Tolicizumab与风湿免疫性疾病

IL-6在类风湿关节炎(RA)、幼年特发性全身性关节炎(sJIA)、Castleman病、系统性红斑狼疮(SLE)等多种风湿免疫性疾病发生、进展过程中均有过量表达,且发挥关键作用.Tolicizumab是第一个人源性的IL-6R抗体,通过特异性识别结合IL-6R而阻断IL-6生物学活性,发挥抑制上述疾病炎症反应的作用.大量研究结果证实,tocilizumab不仅能明显缓解RA的临床症状,而且能防止关节继续破坏.此外,tocilizumab在治疗全身性和关节型sJIA、Castleman病、SLE、克罗恩病等风湿免疫性疾病也获得了巨大的成功.     

类风湿关节炎患者血清和关节液细胞因子水平的变化及临床意义

目的探讨幼年类风湿关节炎(JRA)及类风湿关节炎(RA)患者IL-6、IL-8、sIL-2R和TNF-α等细胞因子(CK)水平的变化,及其与风湿活动的传统指标血沉(ESR)和C-反应蛋白(CRP)的相关性。方法采用夹心ELISA法,对30例JRA和34例RA患者的血清中,4例JRA、7例RA、6例骨性关节炎(OA)和9例半月板损伤(MT)患者的关节液中IL-6、IL-8、sIL-2R和TNF-α的水平进行检测。结果①30例JRA、34例RA患者血清IL-6和sIL-2R的水平与对照组相差非常显著(P〈0.01);30例JRA患者血清IL-8水平与对照组比较相差显著(P〈0.05)。②JRA全身型、少关节型患者血清IL-8、sIL-2R的水平和JRA多关节型患者血清IL-6的水平与对照组相差非常显著(P〈0.01)。③4例JRA及7例RA患者关节液sIL-2R的水平和RA患者关节液的IL-6水平与对照组相差显著(P〈0.05)。④JRA患者血清IL-6和sIL-2R的水平与ESR和CRP的变化呈明显的相关关系(r值分别为0.532和0.621)。结论①IL-6、sIL-2R的水平与JRA、RA病的活动性有关,是类风湿活动性的主要指标。②sIL-2R不仅参与JRA和RA的全身病理损伤,而且是引起关节局部损伤的主要CK,IL-6也参与JRA关节局部的病理损伤,在RA关节局部损伤似乎更为重要。③IL-8主要参与JRA的全身病理损伤,对关节局部病理损伤似乎并不重要。     

类风湿性关节炎滑膜成纤维细胞骨保护素和骨形态发生蛋白-2的表达及干预

目的 探讨甲氨蝶呤（MTX）及白细胞介素-6受体（IL-6R）抗体对类风湿关节炎（RA）滑膜成纤维细胞增殖的干预及对骨保护素（OPG）、骨形态发生蛋白-2（BMP-2）的影响.方法 获取RA患者滑膜组织,消化并传代培养成纤维细胞.CCK-8法检测IL-6R抗体、甲氨蝶呤（MTX）对RA滑膜成纤维细胞活性影响;荧光定量（qRT）-PCR检测OPG和BMP-2表达.结果 与空白组相比,MTX组、IL-6R抗体组成纤维细胞的活性受到抑制（F=29.30,34.22,P＜0.05）,MTX联合IL-6R抗体组成纤维细胞的活性显著受到抑制（F=52.04,P ＜0.01）.qRT-PCR显示与空白组相比,IL-6R抗体组、MTX联合IL-6R抗体组OPG、BMP-2的表达均上升（P＜0.05）.与MTK组相比,IL-6R抗体组OPG、BMP-2的表达增加（P＜0.05）.结论 IL-6R抗体单独或联合MTK使用均能明显抑制RA滑膜成纤维细胞的活性,与MTX相比,IL-6R抗体能升高OPG、BMP-2的表达.本研究为应用IL-6R抗体预防和治疗RA关节破坏提供实验依据.     

以Th17细胞为靶点治疗类风湿性关节炎研究进展

类风湿性关节炎是一种以慢性、进行性、侵袭性关节炎为主要表现的全身性自身免疫病,如果不经过正规治疗,病情会逐渐发展,最终导致关节畸形、功能丧失。Th17细胞是最近发现的不同于Th1和Th2的CD4+T细胞的新亚群,它可以分泌IL-17,IL-6,TNF-α等促炎因子。最近的研究发现Th17与RA的发生有密切关系,针对Th17来治疗RA是一种新的手段。本文就最近针对Th17细胞治疗RA所取得的成果做一综述。     

IL-6抑制剂在全身型幼年特发性关节炎治疗中的应用进展

全身型幼年特发性关节炎(systemic juvenile idiopathic arthritis, sJIA)是一种自身免疫性疾病,以发热、皮疹、肝脾肿大、淋巴结肿大以及浆膜炎为主要临床表现,细胞因子分泌水平升高是sJIA的典型特征。IL-6在sJIA的发病机制和临床表现中发挥重要作用,为该病的治疗提供了新思路。目前,有关IL-6抑制剂的临床试验已经展开,其具有一定的安全性和有效性。文章重点介绍IL-6抑制剂在sJIA临床治疗中的研究现状。     

生物制剂治疗幼年特发性关节炎的研究进展

幼年特发性关节炎(JIA)是儿童时期一种常见的慢性结缔组织病.随着生物制剂的广泛使用,JIA患者在疾病活动方面得到了持续而显著改善.研究表明,对传统治疗不耐受的JIA患者,生物制剂可短期内改善其症状.TNF-α拮抗剂、CD80拮抗剂对多关节型JIA (pJIA)疗效及安全性良好,IL-6拮抗剂、IL-1拮抗剂对全身型JIA(sJIA)具有较好疗效及安全性.     

疼痛干预对提高类风湿性关节炎患者生活质量的护理调查

类风湿关节炎（Rheumatoid arthritis,RA）是以多关节炎症为主要表现的慢性全身性疾病。关节疼痛是RA最常见的临床表现,其程度因人而异。类风湿关节炎患者常见的主要症状之一是疼痛,由于遭受疼痛的折磨,其生活质量下降,同时伴有焦虑、忧郁、悲伤、绝望等负性情绪,而且这些情绪又可加重疼痛症状。     

类风湿性关节炎患者IL-6、IL-18和CRP的水平变化及意义

目的：研究类风湿性关节炎（RA）患者血清白细胞介素-6（IL-6）、白细胞介素-18（IL-18）和C-反应蛋白（CRP）水平的变化及其临床意义。方法：收集84例RA患者,以70例健康体检者作对照。采用双抗体夹心酶联免疫吸附法测定血清IL-6、IL-18和免疫荧光法测定CRP的水平,并测定血小板计数（Plt）、血沉（ESR）、类风湿因子（RF）。结果：RA患者的血清Plt、ESR、RF、IL-6、IL-18和CRP的含量明显高于健康对照组（P〈0.01）。RA患者活动期上述指标含量（除RF外）均显著高于稳定期（P〈0.01）,Plt升高RA患者组与Plt正常组相比,RF、ESR、IL-6、IL-18和CRP水平均有明显统计学差异（P〈0.05）。结论：IL-6、IL-18和CRP在RA患者的疾病发展过程中发挥着重要作用,它们的水平变化与RA患者病情有关,联合动态监测有助于临床观察RA患者的病情变化和治疗效果。     

类风湿关节炎患者血清IL 37和可溶性PD 1分子的表达水平及临床意义

目的：通过研究类风湿关节炎（RA）患者血清IL 37和可溶性PD 1分子的表达水平,初步探讨其与RA的相关性以及临床意义。方法：收集RA患者及对照组人群的外周血,然后采用酶联免疫吸附法（ELISA）检测30例RA患者（RA标准评分≥6）和30名健康对照组血清中IL-37、sPD-1的表达水平,结合分析两组人群外周血IL-18、IL-6和IL-18BP三种细胞因子的表达,并通过Pearson相关分析其相关性。结果：经ELISA检测发现,RA组患者外周血中IL-37和sPD-1以及其他几种炎症相关细胞因子IL-18、IL-18BP、IL-6的表达水平均高于健康对照组（P＜0.05）;且IL-37与细胞因子IL-18、IL-18BP、IL-6均呈正相关,sPD-1仅与细胞因子IL-6呈正相关,IL-37、sPD-1均与患者病情程度评分呈正相关。结论：IL-37、sPD-1在RA患者中表达水平升高,且与其他炎性细胞因子及疾病严重程度具有相关性,两者在RA的进展中可能发挥着重要的调控作用,为今后RA治疗提供新的依据。     

类风湿关节炎患者关节液中HSP72水平变化与疾病活动性及炎症因子水平相关性分析

目的观察类风湿关节炎(RA)患者关节液中热休克蛋白72(HSP72)的水平变化,并对其与疾病活动性相关指标和细胞因子之间的相关性进行分析。方法采用酶联免疫吸附法(ELISA)检测RA患者和骨关节炎(OA)患者关节液中HSP72、TNF-α、IL-6、IL-10的表达水平。结果活动期RA患者关节液中HSP72水平明显高于非活动期RA患者和OA对照组(P<0.01)。活动期RA患者关节液中TNF-α、IL-6的水平均高于非活动期RA患者和OA对照者(P<0.01),关节液中IL-10在各组之间无显著差异。RA患者关节液中HSP72的水平与血沉(ESR)、C反应蛋白(CRP)、风湿因子(RF)呈正相关;RA患者关节液中HSP72的水平与关节液中TNF-α、IL-6水平呈正相关。结论关节液中HSP72可能与RA的炎症相关,与RA病情活动有关。     

Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women

Rheumatoid and juvenile idiopathic arthritis (RA, JIA) are chronic inflammatory arthropathies with polygenic autoimmune background. We analysed the IL-4 +33 C/T and IL-4R Q551R single nucleotide polymorphisms (SNPs) in 294 RA, 72 JIA and 165 controls from Northern Ireland. Analysis of the individual phenotypes (RA or JIA) showed that both the IL-4 +33 TT (P = 0.02; OR: 0.25, 95% CI: 0.07-0.87) and the IL-4R Q551R CC genotypes (P = 0.001; OR: 0.19, 95% CI: 0.06-0.56) were exclusively decreased in female RA patients compared to female controls. Similar non-significant trends were observed in female JIA patients (OR: 0.25, 95% CI: 0.03-2.11 and OR: 0.31, 95% CI: 0.07-1.47, respectively). Analysis of the common phenotype (inflammatory arthropathy; i.e. JIA and RA combined) corroborated the unique association of these polymorphisms with female inflammatory arthropathy (P = 0.013 and 0.002, respectively). This is the first demonstration of sex-specific association of the two foremost genes of the IL-4 signalling cascade with chronic inflammatory arthropathies.     

Significant IFNγ responses of CD8+ T cells in CMV-seropositive individuals with autoimmune arthritis

BackgroundLatent Cytomegalovirus (CMV) infection accelerates immunosenescence in elderly with reactivations reported in Rheumatoid Arthritis (RA) and abnormal responses towards CMV in Juvenile Idiopathic Arthritis (JIA).ObjectivesConsidering the signs of premature T-cell immunosenescence in arthritis patients, the known effect of CMV latency on speeding up many of these signs in an age-dependent manner and the role of CMV on IFNγ-mediated inflammation in healthy elderly and RA, we hypothesized that latent CMV infection accelerates TCR repertoire restriction, loss of CD28, peripheral T-cell proliferation and aberrant IFNγ responses in arthritis patients.Study designUnspecific and CMVpp65-specific IFNγ responses were investigated in peripheral CD8+ T-cells in RA or JIA patients and healthy, age-matched controls.ResultsDespite higher prevalence and concentrations of IgG-anti-CMV, arthritis patients showed lower unspecific IFNγ production, lower CD69-mediated activation and lower CD8+ T-cell proliferation. CMV-seropositive RA patients showed higher intracellular IFNγ production and increased proportions of CD28-CD8+ T-cells after specific CMVpp65 long-term stimulation which was not altered by in vitro blockade of TNFα or IL-6. A skewed TCR repertoire towards oligoclonality and less polyclonality was found in JIA.DiscussionCMVpp65-specific IFNγ production with expansion of CD28-CD8+ T-cells suggests an efficient control of latent CMV regardless of immunosuppressive therapy or in vitro blockade of TNFα or IL-6 in CMV-seropositive arthritis patients. Increased IgG-anti-CMV antibody concentrations and increased proportions of intracellular IFNγ-producing CMVpp65-specific CD8+ T-cells in long-term cultures propose a possibly role of endogenous CMV reactivations boosting antibody levels and a higher possibly CMV-driven IFNγ-mediated inflammatory potential of CD8+ T-cells in arthritis patients.     

Association of the HLA-G 14-bp insertion/deletion polymorphism with juvenile idiopathic arthritis and rheumatoid arthritis

We tested the possible association of the 14-bp polymorphism of the HLA-G gene in the course of two inflammatory diseases, rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Patients and controls were genotyped for the 14-bp polymorphism by polymerase chain reaction with specific primers for the exon 8 of the human leukocyte antigen (HLA)-G gene and the amplified fragment was visualized in a 6% polyacrylamide gel. A total of 106 JIA patients, 265 RA patients, 356 healthy adults and 85 healthy children were genotyped for the 14-bp polymorphism. Female JIA patients presented a higher frequency of the -14 bp allele when compared with female healthy children (0.743 and 0.500, corrected P=0.003), which reflected in the JIA group as a whole. This increased frequency of the -14-bp allele was observed in all JIA subtypes. In RA patients, no differences in allelic and genotypic frequencies were observed between patients and controls. No correlations were observed among genotype and disease severity or clinical manifestations. Our data suggest that the HLA-G -14 bp allele is probably a risk factor for JIA, mainly in females. Considering the differences observed in relation to gender, we suggest that hormonal differences can interfere with the development of JIA. Considering the RA patients, our data agree with results from the literature and highlight the differences in the etiology of RA and JIA.     

Expression of Cathepsin B,D and L Protein in Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is the most common childhood autoimmune rheumatic disease and like rheumatoid arthritis (RA), it is characterized by inflammation and the progressive destruction of joints. In RA, cathepsins as proteinases play a major role in destroying synovial tissue and cartilage matrix. So far no data on cathepsin expression in pannus tissue of JIA patients exist. The aim of this study was to characterize the expression levels of cathepsins B, D, H, and L in JIA and to compare them with those in RA. Synovectomy tissue from 16 JIA and 12 RA patients was investigated for cathepsin expression levels by Western blot analysis. Expression of cathepsins B, D and L was on comparable levels in the synovectomy tissue of JIA and RA patients. The following graduation of expression was determined: cathepsin D>cathepsin L>cathepsin B. Cathepsin H was neither found to be expressed in JIA nor in RA patients. The expression levels of cathepsins in pannus tissue showed no clear difference between patients with systemic JIA and patients with monoarticular JIA. In summary, the comparable expression of cathepsins B, D and L in RA and JIA synovectomy tissue suggests that they may play a similarly important role in destroying synovial tissue and cartilage matrix in the course of JIA and RA.     

Tocilizumab for the treatment of systemic juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood, resulting in short- and long-term disability. It includes a heterogeneous group of diseases, of which systemic JIA is often resistant to treatment. IL-6 plays a significant role in systemic JIA since it is elevated in serum and correlates with disease activity, including joint involvement, acute phase reactants and fever. Blocking the IL-6-induced signal could therefore be an attractive treatment approach. The use of tocilizumab, a humanized anti-IL-6 receptor antibody, for the treatment of systemic JIA is described. The purpose has been to review the controlled clinical trials evaluating the efficacy and safety of tocilizumab for the treatment of systemic JIA. In two Phase III randomized, double-blind controlled studies a rapid and high response rate has been achieved both regarding systemic features and arthritis activity together with a tolerable safety profile in children with systemic JIA refractory to conventional treatment.     

The CTLA4+49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland

Rheumatoid and juvenile idiopathic arthritis (RA, JIA) are chronic inflammatory arthropathies with an autoimmune background. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation. We analyzed the CTLA4 +49A/G and CT60 polymorphisms in cohorts of Northern Irish RA and JIA patients and healthy control subjects using restriction fragment length polymorphism methods. The +49 A allele was increased in RA (61.2%; P=0.02; OR=1.28; 95% C.I.=1.04-1.58) and JIA (61.8%; P=0.14) patients compared to the control population (55.3%). No significant association was observed for the CT60 polymorphism. Haplotype analysis revealed a significantly different distribution of +49 A/G-CT60 haplotypes in RA and JIA patients compared to controls (P value<0.00001 and 0.030 for comparison of RA and JIA patients with controls, respectively). Our results suggest that the CTLA-4 gene is involved in predisposition to inflammatory arthropathies in the Northern Irish population.     

Expression of cathepsin B,D and L protein in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common childhood autoimmune rheumatic disease and like rheumatoid arthritis (RA), it is characterized by inflammation and the progressive destruction of joints. In RA, cathepsins as proteinases play a major role in destroying synovial tissue and cartilage matrix. So far no data on cathepsin expression in pannus tissue of HA patients exist. The aim of this study was to characterize the expression levels of cathepsins B, D, H, and L in HA and to compare them with those in RA. Synovectomy tissue from 16 HA and 12 RA patients was investigated for cathepsin expression levels by Western blot analysis. Expression of cathepsins B, D and L was on comparable levels in the synovectomy tissue of HA and RA patients. The following graduation of expression was determined: cathepsin D > cathepsin L > cathepsin B. Cathepsin H was neither found to be expressed in HA nor in RA patients. The expression levels of cathepsins in pannus tissue showed no clear difference between patients with systemic JIA and patients with monoarticular JIA. In summary, the comparable expression of cathepsins B, D and L in RA and JIA synovectomy tissue suggests that they may play a similarly important role in destroying synovial tissue and cartilage matrix in the course of HA and RA.     

Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis

We investigated the hypothesis that low-penetrance mutations in genes (TNFRSF1A, MEFV and NALP3/CIAS1) associated with hereditary periodic fever syndromes (HPFs) might be risk factors for AA amyloidosis among patients with chronic inflammatory disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Crohn's disease, undiagnosed recurrent fevers and HPFs themselves. Four of 67 patients with RA plus amyloidosis had MEFV variants compared with none of 34 RA patients without amyloid (P value=0.03). The E148Q variant of MEFV was present in two of the three patients with TNF receptor-associated periodic syndrome (TRAPS) complicated by amyloid in two separate multiplex TRAPS families containing 5 and 16 affected members respectively, and the single patient with Muckle-Wells syndrome who had amyloidosis was homozygous for this variant. The R92Q variant of TNFRSF1A was present in two of 61 JIA patients with amyloidosis, and none of 31 nonamyloidotic JIA patients. No HPF gene mutations were found in 130 healthy control subjects. Although allelic variants in HPFs genes are not major susceptibility factors for AA amyloidosis in chronic inflammatory disease, low-penetrance variants of MEFV and TNFRSF1A may have clinically significant proinflammatory effects.     

The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) has had a long and difficult problem with classification. It is clearly a heterogeneous and multi-factorial autoimmune disease but all too often the distinctions among subtypes were unclear. In fact, there is now increasing evidence of a distinct pathogenesis of oligo/polyarticular JIA compared to systemic JIA. Oligo/polyarticular JIA is an antigen-driven lymphocyte-mediated autoimmune disease with abnormality in the adaptive immune system. Cartilage-derived auto-antigens activate autoreactive T cells including Th1 and Th17 cells with production of pro-inflammatory cytokines IFN-γ and IL-17. On the other hand, the inhibition of regulatory T (Treg) cells including natural Foxp3(+) Treg and self-heat shock protein-induced Treg cells with decreased anti-inflammatory cytokine IL-10 results in the loss of immune tolerance. Imbalance between autoreactive Th1/Th17 and Treg cells leads to the failure of T cell tolerance to self-antigens, which contributes to the synovial inflammation of oligo/polyarticular JIA. By contrast, systemic JIA is an autoinflammatory disease with abnormality in the innate immune system. A loss of control of the alternative secretory pathway leading to aberrant activation of phagocytes including monocytes, macrophages and neutrophils seems to be involved in the release of pro-inflammatory cytokines IL-1, IL-6, IL-18 and pro-inflammatory S100-proteins, which contribute to the multisystem inflammation of systemic JIA. Markedly distinct pathogenesis of oligo/polyarticular JIA and systemic JIA implies that they might need different treatment strategies.