Cut-off values of immunological tests to identify patients at high risk of severe lupus nephritis

Cut-off values for anti-dsDNA, anti-nucleosome and anti-C1q antibodies tests and for complement-mediated hemolytic activity (CH50) were explored to identify patients with high risk of developing severe lupus nephritis (LN). Forty-one patients with confirmed systemic lupus erythematosus (SLE) were identified; their levels for the three antibodies and complement had been measured on a same serum sample. These patients were classified based on the presence of renal involvem ent; sixteen had active proliferative LN. With the cut-off values accepted in the laboratory for SLE diagnosis (anti-dsDNA > 100 UI/ml, anti-nucleosome > 50 U/ ml or CH50 < 190 UCH50%) no significant differences were found between patients with and without LN. Anti-C1q > 40 U/ml showed a statistically significant association with LN and had 80% of specificity. Cut-off values for LN identified by Receiver Operating Characteristic curves (ROC) were higher for anti-dsDNA (> 455 IU/ml) and anti-nucleosome (>107 U/ml), lower for CH50 (< 150 UCH50%) and, for anti-C1q (> 41 U/ml) coincided with the cut-off values accepted for SLE. Anti-C1q > 134 U/ml had a 92% of specificity, 56% of sensibility and was associated with a fifteen-fold increased risk of LN. The simultaneous presence of anti-nucleosome > 107 U/ml and anti-C1q > 134 U/ml was associated with a 27-fold higher probability for LN. According to these results, the cut-off values used to detect SLE activity could be inadequate to identify patients at high risk of severe LN.

Se exploraron valores de corte para los ensayos de anti-ADNdc, anti-nucleosoma, anti-C1q y complemento hemolítico total (CH50) capaces de identificar los casos con mayor riesgo de nefritis lúpica (NL) grave. Se seleccionaron 41 pacientes ≥ 16 años con lupus eritematoso sistémico (LES) confirmado que tenían titulados los niveles de los tres anticuerpos y CH50, en una misma muestra de suero. Fueron clasificados según presencia de compromiso renal; 16 presentaron formas proliferativas de NL activa. Con los valores de corte aceptados por el laboratorio para el diagnóstico de LES (anti-ADNdc > 100 UI/ml, anti-nucleosoma > 50 U/ml o un CH50 < 190 UCH50%) no se encontraron diferencias significativas entre casos con y sin NL. Un anti-C1q > 40 U/ml tuvo una especificidad del 80% y mostró una asociación estadísticamente significativa con NL. Al aplicar curvas Receiver Operating Characteristic (ROC) para NL, se identificaron valores de corte más altos para anti-ADNdc (> 455 IU/ml) y anti-nucleosoma (> 107 U/ml), más bajo para CH50 (< 150 UCH50%) y para el anti-C1q (> 41 U/ml) coincidió con el aceptado para diagnóstico de LES. Un anti-C1q > 134 U/ml presentó una sensibilidad del 56%, una especificidad del 92% y se asoció con quince veces más riesgo de NL. La presencia simultánea de anti-C1q > 134 U/ml y anti-nucleosoma > 107 U/ml se asoció 27 veces más riesgo de NL. De acuerdo a estos resultados los valores de corte empleados para actividad en pacientes con LES podrían resultar inadecuados para identificar pacientes con mayor riesgo de NL grave.

Association between the presence of anti-c1q antibodies and active nephritis in patients with systemic lupus erythematosus

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). A retrospective analysis was carried out on a group of 24 patients with SLE to evaluate whether the presence of anti-C1q antibodies (anti-C1q) is related to renal involvement and to explore the behaviour of anti-C1q with respect to LN during a four-year follow-up period. A first serum sample stored at the serum bank, taken not more than three years after SLE diagnosis and one serum sample per year for the subsequent four years were used to detect anti-C1q. Lupus clinical manifestations and serological markers of activity corresponding to the date of each serum sample selected were collected from medical records. In the first serum sample, anti-C1q were found in 8 active SLE. LN was confirmed by histology in 5/8 patients who were positive for anti-C1q and in 1/16 patients who were negative for these autoantibodies (p = 0.0069). Three patients (3/8) had anti-C1q without renal involvement but with lupus skin manifestation. Anti-C1q levels decreased in 3/5 patients with LN who responded to treatment and remained higher in 2/5 patients who needed a new renal biopsy which showed severe renal disease. The 15 patients without severe kidney disease and anti-C1q negative at diagnosis did not develop LN and anti-C1q remained negative in the 4 years of follow up. Anti-C1q were found in SLE patients with active renal involvement or with lupus skin disease. The absence of anti-C1q seemed to be linked to low probabilities of renal involvement.

La nefritis lúpica (NL) es una complicación grave del Lupus Eritematoso Sistémico (LES). Se analizó retrospectivamente en 24 pacientes con LES si la presencia del anticuerpo anti-C1q (anti-C1q) se asociaba con NL y el comportamiento del anti-C1q respecto a la NL en un período de seguimiento de cuatro años. El anti-C1q se determinó en una primera muestra de suero no distante en más de tres años del diagnóstico de LES y en una muestra por año en los siguientes cuatro años. Se obtuvo información de las historias clínicas, sobre manifestaciones clínicas de LES y marcadores serológicos de actividad para las fechas de selección de cada suero. En la primera muestra de suero se detectó anti-C1q en 8 pacientes con LES activo. NL fue confirmada por histología en 5 de ellos y en uno de 16 pacientes con anti-C1q negativos (p = 0.0069); 3 de 8 pacientes fueron anti-C1q positivos sin NL y con lesiones en piel. Los niveles de anti-C1q disminuyeron en 3/5 pacientes con NL que respondieron al tratamiento y se mantuvieron aumentados en 2/5 que necesitaron una nueva biopsia, que evidenció compromiso renal grave. Los 15 pacientes sin enfermedad renal grave y con anti-C1q negativo al diagnóstico no desarrollaron NL y el anti-C1q se mantuvo negativo en los 4 años de seguimiento. El anti-C1q se asoció en pacientes con LES a NL activa o con compromiso en piel. La ausencia del anti-C1q parecería relacionarse a un menor riesgo de desarrollar nefropatía lúpica.

Anticorpos anti-C1q e sua correlação com atividade do lúpus eritematoso sistêmico / Anti-C1q antibodies and systemic lupus erythematosus activity

JUSTIFICATIVA E OBJETIVO: Anticorpos Anti-C1q têm sido fortemente associados a envolvimento renal por lúpus eritematoso sistêmico. A principal hipótese para explicar a patogênese dos anticorpos anti-C1q no lúpus eritematoso sistêmico é a de que a doença é exacerbada por um decréscimo na depuração de células apoptóticas. O objetivo deste estudo foi verificar a associação entre títulos séricos de anti-C1q em portadores de lúpus eritematoso sistêmico, quanto à atividade da doença e quanto às suas manifestações clínicas, com ênfase para manifestações renais. MÉTODOS: Estudo de corte transversal realizado com 62 pacientes com diagnóstico recente de lúpus eritematoso sistêmico, quanto à presença ou não de autoanticorpos anti-C1q no soro, no período de junho a dezembro de 2012. Os critérios clínicos utilizados para caracterizar nefrite lúpica foram: (1) anormalidades ao sumário de urina, como proteinúria de 24 horas >500mg/24 horas ou (2) cilindrúria (cilindros granulosos, hemáticos ou leucocitários), ou (3) aumento da creatinina sérica em relação à creatinina imediatamente anterior >50%. RESULTADOS: A amostra foi constituída predominantemente por mulheres jovens e afrodescendentes. Observou-se que os títulos de anti-C1q se associaram à atividade de lúpus eritematoso sistêmico de maneira geral, uma vez que a correlação de Sperman apresentou correlação moderada positiva entre o escore Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) e a titulação de anti-C1q sérico...

BACKGROUND AND OBJECTIVE: Anti-C1q antibodies have been strongly associated with renal involvement in systemic lupus erythematosus. The main hypothesis to explain the pathogenesis of anti-C1q antibodies in systemic lupus erythematosus is that the condition is exacerbated by a decrease in the clearance of apoptotic cells. This study aimed to assess the association between serum titers of anti-C1q with activity systemic lupus erythematosus and with its clinical manifestations, with emphasis on renal manifestations. METHODS: This was a cross-sectional study conducted on 62 patients with newly diagnosed systemic lupus erythematosus for the presence or absence of anti-C1q autoantibodies in serum, in the period June to December 2012. The clinical criterioa used to characterize lupus nephritis were: (1) presence of proteinuria 24 hours >500mg/24 hours, or (2) urinary casts (granular cylinders, hematic or leukocyte), or (3) increased serum creatinine >50% related to the basal levels. RESULTS: The sample was mainly constituted by young females and afrodescendent. We observed that the titers of anti-C1q were associated with the activity of systemic lupus erythematosus in general, since the Spearman correlation showed moderate positive correlation between the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and the titration of anti-C1q serum...

The role of apoptosis proteins and complement components in the etiopathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus is a prototypical autoimmune disease characterized by the deregulation of T and B cells, tissue infiltration by mononuclear cells, tissue damage and the production of autoantibodies. There is a consensus that accelerated apoptosis of circulating lymphocytes and/or impaired clearance of apoptotic bodies may increase the amount of nuclear antigens presented to T lymphocytes. This process is accompanied by autoimmune responses that can lead to the development of lupus. The dysfunction of apoptosis may be a direct consequence of alterations in proteins/genes such as Fas, Bcl-2 and C1q. Increased expression of Fas antigen could intensify the exposure of hidden antigens. The overexpression of Bcl-2 protein might inhibit the removal of auto-reactive cells, and the lack of C1q could impair the clearance of self-antigens. The complete knowledge of the role of apoptosis components in the etiopathogenesis of lupus could lead to the development of new therapies targeting the apoptotic threshold, which could result in a more specific and effective disease response compared to global immunosuppression. This review summarizes the role of each component of the apoptotic process in the pathogenesis of lupus.

Correlation between the renal C1q deposition and serum anti-C1q antibody: a potential role of anti-C1q antibody in lupus nephritis.

The anti-C1q antibody has been shown to be associated with lupus patients with renal involvement. We conducted a study to determine the relationship between the serum anti-C1q titer and the renal deposition of C1q. The serum anti-C1q was measured in 26 healthy controls and 47 systemic lupus erythematosus (SLE) patients who were divided into 2 groups as non-nephritis and nephritis SLE. We analyzed the relationship between the anti-C1q titers and SLE, renal C1q staining and the WHO classification for lupus nephritis. The result revealed that the serum anti-C1q was present in 50.8% of the SLE patients, that its levels in those with renal involvement were significantly higher than in the normal control group (61.540 +/- 87.720 U/ml vs 15.750 +/- 2.530 U/ml, p = 0.005). Besides, the serum anti-C1q levels were higher in the patients with lupus nephritis with C1q deposition in the kidney tissue (66.038 +/- 91.141 U/ml vs 16.652 +/- 3.097 U/ml, p < 0.01). There seems to be evidence supporting that the autoantibody anti-C1q might play a pathogenic role in lupus nephritis.

Anti-C1q antibody as a marker of disease activity in systemic lupus erythematosus.

The present study was conducted to examine the usefulness of anti-C1q antibody as a marker of disease activity in Indian patients with systemic lupus erythematosus (SLE). We standardized the assay for detection of IgG anti-C1q antibody using ELISA. The normal cut-off level was determined by testing 57 healthy, age and sex matched controls to be 53 units/m1 (mean +/- 2 SD). Patients with SEL (97 females and 13 males) were studied and the following parameters were obtained on all: SLE disease activity index (SLEDAI), anti-C1q, anti-ds DNA and C3. Correlations were tested between these parameters using Spearman's rank correlation coefficients. Anti-C1q was found positive in 66 (60%) patients while anti-ds DNA was found in 78 (71%). The positive predictive values of anti-C1q and anti-ds DNA for lupus nephritis were 59 and 61 per cent respectively. The titres of anti-C1q correlated positively with SLEDAI (P < 0.01) and anti-ds DNA (P < 0.01) and negatively with C3 levels (P < 0.001). No significant correlation was observed between anti-C1q positivity and any particular organ involvement. Similarly, no correlation was found between anti-C1q and proliferative lupus nephritis. Anti-C1q was found positive in 5 of 9 patients with moderate SLEDAI scores and negative for anti-ds DNA antibody. It is concluded that anti-C1q antibody can serve as a general marker for lupus activity, supplementing the currently used serum markers.

Edema crónico centrofacial con consumo del componente C1q del complemento / Centrofacial chronic edema with consumption of the component C1q of the complement

Se estudia un paciente de sexo masculino de 29 años, que padecía en el momento de la consulta edema de labios y párpados de un año y medio de evolución. Al confeccionar la historia clínica se determinó que los edemas se presentaban con reagudización, acompañados con úlceras de la mucosa yugal y fiebre de 40§C coincidente con las crisis. El edema de los párpados remitía casi en su totalidad con cada tratamiento esteroide, aunque no así el de labios. Los estudios de laboratorio mostraron anormalidades en la fracción C1q del complemento (0.3 mg ciento por ciento). El estudio histopatológico de un corte de labio halló infiltración mononuclear en el estroma, con disposición angiocéntrica. El infiltrado tenía células linfoides atípicas, que fueron positivas a la inmunomarcación con el anticuerpo monoclonal UCHL-1. Se diagnosticó linfoma T de presentación cutánea centrofacial. El caso se presenta por la interesante coexistencia en un individuo de un desorden linfoproliferativo con edema de labios inflamatorio crónico y edema de párpado recurrente por deficiencia adquirida del C1INH