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Abstract
Autoantibodies to complement are associated with various diseases. Anti-C1q antibodies are present in all patients with hypocomplementemic urticarial vasculitis, but also with varying prevalence in other conditions. Anti-C1q may interfere with the clearance of apoptotic cells, so influencing induction and expression of autoimmunity. The aim of this work is to study the relation between anti-C1q antibodies and systemic lupus erythematosus (SLE) and its manifestations including renal affection. The presence and levels of anti-C1q antibodies were investigated using enzyme-linked immunosorbent assay technique. The study included 70 Egyptian patients suffering from SLE and 18 healthy controls. They were 65 females and five males. Their age ranged from 12 to 48.5 years with a mean value of 27.4 ± 8.4. Anti-C1q antibodies were statistically significantly elevated in cases compared with controls being positive in 37.2% (mean 18.3 ± 27.1) in patients versus 11.1% (mean value 4.1 ± 3.5) in controls (P = 0. 03). Anti-C1q antibody-positive patients (n = 226) had significantly higher SLE Disease Activity Index (SLEDAI) (16.1 ± 9.9) compared to negative patients (n = 44) (SLEDAI = 8.1 ± 7.7) P = 0.000. Regarding renal affection, the presence of anti-C1q-positive antibodies was associated with proteinuria, P = 0.002. In conclusion, anti-C1q was more common in patients with SLE and disease activity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies.
Introduction 
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the occurrence of autoantibodies, resulting in a broad spectrum of immunological and clinical manifestations. Among the severe manifes-tations of SLE, renal involvement is the most frequent and in its most aggressive forms, can lead to renal failure. Major pathogenic hypothesis is that SLE involves defective renal clearance of immune complexes.[1] Among immunological parameters, consumption of early components of classical complement pathway, such as C1q and C4, is strongly associated with SLE.[2] C1q is the first component of the classical complement pathway playing an important role in the clearance of immune complexes from tissues and apoptotic cell debris.[3],[4],[5] Hereditary deficiency of C1q is the strongest genetic risk factor for the development of SLE, about 90% of patients with homozygous C1q deficiency developing SLE or lupus-like syndromes. However, this genetic deficiency is rare. Instead, SLE patients often have secondary C1q deficiency caused by the presence of anti-C1q antibody.[6],[7],[8] It has been shown that anti-C1q antibody might be a predictor of proliferative lupus nephritis (LN) and is more closely correlated with renal disease activity than other autoantibodies like anti-double stranded DNA (anti-dsDNA).[6],[9] The pathologic mechanism of anti-C1q in lupus suggests that additional binding of anti-C1q to glomerular deposits of C1q alters the function and/or exacerbates the activation of the complement cascade. Such an interference of anti-C1q with the complement cascade or even complement activation might lead to a critical aggravation of the glomerular pathology leading to proliferative forms of LN.[10] Thus, the objective of the current study was to evaluate the role of anti-C1q antibodies in Egyptian SLE patients and to assess the correlation between these antibodies and disease activity especially renal activity.
Patients and Methods Seventy Egyptian patients suffering from SLE diagnosed at the Department of Rheumatology, Faculty of Medicine, Cairo University, were selected with 18 age-matched normal Egyptians as a control group.
Inclusion criteria
SLE patients older than 18 years andPatients suffering from SLE who fulfilled four or more criteria (at least one clinical and one laboratory criterion).Exclusion criteria
Patients with other systemic autoimmune diseasesPatients with urinary tract infection (≥100000 colony-forming units in urine culture)LN patients undergoing hemodialysis or those with a history of renal transplan-tation.All patients were subjected to careful history taking, full clinical examination, and routine laboratory investigations including complete blood count, serum creatinine, albumin, erythrocyte sedimentation rate (ESR) in 1st h, in addition to anti-dsDNA, and complements (C3, N: 3.7–10.5 μg/mL; C4, N: 2.4–7 μg/mL). Complete urine analysis for hematuria, pyuria, proteinuria, urinary casts. All patients fulfilled the 1997 American College of Rheumatology revised criteria for SLE.[11] The disease activity was assessed by the SLE Disease Activity Index (SLEDAI). Patients were considered active if SLEDAI score was 8 or more and inactive if SLEDAI score was less than 8. Sera from SLE patients and controls were obtained from peripheral blood and stored at –20°C until use.
Detection of anti-Clq antibodies using enzyme-linked immunosorbent assay
Anti-C1q antibodies were measured using enzyme-linked immunosorbent assay (ELISA) kits (Orgentec Diagnostika GmbH, Mainz, Germany) on the automatic ELISA reader Alegria® (Orgentec Diagnostika GmbH, Mainz, Germany) according to the manufacturer’s instructions. Positivity cutoffs were set at ≥10U/mL for anti-C1q antibodies, in compliance with the manufacturer’s instructions.
Ethical approval was obtained from the local authority of the Faculty of Medicine. An informed consent form was prepared in Arabic language to be read by the participating patients or to be read out to them if they were illiterate and then to be signed. This study was carried out during the period from January 2016 to May 2016.
Confidentiality
The participating patients would not be named in any publications from the trials.
Statistical Analysis The statistical analyses were carried out using software Statistical Package for the Social Sciences (SPSS) for Windows version 16.0 (SPSS Inc., Chicago, Ill, USA). The association between qualitative variables was evaluated by a Chi-squared test, and the quantitative variables were compared by t-test or Mann-Whitney U test. Data are presented in the format of mean ± standard, and the significance level was set at a P = 0.05.
Results This study included 70 SLE patients. Their mean age was 27.3 ± 8.4 years while their mean disease duration was 4.5 ± 4.4 years. Their main manifestations included arthritis found in 82.9%, malar rash in 57.1% followed by mucosal ulcers in 52.9% of patients. The mean value of SLEDAI was 11.1 ± 9.3 [Table 1]. Anti-C1q antibodies level ranged from 0.9 to 123.04 with a mean value of 18.3 ± 27.1. SLE patients were found positive for anti-C1q antibodies in 26 (37.1%) patients which was statistically significantly higher in patients compared to controls having only two positives (11.1%) for anti-C1q antibodies with P = 0.03. Comparison between anti-C1q-positive and anti-C1q-negative cases is shown in [Table 2]. Patients positive for anti-C1q antibodies were statistically having higher ESR levels, lower serum complement levels (C3 and C4), lower serum albumin levels and higher mean SLEDAI score (P = 0.008, 0.02, and 0.00, respectively). The presence of anti-C1q positive was associated with proteinuria, P = 0.002. There was a positive correlation between the titers of C1q antibodies and the SLEDAI score (r = 0.35; P = 0.002). There was significantly longer disease duration in negative cases (5.9 ± 4.8) compared to positive (2.05 ± 2.15) cases (P = 0.0003). Otherwise, no statistically significant association could be found regarding other parameters [Table 2]. Red cell casts were found in 29 (41.4%) SLE patients. Among them, nine (34.6%) were positive for anti-C1q antibodies and 20 were negative.
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Table 2: Comparison between anti-Clq-positive and anti-Clq-negative systemic lupus erythematosus. Discussion SLE is a prototypical autoimmune disease characterized by a variety of autoantibodies.[12] The pathologic events in SLE are mediated by the formation of immune complexes, activation of the complement cascade, and engagement of cellular Fc and complement receptors.[13] These autoantibodies and the consecutive formation of immune complexes apparently constitute the major pathophysiological force of lupus disease, ultimately inflicting injury on a variety of organ systems.[14] We investigated the anti-C1q antibodies in Egyptian SLE patients to evaluate their clinical significance. In this study, a prevalence of 26/70 (37.1%) of positive anti-C1q antibodies was found in Egyptian SLE patients. This agreed with the study of Sinico et al, who found anti-C1q antibodies in 27/61 (44%) SLE patients.[15] We found an association of anti-C1q antibodies with proteinuria and was statistically significant (P = 0.02), which agrees with Akhter et al[16] who found that anti-C1q had the highest association with proteinuria (P = 0. 079). Our results agree with Orbai et al.[17] who also found an association between anti-C1q antibodies and proteinuria and red cell casts in SLE patients. No association between anti-DNA antibodies and anti-C1q antibodies was found in our study which agrees with Moura et al[18] who found that the presence of anti-C1q antibodies was associated with proteinuria (P = 0.028) but not with other laboratory or clinical features, such as anti-nucleosome or anti-dsDNA antibodies, hematuria, urinary casts or renal failure, leukopenia, pericarditis, pleuritis, malar rash, seizures, and psychosis but disagree with Braun et al study who found significant correlation between the two antibodies.[19] An indirect evidence for the role of these antibodies in the pathogenesis of LN was observed be Chen et al, who found higher titers of anti-Clq in patients with LN and C1q deposition in kidney tissue.[20] An association between positive anti-C1q and SLEDA score was found (r = 0.35, P = 0.0002). This agrees with Soliman et al who found anti-C1q autoantibodies as a marker of disease activity in Egyptian lupus patients.[21] Also, Zhang et al[22] found that anti-C1q antibody levels were positively correlated with levels of SLEDAI scores (P <0.05). An association between hypocomplementemia and anti-C1q antibodies was found in our study which agrees with Katsumata et al who found a strong correlation between the occurrence of these autoantibodies and hypocomplementemia.[23] Our results were not compatible with Bernstein et al[24] and Oelzner et al[25] who found a non-significant difference in levels of anti-C1q antibodies in the SLE group between LN patients and non-LN patients. This discrepancy with previously published results can be explained by different testing platforms used, differences in patient populations, or it might be possible that some patients with LN no longer had an active disease at the time of blood sampling. We did not have flare data, treatment data, or repeat anti-C1q antibody levels, because of the cross-sectional nature of this study. Therefore, any temporal relationship of anti-C1q antibody levels to flares of LN or change in treatment could not be assessed. Our recommendations include inclusion of a larger sample size in the following studies and studying the relationship of anti-C1q levels with histopathological changes in LN by means of kidney biopsy.
In conclusion, we found a higher level of anti-C1q in Egyptian SLE patients and correlated with SLEDAI score and proteinuria, and hence can be used as a surrogate marker for SLE activity and renal involvement.
Conflicts of interest: None declared.
References 
Correspondence Address:
Mohamed A Marie
Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.367827
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