [1]. Years later, disease subsets were further characterized based, in part, on clinical manifestations such as erosions and nodules or laboratory values such as autoantibodies in the blood. For instance, patients with rheumatoid factors and anti-citrullinated protein antibodies (ACPAs) tend to have more severe disease and worse long-term outcomes than seronegative patients.The broad range of genes associated with RA, the role of the environment in disease initiation, and the diversity of responses to targeted therapies necessitate a re-evaluation of time-honored stratification based on carefully documented clinical phenotypes. Moreover, we should reconsider whether RA should be viewed as the disease that Garrod described or whether it represents a final common pathway of divergent mechanisms in an organ (synovium) with a limited repertoire of responses. In this context, RA could be thought of as a syndrome with multiple etiologic events.RA susceptibility is determined, in part, by inherited risk factors that are predetermined. The single nucleotide polymorphisms (SNPs) associated with RA are dispersed widely across the genome, with notable concentration in genes that participate in adaptive and innate immune responses [2]. Multiple genome-wide association studies have identified scores of disease-associated SNPs. By far the greatest genetic risk is conferred by the class II major histocompatibility gene HLA-DR, which participates in antigen presentation to T lymphocytes [3]. The critical regions of the encoded protein have been well characterized and are located in and around the antigen-binding groove. However, the observation that identical twins only have perhaps a 15% concordance rate for RA indicates that inherited DNA sequences account for a minority of risk and might not be as important as other influences [4]. Put another way, full diploid genome sequencing of patients ignores over 80% of disease risk.Many SNPs outside the major histocompatibility complex also contribute to susceptibility, but their influence is much lower, with relative risks typically <1.2 [5]. One need not have all of these SNPs to develop RA; only a limited subset are probably needed in the presence of the proper environmental exposures. Individual and combinations of low-penetrance susceptibility genes have not offered major insights into the clinical phenotype, although it is still early days for these complex analyses. The fact that various combinations of genes and types of environmental stress lead to the same phenotype suggests that we are not looking at a single disease but at a process with multiple pathways.The “original sin” in ACPA-positive RA is probably due to an interaction between disease-associated HLA-DR genes and the environment, especially at mucosal surfaces (reviewed in [6]). The first steps could be viewed as a normal adaptive immune response against stress-induced modification of peptides, most notably by citrullination. Stochastic events such as smoking, infection, periodontitis, lung inflammation, or the gut microbiome thus lead to induce enzymes (for example, peptidyl arginine deiminases) that alter peptides and produce neo-epitopes not encountered by the thymus during early development. This concept is especially relevant since recent studies suggest that the gastrointestinal flora in early RA might be unique, with an overabundance of Provatella copri[7]. These environmental differences could potentially contribute also to altered polarization of T cells to the pathogenic T-helper type 17 phenotype [8].The autoreactive clones that recognize altered antigens were not deleted during development and can respond appropriately to the antigen. An array of citrullinated peptides fit avidly into the HLA-DR binding groove and activate T cells much more efficiently than the native protein [9]. These early steps probably represent a normal adaptive immune response against altered antigens rather than true autoimmunity. Production of ACPAs directed against a variety of peptides ensues. In the presence of a second hit, such as immune complexes or other mechanisms that activate innate immunity and prepare the synovium, ACPAs gain access to the joint, engage complement, and recruit inflammatory cells that amplify the response. Ultimately, breakdown of tolerance and true autoimmunity against the native proteins ensue, possibly by epitope spread. Interestingly, recently described novel antibody systems to other altered antigens associated with RA, such as through carbamylation rather than citrullination [10], could lead to a similar process.The most persuasive argument that RA has multiple pathways to the same phenotype is the diversity of responses to highly specific immunotherapies. T-cell co-stimulation blocker, B-cell depletion, tumor necrosis factor inhibitors, or interleukin-6 inhibitors demonstrate similar clinical response rates; that is, about one-half of patients treated with any single agent have a major benefit [11]. If a patient does not respond to one targeted agent, a good response to another agent with a distinct mechanism of action is only slightly less likely than in a biologic-naïve patient [12].Evaluation of genes or other analytes to stratify patients based on their underlying pathogenesis rather than on clinical phenotype could shed light on how the variable responses occur. Figure 1 shows an example (which is clearly a simplification), focusing only on gene associations. In this model, a patient with clusters of disease-associated SNPs enriched for tumor necrosis factor regulation, for example, might be expected to be a tumor necrosis factor responder. A B-cell genotype, a T-cell genotype, and so on, would also provide clues on how to treat a patient. If no particular clustering occurs and the gene associations are spread across multiple pathways, then any individual targeted therapy would have a low likelihood of success.Open in a separate windowFigure 1Simplified schema showing how genes might affect clinical responses to targeted therapies. Various genes with associated single nucleotide polymorphisms (SNPs) could be generally categorized into various pathogenic mechanisms (for example, tumor necrosis factor (TNF), T cells, B cells, others in this version). A particular individual might only inherit a subset of each of these SNPs. If the majority of inherited SNPs cluster in one mechanism, such as TNF blocker (see bottom rows), then the individual would have a response to the agent that targets this pathway. If the SNPs are not enriched for any particular pathway, then the patient would be a nonresponder. This schema only focuses on SNPs, but would be integrated with pathways that are enriched for epigenetic marks or other regulators of gene expression/function.As attractive as this notion might be, RA is not that simple and, despite individual studies with potential signals, we cannot reliably predict which patients will respond to a particular biologic despite evaluating many gene associations as well as studies of blood cytokines, synovial pathology, or serum autoantibody profiles. Success will probably require integrating more sophisticated datasets that also take into account many nongenetic influences, such as epigenomics, microbiomics, proteomics, metabolomics, or immunomics, to define the deep profile of a particular individual’s version of RA. Initial studies examining potential pathogenic pathways focusing on DNA methylation in RA synoviocytes or integrating DNA methylation and gene associations in peripheral blood cells provide insights into how this information might begin to identify previously unrecognized subsets [13-15]. Systems biology approaches to nongenetic and genetic influences also permit application of computational methods to test the effects of perturbing networks in silico. While this approach is still in its infancy, it could ultimately decrease the need for biologic validation of every potential target or could identify combinations of therapies that will be additive or synergistic.These observations suggest that RA might be thought of as a collection of distinct mechanisms rather than a single pathway; that is, as a syndrome rather than a disease. A similar conceptual evolution has occurred with other diseases, such as acute myelogenous leukemia, with a transition from phenotype or histologic diagnosis to segmenting the disease by genotype. We face the reverse of past progress in medicine, where a unifying cause ultimately links many clinical phenotypes, such as the great imitator syphilis. Instead, our understanding of RA as a clinical phenotype is devolving into multiple pathogenic pathways. RA might have a common entry point, such as adaptive immune responses to altered peptides followed by immune complexes and autoimmunity, but the subsequent byzantine pathway to the clinical phenotype is so convoluted and personalized that solving RA for a particular patient requires a systems approach using multiple emerging technologies.We have come a long way from “acute rheumatism”, but still have far to go before these pathogenic processes can be meaningfully dissected. The therapeutic successes with the average patient have been stunning, but we have reached the limit of this traditional approach. We must begin the process of deconvoluting RA using unbiased technology and carefully integrating predetermined and stochastic influences that lead to the syndrome we call RA.     

Unmet needs in rheumatoid arthritis

Until the pathophysiology/etiology of rheumatoid arthritis (RA) is better understood, treatment strategies must focus on disease management. Early diagnosis and treatment with disease-modifying antirheumatic drugs (DMARDs) are necessary to reduce early joint damage, functional loss, and mortality. Several clinical trials have now clearly shown that administering appropriate DMARDs early yields better therapeutic outcomes. However, RA is a heterogeneous disease in which responses to treatment vary considerably for any given patient. Thus, choosing which patients receive combination DMARDs, and which combinations, remains one of our major challenges in treating RA patients. In many well controlled clinical trials methotrexate and other DMARDs, including the tumor necrosis factor-alpha inhibitors, have shown considerable efficacy in controlling the inflammatory process, but many patients continue to have active disease. Optimizing clinical response requires the use of a full spectrum of clinical agents with different therapeutic targets. Newer therapies, such as rituximab, that specifically target B cells have emerged as viable treatment options for patients with RA.     

Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity

Introduction

B-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA). Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial. The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells.

Methods

In this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients.

Results

Fixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium. Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella). This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion.

Conclusion

By studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion. This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells.     

Revealing a natural marine product as a novel agonist for retinoic acid receptors with a unique binding mode and inhibitory effects on cancer cells

Retinoids display anti-tumour activity on various cancer cells and therefore have been used as important therapeutic agents. However, adverse side effects and RA (retinoic acid) resistance limit further development and clinical application of retinoid-based therapeutic agents. We report in the present paper the identification of a natural marine product that activates RARs (RA receptors) with a chemical structure distinct from retinoids by high-throughput compound library screening. Luffariellolide was uncovered as a novel RAR agonist by inducing co-activator binding to these receptors in vitro, further inhibiting cell growth and regulating RAR target genes in various cancer cells. Structural and molecular studies unravelled a unique binding mode of this natural ligand to RARs with an unexpected covalent modification on the RAR. Functional characterization further revealed that luffariellolide displays chemotherapeutic potentials for overcoming RA resistance in colon cancer cells, suggesting that luffariellolide may represent a unique template for designing novel non-retinoid compounds with advantages over current RA drugs.     

Targeting B cells for the treatment of rheumatoid arthritis

The role of B cells in rheumatoid arthritis (RA) has been debated for decades. However, recent clinical trial data indicating that depletion of B cells in RA patients is of therapeutic benefit has validated the importance of this cell type in the pathogenesis of the disease. Elucidation of the molecular basis of B cell development and activation has allowed the identification of a number of possible therapeutic targets that are appealing for drug development. This review discusses briefly a number of these molecules and the rationale for targeting them for the treatment of RA.     

Restoring the balance: immunotherapeutic combinations for autoimmune disease

Autoimmunity occurs when T cells, B cells or both are inappropriately activated, resulting in damage to one or more organ systems. Normally, high-affinity self-reactive T and B cells are eliminated in the thymus and bone marrow through a process known as central immune tolerance. However, low-affinity self-reactive T and B cells escape central tolerance and enter the blood and tissues, where they are kept in check by complex and non-redundant peripheral tolerance mechanisms. Dysfunction or imbalance of the immune system can lead to autoimmunity, and thus elucidation of normal tolerance mechanisms has led to identification of therapeutic targets for treating autoimmune disease. In the past 15 years, a number of disease-modifying monoclonal antibodies and genetically engineered biologic agents targeting the immune system have been approved, notably for the treatment of rheumatoid arthritis, inflammatory bowel disease and psoriasis. Although these agents represent a major advance, effective therapy for other autoimmune conditions, such as type 1 diabetes, remain elusive and will likely require intervention aimed at multiple components of the immune system. To this end, approaches that manipulate cells ex vivo and harness their complex behaviors are being tested in preclinical and clinical settings. In addition, approved biologic agents are being examined in combination with one another and with cell-based therapies. Substantial development and regulatory hurdles must be overcome in order to successfully combine immunotherapeutic biologic agents. Nevertheless, such combinations might ultimately be necessary to control autoimmune disease manifestations and restore the tolerant state.KEY WORDS: Tolerance, Autoimmune, Biologic     

Effective use of TNF antagonists

Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved functional outcomes in patients with rheumatoid arthritis (RA). RA is a progressive disease in which structural joint damage can continue to develop even in the face of symptomatic relief. Before the introduction of biologic agents, the management of RA involved the use of disease-modifying antirheumatic drugs (DMARDs) early in the course of disease. This focus on early treatment, combined with the availability of the anti-TNF agents, has contributed to a shift in treatment paradigms favoring the early and timely use of DMARDs with biologic therapies. Improvement in symptom control does not always equate to a reduction in disease progression or disability. With the emergence of structure-related outcome measures as the primary means for assessing the effectiveness of antirheumatic agents, the regular use of X-rays is recommended for the continued monitoring and evaluation of patients. In addition to the control of symptoms and improvement in physical function, a reduction in erosions and joint-space narrowing should be considered among the goals of therapy, leading to a better quality of life. Adherence to therapy is an important element in optimizing outcomes. Durability of therapy with anti-TNF agents as reported from clinical trials can also be achieved in the clinical setting. Concomitant methotrexate therapy might be important in maintaining TNF antagonist therapy in the long term. Overall, the TNF antagonists have led to improvements in clinical and radiographic outcomes in patients with RA, especially those who have failed to show a complete response to methotrexate.     

Rheumatoid arthritis: regulation of synovial inflammation

Rheumatoid arthritis (RA) is a systemic, inflammatory autoimmune disorder that presents as a symmetric polyarthritis associated with swelling and pain in multiple joints, often initially occurring in the joints of the hands and feet. Articular inflammation causes activation and proliferation of the synovial lining, expression of inflammatory cytokines, chemokine-mediated recruitment of additional inflammatory cells, as well as B cell activation with autoantibody production. A vicious cycle of altered cytokine and signal transduction pathways and inhibition of programmed cell death contribute to synoviocyte and osteoclast mediated cartilage and bone destruction. A combination of targeted interventions at various stages in the pathogenesis of RA will likely be required to control symptoms in certain patients with this complex and potentially disabling disease. The regulation of rheumatoid synovial inflammation will be reviewed, followed by a brief summary of the therapeutic implications of these advances, including strategies targeting key cytokines, signal transduction molecules, co-stimulatory molecules, B cells, chemokines, and adhesion molecules.