Clinical significance of anti-CCP antibodies in rheumatoid arthritis

A number of novel autoantibodies have been recently described in rheumatoid arthritis (RA), and their clinical significance and possible pathogenic roles have been discussed. In particular, new autoantibodies to citrullinated proteins such as filaggrin and its circular form (cyclic citrullinated peptide: CCP) are especially noteworthy because of their high sensitivity and high specificity. There are many studies that anti-CCP antibodies may serve as a powerful serologic marker for early diagnosis of RA and prognostic prediction of joint destruction. Anti-citrullinated protein antibodies are locally produced in RA joints, and citrullinated proteins (most are fibrins) are localized in RA synovial tissue. This finding strongly suggests a possibility that local citrullination of intraarticular proteins might be the initial event leading to autoantibody production in RA. Genetic factors such as a gene polymorphism of the citrullinating enzyme, PADI, might be associated with the breakage of self-tolerance and induction of autoimmunity against citrullinated proteins.     

抗Sa抗体、抗环瓜氨酸肽抗体、葡萄糖6-磷酸异构酶抗原和类风湿因子联合检测对类风湿关节炎的诊断意义

目的 探讨抗Sa抗体、抗环瓜氨酸肽(CCP)抗体、葡萄糖6-磷酸异构酶(GPI)抗原及类风湿因子(RF)联合检测对类风湿关节炎(RA)诊断的意义.方法 采用酶联免疫吸附试验(ELISA)检测抗Sa抗体、抗CCP抗体及RF亚型RF-IgA、RF-IgG、RF-IgM,免疫比浊法检测RF.结果 抗Sa抗体、抗CCP抗体、GPI抗原、RF对RA诊断的特异性和敏感性分别为95.69％和59.79％、98.28％和90.72％、76.14％和78.35％、67.24％和91.75％.RF-IgA、RF-IgG、RF-IgM对于RA诊断的特异性和敏感性分别为89.66％和58.76％、90.52％和68.04％、79.31％和79.38％.两项指标联合检测对RA诊断的特异性和敏感性为92.24％ ～ 100.00％和47.42％～86.60％;3项指标联合检测对RA诊断的特异性和敏感性为99.14％～100％和46.39％～71.13％;4项指标联合检测对RA诊断的特异性和敏感性为100.00％和46.39％.抗Sa抗体阳性组患者C反应蛋白水平高于阴性组(P＜0.05).结论 两项及两项以上指标联合检测可以显著提高RA诊断的特异性,有利于RA的早期诊断及治疗.     

Actinobaculum schaalii pyelonephritis in a kidney allograft recipient

We present a case of a 64-year-old man, a kidney transplant recipient with acute pyelonephritis and acute graft deterioration. He was diagnosed with Actinobaculum schaalii infection in urine cultures. He was treated with antibiotics for 3 weeks and recovered well. The case describes an unusual pathogenic infection in a kidney transplant patient.     

Genetic polymorphism of rs9277535 in HLA-DP associated with rheumatoid arthritis and anti-CCP production in a Chinese population

HLA-II molecules are critical in triggering human immune response, especially in activating CD4+ T cells. HLA-DP, belonging to HLA-II molecules, draws increasing attention for its role in presentation of viral antigen and autoantigen to T cells. Researches reported single nucleotide polymorphism (SNP) of HLA-DP associated with HBV infection and autoimmune diseases such as SLE. However, little is known about the relationship between HLA-DP and rheumatoid arthritis (RA). Rs9277535 is located in 3′ UTR region of HLA-DPB1, a subunit of HLA-DP, and was reported to affect HLA-DP mRNA expression. In the present study, we explored the relationship between gene polymorphism of rs9277535 in HLA-DPB1 and RA susceptibility and progression. Samples from 254 patients with RA and 391 age- and sex-matched healthy controls were collected and genotyped by a polymerase chain reaction-high-resolution melting (PCR-HRM) assay. Serological tests (anti-CCP, rheumatoid factor, C-reactive protein, anti-keratin antibody) were detected by laboratory assays. Strong association was observed between SNP rs9277535 in HLA-DP and RA susceptibility (allele frequency distribution: OR?=?1.409, 95%CI?=?1.121–1.773, P?=?0.004). Further validation was provided by disease model analysis (recessive model: OR?=?1.889, 95%CI?=?1.194–2.990, P?=?0.008; dominant model: OR?=?1.464, 95%CI?=?1.050–2.041, P?=?0.025; additive model: OR?=?2.208, 95%CI?=?1.335–3.652, P?=?0.003). Allele A was correlated to increased risk of RA. Serological test results demonstrated patients carrying allele A of rs9277535 had elevated serum anti-CCP antibody level. The present study provided evidence that HLA-DP gene polymorphism associated with RA susceptibility. Allele A of rs9277535 in HLA-DP correlated to increased risk of RA and elevated serum anti-CCP level.     

Lack of beneficial effect of zinc sulphate in rheumatoid arthritis

Twenty-two patients with severe long-standing rheumatoid arthritis were treated with oral zinc sulphate in a prospective long-term open trial. Six patients had (only subjective) improvement during the first 6 months of treatment, but all deteriorated subsequently. The remaining 16 deteriorated or did not improve and these patients expressed a wish to stop taking the drug after a mean period of 5 months. In the whole group of 22 patients, neither the number of affected joints, the ARA grading, nor functional classification changed significantly, nor did ESR, haemoglobin, haematocrit, or platelet count. The unpleasant taste and nausea caused by zinc sulphate was the main side effect. Our study confirms that ZnSO4 has no long-lasting beneficial effect for patients severely affected with rheumatoid arthritis.     

Lack of effect of tranexamic acid on rheumatoid arthritis

In a double-blind controlled study on 45 rheumatoid arthritis patients, no effect of tranexamic acid (Cyklocapron, 4.5 g per day for 6 weeks) was found in terms of subjective or objective parameters of disease activity. Tranexamic acid did not reduce complement activation, measured by plasma concentrations of the complement C3 split product C3d. Immune complex concentrations in serum were also unaffected. We conclude that plasmin inhibitors do not reduce immune complex mediated complement activation, and they should not be used for treatment of rheumatoid arthritis.     

The diagnostic utility of the anti-CCP antibody test is no better than rheumatoid factor in South Africans with early rheumatoid arthritis

To establish the diagnostic utility of the anti-cyclic-citrullinated peptide antibody (aCCP) test in Black South Africans with early rheumatoid arthritis (RA). A cross-sectional study comparing the rheumatoid factor (RF) and aCCP status in RA patients and a control group consisting of healthy subjects, and patients with systemic lupus erythematosus (SLE) and scleroderma. The sensitivity, specificity, positive (PPV) and negative predictive values of the aCCP test alone were 82.5%, 84.9%, 87.6% and 79% versus 81.7%, 90.7%, 92.5% and 78% for RF alone. The best specificity (95.3) and PPV (95.8%) was observed when both aCCP and RF tests were positive. Patients with erosive disease had a significantly higher mean RF titre compared with those with non-erosive disease (p = 0.007). There was a trend towards an association of smoking (OR = 4.1, 95% CI = 0.9–18.6) and functional disability (p = 0.07) with RF-positive status. No similar clinical associations were observed with aCCP. Almost a third of SLE patients were aCCP positive. Despite the best specificity and PPV observed when both the aCCP and RF tests were positive, our findings suggest that testing for aCCP is only cost-effective in the RF-negative patient in whom there is a strong clinical suspicion of RA.     

The association of anti-CCP antibodies with disease activity in rheumatoid arthritis

Antibodies to citrullinated proteins have been described in patients with rheumatoid arthritis (RA) and these appear to be the most specific markers of the disease. Our objective was to determine the frequency of antibodies to cyclic citrullinated peptides (CCPs) in patients with RA and the association of anti-CCP antibodies with disease activity, radiological erosions and HLA DR genotype. Forty patients with RA and 38 patients with fibromyalgia were included in this study. Serum samples were collected from both patient groups with RA and fibromyalgia. Anti-CCP was measured by the corresponding enzyme-linked immunosorbent assay. Additionally, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), disease activity score (DAS), visual analog scala (VAS), HLA genotype and radiographic information were determined in patients with RA. The rate of sensitivity and specificity of anti-CCP reactivity for the diagnosis RA were measured (sensitivity 50%, specificity 100%). There is no significant difference between anti-CCP (+) and anti-CCP (-) RA patients for DAS28, VAS, ESR, CRP, disease duration, HLA genotype, and radiological assessment of hand. However, there was a significant difference between anti-CCP (+) and anti-CCP (-) RA patients for RF and the radiological assessment of left and right wrists (respectively, P < 0.05, P = 0.04, P = 0.01). There was no significant correlation between anti-CCP antibody and ESR, CRP, VAS, DAS 28 or radiological assessment. A small but significant correlation was found between RF and anti-CCP antibody (P = 0.02, r = 0.35).     

类风湿关节炎患者抗环瓜氨酸抗体、HLA—DR4基因与其临床特征的关系

目的 探讨抗环胍氨酸（CCP）抗体、人类白细胞抗原HLA-DR4基因与进展性类风湿关节炎（RA）临床特征的关系.方法 记录73例类风湿关节患者的临床资料和实验室检查结果,并采用细胞毒法检测全部病例的HLA-DR4基因携带情况,比较HLA-DR4阳性组与阴性组的临床表现、实验室指标、X线表现及关节功能分级.结果 HLA-DR4阳性者27例,基因频率为37%.HLA-DR4阳性组关节肿胀指数、疼痛指数较高,晨僵持续时间较长,关节功能分级为Ⅲ～Ⅳ级的比例较高,出现骨质破坏比例也较高,抗CCP抗体、类风湿因子、血沉、C反应蛋白值均高于阴性组.结论 HLA-DR4和抗CCP抗体阳性的RA患者与HLA-DR4阴性组的RA患者比较炎症活动严重,且进展较快,应积极治疗.     

抗Sa抗体的检测及其临床意义

目的　了解抗Sa抗体的临床意义。方法　从新鲜人胎盘中提取Sa抗原 ,应用免疫印迹法检测类风湿关节炎 (RA)及其他风湿病患者血清的抗Sa抗体 ,结合临床资料进行分析。结果　 192例RA中抗Sa抗体阳性 6 5例 ,对RA诊断的敏感性为 33 9% ,特异性为 96 9%。其中同时出现相对分子量为 5 0 0 0 0、5 5 0 0 0两条带的 15例 (2 3 1% ) ,其医师和患者对病情活动性的评价、患者对关节痛的评价及C反应蛋白 (CRP)增高与单独出现 5 0 0 0 0条带者相比 ,均显著增高。 31例早期RA抗Sa抗体阳性率为 32 3% ,9例经随访确诊RA者 4例抗Sa抗体阳性 ;6 3例RF阴性RA中抗Sa抗体阳性率为 2 7%。抗Sa抗体阳性组以小关节起病为主 ,且RF滴度明显较阴性组高。结论　抗Sa抗体有助于早期RA和RF阴性RA诊断 ,同时出现 5 0 0 0 0、5 5 0 0 0两条带可能与病情活动有关。     

Diagnostic utility of the Elecsys anti-CCP assay in patients with rheumatoid arthritis

Abstract

Objective. The automatic anti-cyclic citrullinated peptide (anti-CCP) antibodies assay offered great advantages over traditional methods in terms of improved precision, reliability, technical simplicity, short turnaround time and high-speed throughput. In this study, we evaluated the main technical performance and diagnostic accuracy of the first automatic anti-CCP assay approved in China.

Methods. The study comprised 106 rheumatoid arthritis (RA) patients, 203 non-RA rheumatic disease controls and 46 healthy persons. Anti-CCP, rheumatoid factor (RF), α₁-acid glycoprotein, C-reactive protein and erythrocyte sedimentation rate were measured and compared. The precision, reference intervals for Chinese population and cut-off value for RA diagnosis, as well as the suitable diluent for anti-CCP were assessed. The positive rate and score of anti-CCP were compared with RF and acute-phase reactants, according to the new RA criteria.

Results. Within- and between-run imprecision, expressed as the coefficient of variation, were 0.47–1.36% and 1.15–2.63%, respectively. Upper 95% reference limit of anti-CCP in healthy Chinese was 8.8 U/mL. The area under curve of the receiver operating characteristic(ROC) for anti-CCP and RF were 0.882 (95% CI 0.833–0.930) and 0.844 (95% CI 0.792–0.897), respectively. Based on the cut-off value set by ROC, compared to RF, anti-CCP had higher sensitivity (96.8% vs. 78.3%) and specificity (90.9% vs. 70.7%). With 17 U/mL set as the optimal cut-off for anti-CCP, the total positivity of anti-CCP was comparable to that of RF (76.4% vs. 75.5%), but the high-positivity rate of anti-CCP was significantly higher (74.5% vs. 62.3%, p < 0.005).

Conclusions. Our results confirm anti-CCP as a more sensitive and specific marker than RF for the diagnosis of RA. The diagnostic performance of the Elecsys anti-CCP assay makes it a useful adjunct to clinical practice in the Chinese population.     

Progressive outer retinal necrosis in immunocompromised kidney allograft recipient

Ocular complications in patients who underwent renal transplantation are attributed to side effects of the immunosuppressive regimen. Progressive outer retinal necrosis (PORN) syndrome is a clinical variant of necrotizing herpetic retinopathy and it occurs almost exclusively in patients with acquired immunodeficiency syndrome. We present a case of a human immunodeficiency virus‐negative patient who underwent renal transplant and, after a few years, developed bilateral PORN associated with viral infections. Varicella zoster virus (VZV) and BK virus were identified by polymerase chain reaction from the vitreous fluid. It is unclear which of the viruses identified had the dominant role in the pathogenesis of PORN and other organ damage, or whether their actions were synergistic. Adequate antiviral immune surveillance, as well as pre‐transplant vaccination against VZV, may reduce the incidence of VZV infection and its complications.     

老年类风湿关节炎患者抗角蛋白抗体检测意义

目的：了解抗角蛋白抗体（AKA）对老年类风湿关节炎（EORA）的诊断意义。方法：以Wistar大鼠中1／3食管组织冰冻切片为底物，采用间接免疫荧光光检测51例EORA及139例对照组的血清AKA，记录同期临床及实验室指标。结果：AKA对EORA诊断敏感性为31．4％，特异性为98．6％，早期EORA患者AKA阳性率28．6％，AKA阳性组IgM、血沉（ESR）较阴性组高；医生及患者对病情活动性评分、Sharp评分有增高趋势。16例AKA阳性EORA中，类风湿因子（RF）、抗核周因子（APF）、抗Sa抗体阳性数分别为11、15例和4例，AKA和APF相关。结论：AKA有助于EORA诊断及早期诊断，是病情活动性及严重性指标。     

Monoclonal antibody therapy in rheumatoid arthritis

Monoclonal antibodies bind to their targets with high specificity and therefore have excellent potential as therapeutic agents. Biotechnological advances have allowed the production of large quantities of engineered monoclonal antibodies for therapeutic use. Recent research in rheumatoid arthritis has identified important mediators of synovitis. Monoclonal antibodies targeting these have been tested in clinical trials over the last decade. Anti-cytokine therapies, in particular anti-tumour necrosis factor alpha monoclonal antibodies, suppressed inflammation and produced rapid symptomatic improvement. Anti-lymphocyte monoclonal antibodies produced long- lasting disease suppression in animal models of rheumatoid arthritis. The use of depleting anti-lymphocyte monoclonal antibodies in rheumatoid arthritis had been disappointing as they did not penetrate the synovial joint in sufficient quantity to suppress disease without producing severe and protracted peripheral blood lymphopenia. Consequently, their use in rheumatoid arthritis had been abandoned. In contrast, clinical trials of non-depleting anti-CD4 monoclonal antibodies in rheumatoid arthritis showed that they could suppress synovitis. However, it remains unclear whether they could lead to prolonged disease improvement.      

四种抗体联合检测在类风湿关节炎早期诊断中的应用价值

目的 探讨抗核周因子抗体(APF)、抗角蛋白抗体(AKA)、类风湿因子(RF)、抗环瓜氨酸肽抗体(抗-CCP抗体)联合检测在类风湿关节炎(RA)早期诊断中的临床应用价值。方法 对RA患者127例、非RA其他风湿病患者102例及正常对照组43例，采用速率散射免疫比浊法检测RF；酶联免疫吸附法定量检测抗-CCP抗体；免疫荧光法检测AKA、APF，并采用四格表法计算敏感度及特异性。结果RA组的RF、APF、AKA、抗-CCP抗体敏感度分别为65．4％、48．8％、32．3％、83．5％，特异性分别为73．5％、92．2％、93．1％、94．1％，同时出现三种抗体和四种抗体的特异性为99．0％、100％；非RA组无四种抗体同时出现的情况。结论 RF敏感性较高，但特异性较差；APF、AKA、抗-CCP抗体三种自身抗体对RA具有高度特异性，且在RA早期即可出现。四种抗体联合检测有助于提高RA的早期诊断率。