BACKGROUND & AIMS: :Etanercept is a dimeric fusion protein based on the p75 TNF-alpha receptor. It binds to TNF-alpha and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiopathic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-alpha antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.

背景与目标： ：Etanercept是基于p75TNF-α受体的二聚体融合蛋白。它与TNF-α结合并阻断其生物学活性。在随机，双盲，安慰剂对照试验中，依那西普对类风湿关节炎，银屑病关节炎，多关节病，幼年特发性关节炎和强直性脊柱炎具有治疗作用。依那西普改善关节发炎，身体机能并减慢/阻止结构损伤，尤其是与甲氨蝶呤合用时。在相当大比例的患者中观察到持续的反应。尽管在开始依那西普治疗之前应考虑一些安全问题，但总的来说，依那西普是一种耐受性良好的药物，具有可接受的安全性。任何TNF-α拮抗剂的使用都必须与《国家生物治疗建议》相一致，并且在困难的临床情况下，需要在风险/获益之间取得平衡。

BACKGROUND & AIMS: :In rheumatoid arthritis (RA), immunological triggers at mucosal sites, such as the gut microbiota, may promote autoimmunity that affects joints. Here, we used discovery-based proteomics to detect HLA-DR-presented peptides in synovia or peripheral blood mononuclear cells and identified 2 autoantigens, N-acetylglucosamine-6-sulfatase (GNS) and filamin A (FLNA), as targets of T and B cell responses in 52% and 56% of RA patients, respectively. Both GNS and FLNA were highly expressed in synovia. GNS appeared to be citrullinated, and GNS antibody values correlated with anti-citrullinated protein antibody (ACPA) levels. FLNA did not show the same results. The HLA-DR-presented GNS peptide has marked sequence homology with epitopes from sulfatase proteins of the Prevotella sp. and Parabacteroides sp., whereas the HLA-DR-presented FLNA peptide has homology with epitopes from proteins of the Prevotella sp. and Butyricimonas sp., another gut commensal. Patients with T cell reactivity with each self-peptide also had responses to the corresponding microbial peptides, and the levels were directly correlated. Furthermore, HLA-DR molecules encoded by shared-epitope (SE) alleles were predicted to bind these self- and microbial peptides strongly, and these responses were more common in RA patients with SE alleles. Thus, sequence homology between T cell epitopes of 2 self-proteins and a related order of gut microbes may provide a link between mucosal and joint immunity in patients with RA.

背景与目标： 在类风湿关节炎（RA）中，粘膜部位（如肠道菌群）的免疫触发可能会促进影响关节的自身免疫。在这里，我们使用基于发现的蛋白质组学来检测滑膜或外周血单核细胞中HLA-DR呈递的肽，并鉴定了2种自身抗原N-乙酰氨基葡萄糖-6-硫酸酯酶（GNS）和纤维蛋白A（FLNA）作为T和T的靶标B细胞反应分别在52％和56％的RA患者中发生。 GNS和FLNA在滑膜中均高表达。 GNS似乎是瓜氨酸化的，并且GNS抗体值与抗瓜氨酸化的蛋白抗体（ACPA）的水平相关。 FLNA没有显示相同的结果。 HLA-DR呈递的GNS肽与Prevotella sp的硫酸酯酶蛋白的表位具有明显的序列同源性。 HLA-DR呈递的FLNA肽与Prevotella sp。蛋白的表位具有同源性。和Butyricimonas sp。，另一个肠胃奖。与每种自身肽具有T细胞反应性的患者也对相应的微生物肽有反应，并且其水平直接相关。此外，预计由共享表位（SE）等位基因编码的HLA-DR分子会强烈结合这些自身和微生物肽，这些反应在SE等位基因的RA患者中更为常见。因此，两种自身蛋白的T细胞表位与肠道微生物相关顺序之间的序列同源性可能为RA患者的粘膜免疫和关节免疫之间提供了联系。

BACKGROUND & AIMS: :Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this second of 5 sections of the guidelines of care for psoriasis, we give an overview of psoriatic arthritis including its cardinal clinical features, pathogenesis, prognosis, classification, assessment tools used to evaluate psoriatic arthritis, and the approach to treatment. Although patients with mild to moderate psoriatic arthritis may be treated with nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of disease-modifying antirheumatic drugs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis. We will discuss the use of disease-modifying antirheumatic drugs and the biologic therapies in the treatment of patients with moderate to severe psoriatic arthritis.

背景与目标： 银屑病：牛皮癣是一种常见的，慢性，炎性，多系统疾病，主要表现为皮肤和关节表现，约占总人口的2％。在牛皮癣护理指南的5个部分的第二部分中，我们概述了牛皮癣关节炎，包括其主要临床特征，发病机理，预后，分类，用于评估牛皮癣关节炎的评估工具以及治疗方法。尽管轻度至中度银屑病性关节炎患者可以使用非甾体类抗炎药和/或关节内类固醇注射治疗，但将改变病情的抗风湿药（尤其是甲氨蝶呤）与生物制剂一起使用被认为是护理的标准在患有较严重的银屑病关节炎的患者中。我们将讨论在中重度银屑病关节炎患者中使用改变疾病的抗风湿药和生物疗法。

BACKGROUND & AIMS: :Clopidogrel is a potent inhibitor of platelet aggregation and has been used as an alternative, or as an adjunct to aspirin in reducing the risk of thrombosis. A 34-year-old uremic type 1 male diabetic patient who underwent simultaneous kidney-pancreas transplantation was given clopidogrel as he was allergic to aspirin. He developed polyarthralgia one week later, followed in a few days by symmetrical migratory polyarthritis, which resolved completely on withdrawing the drug. The implications to clinical management in a transplant setting are discussed.

背景与目标： ：Clopidogrel是一种有效的血小板聚集抑制剂，已被用作替代品，或作为阿司匹林的辅助剂以降低血栓形成的风险。一名同时接受肾胰腺移植的34岁尿毒症1型男性糖尿病患者因对阿司匹林过敏而接受了氯吡格雷治疗。一周后，他患上了多发性关节痛，几天后又出现了对称性迁徙性多发性关节炎，这种症状在撤药后完全消失了。讨论了对移植环境中临床管理的影响。

BACKGROUND & AIMS: :The inflammatory cytokine cascade plays a pivotal role in the pathogenesis of rheumatoid arthritis. Recently, a novel human cytokine, interleukin-32, was reported to induce tumor necrosis factor (TNF)-alpha. Interleukin-32 is expressed primarily in lymphoid tissues and leukocytes, but also in stimulated epithelial cells and synovial fibroblasts. Although the interleukin-32 receptor has not been reported, interleukin-32 can induce other inflammatory cytokines such as TNF-alpha, interleukin-1beta, and interleukin-6 from monocytes/macrophages in vitro and in vivo, and it synergizes with signals from pattern-recognition receptors. Notably, in the inflamed synovial tissues from rheumatoid arthritis patients, interleukin-32 is prominently expressed and correlates with the severity of arthritis and the expression of other cytokines, including TNF-alpha and interleukin-1. In experimental mice models of arthritis, joint injection of interleukin-32 induces joint inflammation, and overexpression of interleukin-32beta in hematopoietic cells exacerbates collagen-induced arthritis. Interleukin-32 can thus be seen to play an important role in the pathogenesis of rheumatoid arthritis.

背景与目标： ：炎性细胞因子级联在类风湿关节炎的发病机理中起着关键作用。最近，有报道称一种新型的人类细胞因子白介素32可以诱导肿瘤坏死因子（TNF）-α。白细胞介素32主要在淋巴组织和白细胞中表达，但在受刺激的上皮细胞和滑膜成纤维细胞中也表达。尽管尚未报道白细胞介素32受体，但白细胞介素32可以在体外和体内从单核细胞/巨噬细胞诱导其他炎症细胞因子，如TNF-α，白细胞介素1β和白细胞介素6，并且与模式信号协同作用。识别受体。值得注意的是，在类风湿性关节炎患者的滑膜组织发炎中，白细胞介素32显着表达并与关节炎的严重程度以及包括TNF-α和白细胞介素-1在内的其他细胞因子的表达相关。在关节炎的实验小鼠模型中，联合注射白介素32会诱发关节发炎，而造血细胞中白介素32β的过度表达会加剧胶原蛋白诱发的关节炎。由此可见，白细胞介素32在类风湿关节炎的发病机理中起重要作用。

BACKGROUND & AIMS: :Over 3500 patients with recent onset inflammatory polyarthritis (IP) have been recruited by the Norfolk Arthritis Register (NOAR) since 1990. Longitudinal data from this cohort have been used to examine the prevalence and predictors of remission, functional disability, radiological outcome, cardiovascular mortality and co-morbidity and the development of non-Hodgkin's lymphoma. Rheumatoid factor titre, high baseline C-reactive protein and high baseline HAQ score are all predictors of a poor outcome. There is a strong association between possession of the shared epitope and the development of erosions. Patients who satisfy the American College of Rheumatology criteria for rheumatoid arthritis (RA) have a worse prognosis than those who do not. However, it appears that these patients are a poorly defined subset of all those with IP rather than having an entirely separate disease entity. New statistical techniques offer exciting possibilities for using longitudinal datasets such as NOAR to explore the long-term effects of treatment in IP and RA.

背景与目标： ：自1990年以来，诺福克关节炎注册（NOAR）已招募了3500多例最近发作的炎症性多发性关节炎（IP）。该队列的纵向数据已用于检查缓解率，功能障碍，放射学结局，心血管疾病的患病率和预测因素死亡率和合并症以及非霍奇金淋巴瘤的发生。类风湿因子滴度，高基线C反应蛋白和高基线HAQ得分均预示着不良预后。共有表位的拥有与侵蚀的发展之间有着很强的联系。符合美国风湿病学会风湿性关节炎（RA）标准的患者的预后要比不符合标准的患者更差。但是，这些患者似乎是所有IP患者中定义不明确的子集，而不是具有完全独立的疾病个体。新的统计技术为使用纵向数据集（如NOAR）探索IP和RA治疗的长期影响提供了令人兴奋的可能性。

BACKGROUND & AIMS: INTRODUCTION:1alpha,25-dihydroxyvitamin D(3)[1alpha,25(OH)(2)D(3)], the biologically active metabolite of vitamin D3, acts through an intracellular vitamin D receptor (VDR) and has several immunostimulatory effects. Animal studies have shown that production of some matrix metalloproteinases (MMPs) may be upregulated in rat chondrocytes by administration of 1alpha,25(OH)(2)D(3); and cell cultures have suggested that 1alpha,25(OH)(2)D(3) may affect chondrocytic function. Discoordinate regulation by vitamin D of MMP-1 and MMP-9 in human mononuclear phagocytes has also been reported. These data suggest that vitamin D may regulate MMP expression in tissues where VDRs are expressed. Production of 1alpha,25(OH)(2)D(3) within synovial fluids of arthritic joints has been shown and VDRs have been found in rheumatoid synovial tissues and at sites of cartilage erosion. The physiological function of 1alpha,25(OH)(2)D(3) at these sites remains obscure. MMPs play a major role in cartilage breakdown in the rheumatoid joint and are produced locally by several cell types under strict control by regulatory factors. As 1alpha,25(OH)(2)D(3) modulates the production of specific MMPs and is produced within the rheumatoid joint, the present study investigates its effects on MMP and prostaglandin E(2) (PGE(2)) production in two cell types known to express chondrolytic enzymes. AIMS:To investigate VDR expression in rheumatoid tissues and to examine the effects of 1alpha,25-dihydroxyvitamin D(3) on cultured rheumatoid synovial fibroblasts (RSFs) and human articular chondrocytes (HACs) with respect to MMP and PGE(2) production. METHODS:Rheumatoid synovial tissues were obtained from arthroplasty procedures on patients with late-stage rheumatoid arthritis; normal articular cartilage was obtained from lower limb amputations. Samples were embedded in paraffin, and examined for presence of VDRs by immunolocalisation using a biotinylated antibody and alkaline-phosphatase-conjugated avidin-biotin complex system. Cultured synovial fibroblasts and chrondrocytes were treated with either 1alpha,25(OH)(2)D(3) or interleukin (IL)-1beta, or both. Conditioned medium was assayed for MMP and PGE(2) by enzyme-linked immunosorbent assay (ELISA), and the results were normalised relative to control values. RESULTS:The rheumatoid synovial tissue specimens (n=18) immunostained for VDRs showed positive staining but at variable distributions and in no observable pattern. VDR-positive cells were also observed in association with some cartilage-pannus junctions (the rheumatoid lesion). MMP production by RSFs in monolayer culture was not affected by treatment with 1alpha,25(OH)(2)D(3) alone, but when added simultaneously with IL-1beta the stimulation by IL-1beta was reduced from expected levels by up to 50%. In contrast, 1alpha,25(OH)(2)D(3) had a slight stimulatory effect on basal production of MMPs 1 and 3 by monolayer cultures of HACs, but stimulation of MMP-1 by IL-1beta was not affected by the simultaneous addition of 1alpha,25(OH)(2)D(3) whilst MMP-3 production was enhanced (Table 1). The production of PGE(2) by RSFs was unaffected by 1alpha,25(OH)(2)D(3) addition, but when added concomitantly with IL-1beta the expected IL-1beta-stimulated increase was reduced to almost basal levels. In contrast, IL-1beta stimulation of PGE(2) in HACs was not affected by the simultaneous addition of 1alpha,25(OH)(2)D(3)(Table 2). Pretreatment of RSFs with 1alpha,25(OH)(2)D(3) for 1h made no significant difference to IL-1beta-induced stimulation of PGE(2), but incubated for 16h suppressed the expected increase in PGE(2) to control values. This effect was also noted when 1alpha,25(OH)(2)D(3) was removed after the 16h and the IL-1beta added alone. Thus it appears that 1alpha,25(OH)(2)D(3) does not interfere with the IL-1beta receptor, but reduces the capacity of RSFs to elaborate PGE(2) after IL-1beta induction. Cells within the rheumatoid lesion which expressed VDR were fibroblasts, macrophages, lymphocytes and endothelial cells. These cells are thought to be involved in the degradative processes associated with rheumatoid arthritis (RA), thus providing evidence of a functional role of 1apha,25(OH)(2)D(3) in RA. MMPs may play important roles in the chondrolytic processes of the rheumatoid lesion and are known to be produced by both fibroblasts and chondrocytes. The 1alpha,25(OH)(2)D(3) had little effect of basal MMP production by RSFs, although more pronounced differences were noted when IL-1beta-stimulated cells were treated with 1alpha,25(OH)(2)D(3), with the RSF and HAC showing quite disparate responses. These opposite effects may be relevant to the processes of joint destruction, especially cartilage loss, as the ability of 1alpha,25(OH)(2)D(3) to potentiate MMP-1 and MMP-3 expression by 'activated' chondrocytes might facilitate intrinsic cartilage chondrolysis in vivo. By contrast, the MMP-suppressive effects observed for 1alpha,25(OH)2D3 treatment of 'activated' synovial fibroblasts might reduce extrinsic chondrolysis and also matrix degradation within the synovial tissue. Prostaglandins have a role in the immune response and inflammatory processes associated with RA. The 1alpha,25(OH)2D3 had little effect on basal PGE2 production by RSF, but the enhanced PGE2 production observed following IL-1beta stimulation of these cells was markedly suppressed by the concomitant addition of 1alpha,25(OH)2D3. As with MMP production, there are disparate effects of 1alpha,25(OH)2D3 on IL-1beta stimulated PGE2 production by the two cell types; 1alpha,25(OH)2D3 added concomitantly with IL-1beta had no effect on PGE2 production by HACs. In summary, the presence of VDRs in the rheumatoid lesion demonstrates that 1alpha,25(OH)2D3 may have a functional role in the joint disease process. 1 alpha,25(OH)2D3 does not appear to directly affect MMP or PGE2 production but does modulate cytokine-induced production.

背景与目标： 简介：1alpha，25-dihydroxyvitamin D（3）[1alpha，25（OH）（2）D（3）]，维生素D3的生物活性代谢物，通过细胞内维生素D受体（VDR）发挥作用，并具有多种免疫刺激作用。动物研究表明，通过施用1alpha，25（OH）（2）D（3），可在大鼠软骨细胞中上调某些基质金属蛋白酶（MMP）的产量；细胞培养表明1alpha，25（OH）（2）D（3）可能影响软骨细胞功能。还已经报道了维生素D对人单核吞噬细胞中MMP-1和MMP-9的不协调调控。这些数据表明维生素D可能调节表达VDR的组织中MMP的表达。已显示在关节炎关节的滑液内产生1alpha，25（OH）（2）D（3），并且在类风湿滑膜组织和软骨侵蚀部位发现了VDR。在这些站点的1alpha，25（OH）（2）D（3）的生理功能仍然不清楚。 MMP在类风湿关节软骨分解中起主要作用，在调节因子的严格控制下，MMP由几种细胞类型局部产生。由于1alpha，25（OH）（2）D（3）调节特定MMP的产生并在类风湿关节内产生，因此本研究调查了其对MMP和前列腺素E（2）（PGE（2））产生的影响。两种已知表达软骨分解酶的细胞类型。
目的：研究类风湿组织中的VDR表达并检查1α，25-二羟基维生素D（3）对类风湿性滑膜成纤维细胞（RSF）和人关节软骨细胞（HAC）产生MMP和PGE（2）的影响。
方法：对晚期风湿性关节炎患者行关节置换术，获取类风湿滑膜组织。正常的关节软骨是从下肢截肢获得的。将样品包埋在石蜡中，并使用生物素化抗体和碱性磷酸酶偶联的抗生物素蛋白-生物素复合物系统通过免疫定位检查VDR的存在。培养的滑膜成纤维细胞和软骨细胞分别用1alpha，25（OH）（2）D（3）或白介素（IL）-1beta或两者处理。通过酶联免疫吸附测定（ELISA）测定条件培养基中的MMP和PGE（2），并将结果相对于对照值进行标准化。
结果：对风湿性滑膜组织标本（n = 18）进行了VDR免疫染色，染色呈阳性，但分布可变，没有可观察的模式。还观察到VDR阳性细胞与一些软骨-盘nu连接处（类风湿病变）相关。 RSF在单层培养物中产生的MMP不受单独用1alpha，25（OH）（2）D（3）处理的影响，但是当与IL-1beta同时添加时，IL-1beta的刺激作用从预期水平降低了多达50％。相比之下，1alpha，25（OH）（2）D（3）对HACs的单层培养对MMPs 1和3的基础产生有轻微的刺激作用，但IL-1beta对MMP-1的刺激不受该作用的影响。同时添加1alpha，25（OH）（2）D（3），同时提高MMP-3的产生（表1）。 RSF产生的PGE（2）不受1alpha，25（OH）（2）D（3）的添加的影响，但是当与IL-1beta一起添加时，预期的IL-1beta刺激的增加减少到几乎基本水平。相反，同时添加1alpha，25（OH）（2）D（3）不会影响HACs中PGE（2）的IL-1beta刺激（表2）。用1alpha，25（OH）（2）D（3）预处理RSF 1h对IL-1beta诱导的PGE（2）刺激无显着影响，但孵育16h抑制了预期的PGE（2）增加控制值。当在16h后单独加入1alpha，25（OH）（2）D（3）和单独添加IL-1beta时，也注意到了这种效果。因此，似乎1alpha，25（OH）（2）D（3）不会干扰IL-1beta受体，但会降低RSF在IL-1beta诱导后修饰PGE（2）的能力。表达VDR的类风湿病变内的细胞是成纤维细胞，巨噬细胞，淋巴细胞和内皮细胞。这些细胞被认为参与了类风湿关节炎（RA）的降解过程，从而提供了1apha，25（OH）（2）D（3）在RA中的功能作用的证据。 MMPs在类风湿病变的软骨分解过程中可能起重要作用，并且已知由成纤维细胞和软骨细胞产生。 1alpha，25（OH）（2）D（3）对RSF产生基础MMP的影响很小，尽管当用1alpha，25（OH）（2）D处理IL-1beta刺激的细胞时，注意到了更明显的差异。 （3），RSF和HAC表现出截然不同的响应。这些相反的作用可能与关节破坏特别是软骨丧失的过程有关，因为1alpha，25（OH）（2）D（3）可能通过“活化”软骨细胞增强MMP-1和MMP-3的表达。促进体内固有软骨软骨分解。相比之下，观察到的1α，25（OH）2D3治疗“激活的”滑膜成纤维细胞的MMP抑制作用可能会减少外在软骨分解以及滑膜组织内的基质降解。前列腺素在与RA相关的免疫反应和炎症过程中起作用。 1alpha，25（OH）2D3对RSF产生的基础PGE2的影响很小，但是伴随着1alpha，25（OH）2D3的加入，IL-1β刺激后观察到的PGE2产生的增加明显受到抑制。与产生MMP一样，两种细胞类型对1α，25（OH）2D3对IL-1beta刺激的PGE2产生的影响也不同。与IL-1beta一起添加的1alpha，25（OH）2D3对HACs产生PGE2没有影响。总之，类风湿病变中VDR的存在表明1alpha，25（OH）2D3可能在关节疾病过程中发挥功能性作用。 1 alpha，25（OH）2D3似乎不直接影响MMP或PGE2的产生，但可以调节细胞因子诱导的产生。

BACKGROUND & AIMS: :In the present study we investigated the relation between cyclophosphamide and methotrexate toxicity and the presence of HLA- DR B1 alleles in rheumatoid arthritis patients. Seventy-eight such patients (67 women and 11 men) were observed for 12 months. Eighteen were treated with intravenous cyclophosphamide, 28 with oral methotrexate, and 32 with intramuscular gold salts. The prevalence of this shared motif was higher in the study population than in the healthy controls. However, detailed observations did not demonstrate a relation between particular genotype and drug intolerance. Based on the obtained findings we concluded that HLA-DR B1 typing cannot affect cyclophosphamide or methotrexate tolerance in rheumatoid arthritis patients. However, taking into account the relatively small number of patients expressing single genotype, further studies are recommended.

背景与目标： ：在本研究中，我们调查了类风湿关节炎患者中环磷酰胺和甲氨蝶呤毒性与HLA-DR B1等位基因之间的关系。观察了78名这样的患者（67名女性和11名男性），为期12个月。静脉注射环磷酰胺治疗18例，口服甲氨蝶呤治疗28例，肌内金盐治疗32例。在研究人群中，这种共有基序的患病率高于健康对照组。但是，详细的观察结果并未显示出特定基因型与药物耐受性之间的关系。根据获得的发现，我们得出结论，HLA-DR B1分型不能影响类风湿关节炎患者的环磷酰胺或甲氨蝶呤耐受性。但是，考虑到表达单一基因型的患者相对较少，建议进行进一步的研究。