Diagnostic value of serum anti-C1q antibodies in patients with lupus nephritis: a meta-analysis

The autoantibodies against C1q (anti-C1q) have been reported in patients with systemic lupus erythematosus (SLE). In the past decade, though there were increasing studies suggesting it is relatively specific in lupus nephritis (LN), its overall diagnostic value in LN has not been evaluated. The meta-analysis was conducted to quantitatively evaluate the diagnostic accuracy of autoantibodies against C1q in patients with LN, and to provide more precise evidence of a correlation between anti-C1q antibodies and activity of LN. We searched Medline, Embase and Cochrane databases and contacted authors if necessary. A total of 25 studies including 2,502 patients with SLE and 1,317 with LN met our inclusion criteria for this meta-analysis. Among all 25 studies, 22 studies were available for comparison between SLE with and without LN, and 9 studies compared anti-C1q between patients with active and inactive LN. Summary receiver operating characteristic (SROC) curve was used to summarize comprehensive test performance. The QUADAS tool was used to assess the quality of the studies. For the diagnosis of LN, the pooled sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) of anti-C1q were 0.58 (0.56-0.61, 95% confidence interval [95% CI]), 0.75 (0.72-0.77, 95% CI), 2.60 (2.06-3.28, 95% CI), 0.51 (0.41-0.63, 95% CI), and 6.08 (3.91-9.47, 95% CI) respectively. The area under the SROC curve (AUC) was 0.7941. For comparison between active and inactive LN, the weighted sensitivity, specificity, PLR, NLR and DOR were 0.74 (0.68-0.79, 95% CI), 0.77 (0.71-0.82, 95% CI), 2.91 (1.83-4.65, 95% CI), 0.33 (0.19-0.56, 95% CI), and 10.56 (4.56-24.46, 95% CI) respectively. The AUC was 0.8378. In conclusion, this meta-analysis indicates that anti-C1q antibodies have relatively fair sensitivity and specificity in the diagnosis of LN, suggesting that the presence of anti-C1q antibodies may be a valuable adjunct for predicting LN and assessing renal activity.     

血清抗C1q抗体与狼疮肾炎活动性及病理改变的相关性

目的 探讨血清抗C1q抗体与狼疮肾炎(LN)肾组织病理改变的相关性,以及对LN的活动性的评价.方法 用酶联免疫吸附法(ELISA)检测活动期LN患者60例和非LN患者60例血清中的抗C1q抗体,分析这一抗体与LN肾组织病理改变、活动指数及其他实验室参数的相关性.结果 LN患者血清抗C1q抗体水平(89±26)U/ml较非LN患者(57±23)U/ml高(P＜0.01);60例LN患者有同期肾活检病理资料,按世界卫生组织(WHO)分型,Ⅱ型12例,Ⅲ型14例,Ⅳ型18例,Ⅴ型16例.经方差分析显示,各病理类型问抗C1q抗体水平差异有统计学意义,其中以Ⅳ型LN的抗C1q抗体水平显著高于其他病理类型(P＜0.01);C1q在肾组织的沉积与血清抗C1q抗体水平相关;血清抗C1q抗体水平与肾脏病变的活动指数(AI)及尿蛋白含量呈正相关(P＜0.01),与补体C3、C4水平呈负相关(P＜0.01);抗双链DNA(dsDNA)抗体阳性的SLE患者,血清抗C1q抗体水平高于抗dsDNA抗体阴性者(P＜0.01).结论 血清抗C1q抗体水平在一定程度上反映LN肾脏的病理改变,并与肾脏病变活动指数有相关性,检测血清抗C1q抗体对评价LN病情及指导治疗有临床实用价值.     

Predictive value of IgG autoantibodies against C1q for nephritis in systemic lupus erythematosus.

OBJECTIVES--Antibodies against C1q (C1qAb) have been demonstrated in the serum of patients with several immune complex diseases. Patients, particularly those with lupus nephritis, were found to have increased serum titres of IgG C1qAb in a cross-sectional analysis. In the present prospective study correlations were sought between serum titres of IgG C1qAb and clinical as well as laboratory parameters of disease activity in patients with systemic lupus erythematosus (SLE). METHODS--Titres of IgG C1qAb in the serum of 68 SLE patients were measured serially during a three year period. At the same time clinical and laboratory parameters of disease activity were assessed. RESULTS--Increased titres of IgG C1qAb were found in the serum of 56% of SLE patients during the study. Significant correlations were found between increased titres of IgG C1qAb and renal involvement. Clinical signs of renal involvement were found to be associated with significant increases of serum titres of IgG C1qAb in the six months preceding this appearance. Fifty per cent of the increases in serum titres of IgG C1qAb were followed by the development of renal involvement. Elevated serum titres of IgG C1qAb were especially related to proliferative forms of glomerulonephritis. Furthermore, significant correlations were found between serum titres of IgG C1qAb and serum levels of immune complexes, levels of complement components, and titres of antibodies to DNA. CONCLUSIONS--The results suggest that IgG C1qAb play a pathogenic role in the development of lupus nephritis and that serial measurement of serum titres of IgG C1qAb is useful in the management of SLE patients.     

Anti-C1q antibodies in nephritis: correlation between titres and renal disease activity and positive predictive value in systemic lupus erythematosus

OBJECTIVE: To investigate antibodies to complement 1q (anti-C1q) and investigate the correlation between anti-C1q titres and renal disease in systemic lupus erythematosus (SLE). METHODS: 151 SLE patients were studied. In patients with biopsy proven lupus nephritis (n = 77), activity of renal disease was categorised according to the BILAG renal score. Sera were tested for anti-C1q by enzyme immunoassay. Serum samples were randomly selected from 83 SLE patients who had no history of renal disease, and the positive and negative predictive value of the antibodies was studied. RESULTS: Patients with active lupus nephritis (BILAG A or B) had a higher prevalence of anti-C1q than those with no renal disease (74% v 32%; relative risk (RR) = 2.3 (95% confidence interval, 1.6 to 3.3)) (p<0.0001). There was no significant difference in anti-C1q prevalence between SLE without nephritis and SLE with non-active nephritis (BILAG C or D) (32% v 53%, p = 0.06) or between active and non-active nephritis (74% v 53%, p = 0.06). Patients with nephritis had higher anti-C1q levels than those without nephritis (36.0 U/ml (range 4.9 to 401.0) v 7.3 U/ml (4.9 to 401.0)) (p<0.001). Anti-C1q were found in 33 of 83 patients (39%) without history of renal disease. Nine of the 33 patients with anti-C1q developed lupus nephritis. The median renal disease-free interval was nine months. One patient with positive anti-C1q was diagnosed as having hypocomplementaemic urticarial vasculitis syndrome during follow up. CONCLUSIONS: Anti-C1q in SLE are associated with renal involvement. Monitoring anti-C1q and their titres in SLE patients could be important for predicting renal flares.     

Detection of anti-double and anti-single stranded DNA antibodies in chronic liver disease: Significance of anti-double stranded DNA antibody in autoimmune hepatitis

Anti-DNA antibodies were determined by an enzyme-linked immunosorbent assay in 116 patients with chronic liver disease consisting of 21 cases of autoimmune hepatitis (AIH), 17 of primary biliary cirrhosis (PBC), and 78 of non-autoimmune-type of chronic liver disease. The assay was also performed on 83 patients with collagen disease, as a control group. Anti-double stranded DNA antibody (anti-dsDNA) was detected in 10/21 (48%) of the AIH patients and in 3/17 (17%) of the PBC patients, but not in those with other liver diseases. In contrast, anti-single stranded DNA antibody (anti-ssDNA) was positive not only in AIH and PBC, but also in those with non-autoimmune-types of chronic liver disease. Follow-up liver histology disclosed that the 2 patients with AIH who were positive for anti-dsDNA developed liver cirrhosis, whereas the 4 patients who were negative for anti-dsDNA, and those who showed a disappearance of anti-dsDNA following corticosteroid therapy, improved from chronic active to chronic persistent hepatitis.     

A prospective study of anti-chromatin and anti-C1q autoantibodies in patients with proliferative lupus nephritis treated with cyclophosphamide pulses or azathioprine/methylprednisolone

OBJECTIVE: To study the prevalence and course of anti-chromatin (anti-nucleosome, anti-double-stranded (ds) DNA and anti-histone) and anti-C1q autoantibodies in patients with proliferative lupus nephritis (LN), treated in a randomised controlled trial with either cyclophosphamide or azathioprine plus methylprednisolone. METHODS: Autoantibody levels were measured and analysed in 52 patients with proliferative LN, during their first year of treatment. Levels in both treatment arms were compared and associations with clinical, serological and outcome parameters were studied. RESULTS: At study entry, prevalences for anti-nucleosome, anti-dsDNA, anti-histone and anti-C1q autoantibodies were 81%, 96%, 23% and 65%, respectively. Anti-chromatin autoantibodies correlated with each other, but not with anti-C1q levels. If patients were divided for their autoantibody titre at the start of treatment above or below the median, the only significant differences were higher SLE disease activity index with higher anti-nucleosome, and higher creatinine with higher anti-C1q autoantibodies. During the first year, a comparable rapid decline in the levels of anti-nucleosome, anti-dsDNA and anti-C1q autoantibodies was seen in both treatment arms. Anti-histone autoantibody levels were low and did not change. Renal flares were not preceded by rises in autoantibody titres. CONCLUSIONS: These results indicate that measurement of anti-chromatin and anti-C1q autoantibodies is useful for diagnosing LN, but not for monitoring disease course.     

Comparative study of anti-double stranded DNA detection by ELISA and Crithidia luciliae immunofluorescence

Two commercial enzyme-linked immunosorbent assays (ELISA) and two commercial Crithidia luciliae immunofluorescence tests (CLIF) were reevaluated as to the efficiency and degree of correlation of anti-double stranded DNA (anti-dsDNA) detection in systemic lupus erythematosus (SLE). The two ELISAs exhibited an overall agreement of 95% and significantly correlated with each other (r=0.91, p<0.001). They were comparable in sensitivity (64%, 61%) and had the same specificity (95%, 95%). The sensitivity of the two CLIFs was 39% and 29% with corresponding specificities of 100% and 97%, and an overall agreement with each other of 94%. The two ELISAs had comparable specificity to the CLIFs with good agreement (84%, 79%) while they had a much greater sensitivity than the CLIFs. These findings suggest that ELISA is a useful laboratory test for anti-dsDNA detection of SLE due to its simplicity, quantitative results, sensitivity, specificity and cost, as compared to CLIFs.     

Anti-dsDNA antibody subtypes and anti-C1q antibodies: toward a more reliable diagnosis and monitoring of systemic lupus erythematosus and lupus nephritis

The putative distinct diagnostic and pathogenic potential of aDNA-Ab subtypes, differing in their affinity or epitope specificity, was subject of several studies with controversial results. Comparing five assays, characterized by different reaction conditions and nature/source of dsDNA, we investigated the abovementioned problem in a retrospective study on 100 systemic lupus erythematosus (SLE) patients and 100 controls (other CTD, autoimmune hepatopathies). As demonstrated, only assay 3 (Farrzyme, TBS, UK) and 5 (Farr-RIA, Trinity Biotech, Ireland) are really suitable to detect primarily high avidity aDNA-Ab. Both were significantly linked to lupus nephritis (specificity 84%) and highly specific for SLE (95 and 96%). Thereby, assay 3 was found to be the first solid phase ELISA probably suitable to replace the Farr-RIA. Classical ELISAs (assay 1, Orgentec, Germany, and 2, Bindazyme, TBS, UK), detecting aDNA-Ab more or less independent from their avidity, or tests with only intermediate specificity for high avidity Ab (assay 4, ELIAdn, Sweden Diagnostics, Germany), were less specific for SLE (83, 79, 91%, respectively) and not associated with renal involvement (specificity 54-57%). At least in the patients studied here, obvious antigen-related differences could not be observed. With slight differences, all assays were suitable to monitor disease activity and therapy in SLE, agreeing with the ECLAM score in about 70-80% of cases. For lupus nephritis, aC1q-Ab are as specific as high avidity aDNA-Ab and capable to close a diagnostic gap in some cases. Thus, to enhance the specificity (up to 98%) and to consider the distinct diagnostic/pathogenic potential of aDNA-Ab subtypes in SLE, under routine clinical laboratory conditions it should be recommended to combine a sensitive screening test with a more specific second assay.     

抗核小体抗体与抗C1q抗体在狼疮肾炎血清的表达及其临床意义

目的探讨抗核小体抗体与抗C1q抗体在狼疮肾炎（lupus nephritis，LN）患者血清的表达及其临床意义。方法使用酶联免疫吸附试验（ELISA）对46例LN患者血清进行检测，并与31例无肾炎临床表现的SLE患者作对照。结果LN患者血清中抗核小体抗体与抗C1q抗体浓度及阳性率显著高于SLE对照组（P〈0．01）。抗双链DNA（dsDNA）抗体、抗Sm抗体、抗nRNP抗体、抗心磷脂（aCL）IgG抗体有较高的阳性率，与对照组相比差异有统计学意义（P〈0．05）。将抗核小体抗体、抗C1q抗体、抗dsDNA抗体、抗Sm抗体、抗nRNP抗体和aCLIgG抗体分别引入Logistic回归进行统计分析，结果显示入选的自变量包括抗核小体抗体、抗C1q抗体、抗dsDNA抗体（P〈0．05）。结论在LN患者中，存在着抗核小体抗体、抗C1q抗体的高表达。抗核小体抗体及抗C1q抗体在LN发病中起重要的作用。抗核小体抗体、抗C1q抗体、抗dsDNA抗体是反映SLE患者并发肾脏损害的重要指标，在LN诊断和判定其活动性方面有重要作用。     

血清C1q抗体水平与系统性红斑狼疮活动性和狼疮肾炎的关系

目的分析探讨血清C1q抗体水平与系统性红斑狼疮（SLE）活动性以及狼疮肾炎之间的关系。方法采用ELISA方法检测92例SLE患者C1q抗体水平。并与其他SLE活动性指标进行相关分析。结果SLE患者C1q抗体阳性率为67.4%。活动性狼疮组的C1q抗体阳性率及C1q抗体水平显著高于非活动性狼疮组（P〈0.001）。活动性狼疮肾炎组C1q抗体阳性率（P〈0.05）和C1q抗体水平（P〈0.01）显著高于非活动性狼疮肾炎组。联合抗dsDNA抗体检测,没有1例活动性狼疮肾炎患者的C1q抗体和抗dsDNA抗体同时阴性。结论血清C1q抗体与狼疮活动以及活动性狼疮肾炎关系密切,C1q抗体的检测有助于活动性狼疮的诊断,联合抗dsDNA抗体的检测是活动性狼疮肾炎的特异性检测指标。     

补体C1q及抗C1q抗体与系统性红斑狼疮及狼疮肾炎相关性的研究

目的 检测系统性红斑狼疮（SLE）患者血清补体C1q及抗C1q抗体（C1qAb）水平，比较血清C1q与C1qAb之间的相关性；分析血清C1q及C1qAb水平与SLE、狼疮肾炎（LN）以及SLE病情活动的相关性。方法 采用单向免疫扩散法（SRID）检测血清C1q，酶联免疫吸附法（ELISA）检测血清C1qAb。结果 SLE患者的血清C1q水平显著低于其他对照组，而血清C1qAb水平显著高于其他对照组。其中LN患者的血清C1q水平显著低于非LN的SLE患者、血清C1qAb水平显著高于非LN的SLE患者。SLE患者血清C1qAb与C1q之间呈显著负相关。病情活动期的SLE患者血清C1q水平显著低于稳定期患者；血清C1qAb水平显著高于稳定期患者。结论 血清C1q的降低及血清C1qAb的升高与SLE相关。血清C1qAb的升高，可能是导致血清C1q降低的主要原因之一。血清C1q、C1qAb水平与SLE患者肾脏损害显著相关。血清C1q、C1qAb水平与病情活动显著相关。     

Association between ongoing anti-C1q antibody production in peripheral blood and proliferative nephritis in patients with active systemic lupus erythematosus

The aim of this study was to compare ongoing production of anti-C1q antibodies (anti-C1q) in peripheral blood with serum anti-C1q levels in patients with systemic lupus erythematosus (SLE), especially in patients with nephritis. Using the ELISPOT technique for the detection of IgG and IgA anti-C1q production, 21 patients with active SLE were investigated. ELISAs for IgG and IgA anti-C1q were compared with the ELISPOT results. Six of the patients were found to have proliferative nephritis (WHO grade III/IV) confirmed by renal biopsy. High numbers of IgG anti-C1q spot-forming cells (SFC), defined as > 20/10(5) plated peripheral blood mononuclear cells (PBMC), were exclusively observed in patients with proliferative nephritis (P < 0.0001). Serum levels of IgG anti-C1q were significantly increased in patients with proliferative nephritis (P = 0.039). High ongoing IgG anti-C1q production was observed in all patients with proliferative nephritis, which may be a contributory factor in the pathogenesis of this disorder. The detection of IgG anti-C1q production may be valuable in the clinical investigation of patients with suspected SLE nephritis.      

系统性红斑狼疮患者C1q受体和C1q抗体的表达及其与发病相关性的研究

目的 检测系统性红斑狼疮（SEE）患者外周血单个核细胞C1qRp和gC1qR的表达及与C1q抗体、补体C1q水平的关系，并进一步探讨其在SLE发病中的意义。方法 用流式细胞计数法测定58例SLE和30名正常人外周血中性粒细胞、单核细胞、淋巴细胞的C1qRp和gc1qR的表达，同时测血清C1q抗体、C1q水平．并将其与C3、c4、抗核抗体（ANA）、抗dsDNA抗体、SLEDAI积分做相关性分析。结果 SLE患者外周血中性粒细胞、单核细胞的C1qRp表达为（7．2±2-3）％和（3．4±2．1）％，均较正常人[（10．6±2．1）％和（9．0±8．7）％]降低（P〈0．05），淋巴细胞不表达C1qRp，但可表达gC1qR。C1qRp在SLE活动期表达略低于稳定期，但差异无统计学意义。SLE患者的gC1qR表达略高于正常人．gC1qR在活动期高于稳定期，但差异无统计学意义。SLE患者血清C1q抗体水平（98±41）U／ml，明显高于正常，C1q为（0．13±0．08）dE，低于正常值。外周血单个核细胞的C1qRp表达与血清C1qAb水平（Pearsonr=-0．574，P〈0．05）、双链DNA（ds—DNA）抗体滴度呈负相关，与补体C1q（Pearsonr=0．673．P〈0．01）、C3、C4水平呈正相关。gc1qR与C1qAb和补体C1q无明显相关性。结论 SLE患者外周血中性粒细胞、单个核细胞C1qR的表达缺陷，导致SLE吞噬功能受损，凋亡细胞清除障碍，诱导产生自身抗体，在SLE的免疫发病机制中起重要的作用。     

Significance of enzyme linked immunosorbent assay (ELISA) for antibodies to double stranded and single stranded DNA in patients with lupus nephritis: correlation with severity of renal histology.

The correlation between renal histology and class specific (IgG and IgM) antibodies to double stranded DNA (dsDNA) and single stranded DNA (ssDNA) was studied by enzyme linked immunosorbent assay (ELISA) in 40 untreated patients with systemic lupus erythematosus (SLE). The levels of IgG antibodies to dsDNA were significantly higher in patients with World Health Organisation class IV nephritis than in those with class I, class II, or class III nephritis. IgG antibodies to ssDNA were higher in patients with class IV than in those with class II nephritis. IgG antibodies to dsDNA showed a close correlation with the histological activity score and the amount of electron dense deposit. IgG antibodies to ssDNA showed only a weak correlation with the renal histological activity score. IgM antibodies to dsDNA and IgM antibodies to ssDNA were not correlated with renal histological features. Patients with moderate to severe nephritis had a lower ratio of IgM antibodies to dsDNA to IgG antibodies to dsDNA than those with mild nephritis. These results indicate that the measurement of IgG antibodies to dsDNA is predictive in evaluating renal histological activity in patients with SLE.     

Anti-nucleosome antibodies in systemic lupus erythematosus patients: Relation to anti-double stranded deoxyribonucleic acid and disease activity

Aim of the work

To measure the level of anti-nucleosome (anti-NCS) antibodies in systemic lupus erythematosus (SLE) patients and to evaluate their relation with anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies and SLE disease activity.