Utility of anti-C1q and anti-nucleosome antibodies in systemic lupus erythematosus and lupus nephritis in southwestern Colombia / Utilidad de los anticuerpos anti-C1q y anti-nucleosomas en el lupus eritematoso sistémico y la nefritis lúpica en el suroccidente colombiano

ABSTRACT Introduction: Lupus nephritis (LN) is one of the most prevalent and severe complications of systemic lupus erythematosus (SLE), requiring reliable urine and serum biomarkers to evaluate it. Anti-nucleosome and anti-C1q antibodies are associated with LN in several geographic regions. Also, southwest Colombia has a heterogeneous ethnicity, which motivated the evaluation of the frequency and relationship of such markers with LN in this region. Methods: A cross-sectional study was conducted in a health centre in south-west Colombia in 84 patients diagnosed with SLE (57 without LN; 27 with LN) between 2016 and 2018. Demographic and clinical and laboratory features, including anti-dsDNA, complement, and anti-C1q and anti-nucleosome antibodies were compared in these patients. ELISA immunoassays were performed to measure the antibodies of interest in blood samples. Statistical analysis was carried out using STATA14 software (StataCorp, College Station, Texas, USA). Quantitative variables were summarised as means or medians and compared with Mann-Whitney or Two-sample t test. Categorical variables were shown as proportions, and compared with Chi-squared or Fisher's exact test. Correlation analysis between quantitative variables was calculated using Spearman's correlation. Results: Of all 84 patients, 27 patients had LN, of which 16 (59.2%) had a positive test for anti-nucleosome antibodies and 10 (37%) for anti-C1q antibodies. An association was found between anti-C1q and proliferative forms of LN and newly diagnosed LN. A correlation was found between anti-nucleosome and anti-C1q antibodies, and anti-dsDNA and low serum complement concentrations. Conclusion: Although both markers were found in variable percentages in SLE patients and seem not to be specific markers of LN in our population, anti-C1q was associated with proliferative forms of LN and de novo LN.

RESUMEN Introducción: La nefritis lúpica (NL), una de las complicaciones más frecuentes y graves del lupus eritematoso sistémico (LES), requiere biomarcadores confiables de orina y suero para su evaluación. Los anticuerpos anti-nucleosoma y anti-C1q se asocian con la NL en varias regiones geográficas. En el suroccidente colombiano se asienta una etnia heterogénea, lo que motivó la evaluación de la frecuencia y la relación de dichos marcadores con NL en dicha región. Métodos: Realizamos un estudio transversal en un centro de salud en el suroccidente de Colombia, con 84 pacientes diagnosticados con LES (57 sin NL; 27 con NL) entre los anos 2016 y 2018. Se compararon las características demográficas, clínicas y de laboratorio, incluidos los anticuerpos anti-dsDNA, complemento, anti-C1q y anti-nucleosomas entre estos pacientes. Se realizaron inmunoensayos ELISA para medir los anticuerpos de interés en muestras de sangre. El análisis estadístico se llevó a cabo con el software Stata v.14 (Stata-Corp, College Station, Texas, EE. UU.). Las variables cuantitativas se resumieron como medias o medianas y se compararon con la prueba t de Mann-Whitney o Two-sample t test; las variables categóricas se mostraron como proporciones y se compararon con Chi-cuadrado o con la prueba exacta de Fisher. Para el análisis de correlaciones entre variables cuantitativas se calculó el coeficiente de correlación de Spearman. Resultados: Entre los 84 pacientes, 27 presentaban LN, de los cuales 16 (59,2%) tuvieron una prueba positiva para anticuerpos anti-nucleosoma y 10 (37%) para anticuerpos anti-C1q. Se encontró una asociación entre anti-C1q y formas proliferativas de NL, así como formas recientemente diagnosticadas de NL. Hubo una correlación entre los anticuerpos anti-nucleosoma y anti-C1q y el anti-dsDNA y las bajas concentraciones de complemento sérico. Conclusión: Aunque los 2 marcadores se encontraron en porcentajes variables de pacientes con LES y no parecen ser marcadores específicos de NL en nuestra población, la presencia de anti-C1q se asoció con formas proliferativas de NL y NL de novo.

Association of anti-nuclesome and anti C1q antibodies with lupus nephritis in an Egyptian cohort of patients with systemic lupus erythematosus

Abstract Introduction: Anti-nucleosome and anti-C1q antibodies demonstrated an association with the development of glomerulonephritis in systemic lupus erythematosus (SLE). Some investigators have proposed that monitoring anti- C1q and anti-nucleosome antibodies might be valuable for making predictions about lupus nephritis (LN) and assessment of disease activity as a non-invasive biological marker of renal disease. Objectives: The current study was proposed to investigate the presence of anti-C1q and anti-nucleosome antibodies in the sera of Egyptian patients with SLE and their association with LN. Methods: Eighty patients with SLE were included. Patients were classified into, a LN group including 40 cases with active LN (based on the results of renal biopsy and renal SLEDAI≥4) and a non renal SLE group including 40 patients (with no clinical or laboratory evidence of renal involvement that were attributed in the past or present to SLE). They were subjected to full medical history taking, clinical examination, routine laboratory investigations, measurement of antinuclear antibody (ANA), anti-ds DNA, anti-C1q & anti-nucleosome antibodies. Results: Anti-C1q antibody showed a statistically significant association with the presence of vasculitis and nephritis while anti-nucleosome antibody didn't show a significant association with the presence of any clinical features. Double positivity of anti-nucleosome and anti-C1q antibodies showed a statistically significant association with the presence of vasculitis and photosensitivity, high ECLAM score, elevated ESR, low serum albumin and low C3 levels. Conclusion: Serum anti-C1q antibody has a significant association with LN while double positive antibodies have a significant association with vasculitis and low C3 levels in Egyptian patients with SLE.

Optimización del algoritmo diagnóstico de anticuerpos antinucleares / Optimization of the diagnostic algorithm of antinuclear antibodies

Introducción: La prueba de anticuerpos antinucleares es una poderosa herramienta en el diagnóstico de las enfermedades reumáticas. Los anticuerpos antinucleares se determinan en el laboratorio por un algoritmo o secuencia que se inicia con prueba de cribado y sigue con la identificación de las especificidades antinucleares más comunes. Pero, ¿cómo interpretar los resultados discordantes entre los dos niveles de estudio de anticuerpos antinucleares? Objetivo: Determinar las especificidades antinucleares menos frecuentes en pacientes positivos de cribado de ANA y negativos de las especificidades más comunes. Métodos: Estudio prospectivo de 88 pacientes consecutivos remitidos para la detección rutinaria de ANA con resultado positivo de cribado por ensayo inmuno-adsorbente ligado a enzima (ELISA) pero negativo de anticuerpos anti-ADN de doble cadena (dc, IgG) y anti-antígenos nucleares extraíbles comunes (ENAc). Las muestras séricas correspondientes fueron evaluadas por inmunofluorescencia indirecta sobre células de carcinoma epidermoide laríngeo humano (IFI-HEp-2) y por ELISA para la detección individual de ANA específicos. Resultados: La prueba de ANA por IFI/HEp-2 resultó positiva en 56/88 (63,6 por ciento) y las especificidades antinucleares se detectaron en 57/88 (64,8 por ciento) muestras, en el orden decreciente de Anti-Nucs: 16/88 (18,2 por ciento); anti-centrómero (CENP-B): 15/88 (17,0 por ciento); -histona: 15/88 (17 por ciento); -PM/Scl: 13/88 (14,8 por ciento); -ADNsc: 11/88 (12,5 por ciento) y -ENAc individuales: 8/88 (9,1 por ciento). La sensibilidad de la IFI-HEp-2 para las especificidades antinucleares fue de 0,83 (IC95 por ciento: 0,72-0,93). De los pacientes negativos de subserología (26/31), 83,9 por ciento no tenían antecedentes de enfermedad reumática asociada a ANA. Conclusiones: La mayoría de los pacientes con resultados discordantes entre el primer y segundo nivel de ANA fueron positivos de especificidades antinucleares menos comunes, pero de reconocido valor diagnóstico(AU)

Introduction: The antinuclear antibody test is a powerful tool for diagnosing rheumatic diseases. Antinuclear antibodies are determined in the laboratory by an algorithm or sequence that starts with a screening test and continues with the identification of the most common antinuclear specificities. But how to interpret the discordant results between the two levels of study of antinuclear antibodies? Objective: To determine the less frequent antinuclear specificities in positive patients of ANA screening and negative of the most common specificities. Methods: A prospective study was done on 88 consecutive patients referred for the routine ANA screening with a positive result of screening by enzyme-linked immunosorbent assay (ELISA) but negative for anti-double-stranded DNA (dc, IgG) and common extractable anti-nuclear antigens (ENAc). The corresponding serum samples were evaluated by indirect immunofluorescence on human laryngeal epidermoid carcinoma cells (IFI-HEp-2) and by ELISA for the individual detection of specific ANA. Results: The ANA test by IFI / HEp-2 was positive in 56/88 (63.6 percent) and the antinuclear specificities were detected in 57/88 (64.8 percent) samples, in decreasing Anti-Nucs order: 16/88 (18.2 percent); anti-centromere (CENP-B): 15/88 (17.0 percent); -histona: 15/88 (17 percent); -PM / Scl: 13/88 (14.8 percent); -ADNsc: 11/88 (12.5 percent) and -ENAc individual: 8/88 (9.1 percent). The sensitivity of IFI-HEp-2 for antinuclear specificities was 0.83 (95 percent CI: 0.72-0.93). No history of rheumatic disease associated with ANA was read in (26/31) 83.9 percent patients with negative subserology. Conclusions: The majority of patients with discordant results between the first and second level of ANA were positive of less common antinuclear specificities, but of recognized diagnostic value(AU)

Diagnostic value of anti-nucleosome antibody for juvenile systemic lupus erythematosus / 临床检验杂志

Objective To evaluate the diagnostic value of anti-nucleosome antibody for juvenile systemic lupus erythematosus (JSLE).Methods Fifty-four patients with JSLE,28 patients with non-JSLE and 26 healthy children were chosen in this study.antinuclear antibody(ANA),anti-nucleosome antibody (AnuA),anti-dsDNA antibody,anti-histone antibody (AHA) and anti-Sm antibody were detected by ELISA or western-blot method.The relevant clinical data were collected and analyzed.Results For diagnosis of JSLE,the sensitivity and specificity of AnuA was 77.78％ and 96.30％.The sensitivity of AnuA combined with ANA,anti-dsDNA and antiSm was higher than that of single detection.AnuA usually associated with fever,oral/nasal pharyngeal ulcer,lung damage,lymphocyte absolute value,urine protein and C3 level.Conclusion AnuA can be used as a serum marker for JSLE diagnosis.The detection of AnuA combined with anti-dsDNA and anti-Sm should be more helpful for diagnosis of JSLE.

Significance of anti-nucleosome antibody, anti-C1q antibody and anti-double stranded DNA antibody in diagnosis of lupus nephritis / 吉林大学学报(医学版)

Objective:To investigate the clinical and laboratory characteristics of lupus nephritis(LN) patients by detecting the anti-nucleosome antibodies, anti-C1q antibodies and anti-double stranded antibodies(anti-ds DNA), and to clarify the risk factors of LN in the patients with systemic lupus erythematosus(SLE),and the significance of three kinds of antibodies in diagnosis of LN.Methods:A total of 120 SLE patients were selected and divided into LN group(n=60) and non-LN group(n=60).The ANAS data of 120 patients were retrospectively analyzed,the levels of anti-C1q antibodies were measured.The clinical symptoms and laboratory data of the patients with positive anti-dsDNA,-nucleosome and-C1q antibodies (3-pos group)and negative three kinds of antibodies(non 3-pos group) were analyzed in LN group.Results:The positive rate of anti-C1q antibody of the patients in LN group (40.00%) was higher than that in non-LN group (21.67%) (χ2=4.728, P=0.03).The positive rate of anti-dsDNA antibody in LN group was 66.67%, and it was 46.67% in non-LN group;the positive rates of the patients had significant difference between two groups (χ2=4.887, P=0.027).The positive rate of anti-nucleosome antibody in LN group was 58.33%, and it was 40.00% in non-LN group;the positive rates of the patients had significant difference between two groups (χ2=4.034, P=0.045).The positive rates of U1-snRNP, SmD1 and other antibodies Jo-1, SSA/Ro60kD, SSA/Ro52kD, SSB, ScL-70, CENP-B,and P0 had no significant differences between two groups(P>0.05).The levels of C3 and C4 and hemoglobinin of the patients in 3-pos group were higher than those innon 3-pos group (P0.05).The clinical symptoms were not statistically significant in 3-pos and non 3-pos groups (P>0.05).Conclusion:The anti-nucleosome, anti-C1q and anti-dsDNA antibodies are the risk factors of SLE complicated with LN;the positive antibodies can improve the diagnostic rate of LN.The 3-pos patients have more severe damage in complements and blood system with higher renal disease activities.

Identificación de predictores serológicos de recaída en pacientes con lupus eritematoso sistémico: estudio prospectivo de 12 meses / Identification of relapse aerological predictors in patients with systemic lupus erythematous: a prospective study of 12 months

Introducción: las investigativos efectuadas no han tenido éxito en la búsqueda de biomarcadores serológicos o clínicos suficientemente confiables para predecir las recaídas en el lupus eritematoso sistémico (LES). Objetivo: definir el valor predictivo de las especificidades de anticuerpos antinucleares para la recaída del LES y de la nefritis lúpica. Métodos: estudio analítico, observacional, longitudinal y prospectivo en 120 pacientes adultos con LES inactivo (SLEDAI-2K ≤ 5 puntos). La presencia basal de siete especificidades antinucleares, C3 y C4 bajos se correlacionaron con la ocurrencia de recaída del LES (incrementos en la puntuación de SLEDAI-2K ≥ 4) y de la nefritis lúpica mediante análisis univariado. Las variables más valiosas fueron evaluadas adicionalmente como predictoras con un modelo de regresión logística multivariada para calcular los odds ratio (OR). Resultados: las recaídas del LES y de la nefritis lúpica se observaron en 51 (42,5 por ciento) y 29 (24,2 por ciento) de los pacientes, respectivamente. En el análisis multivariado emergieron como factores de riesgo para la recaída del LES la presencia de los anticuerpos anti-Nu (OR= 1523,0; p < 0,001) y los anti-DNAdc (OR= 12,1; p= 0,044) y de la nefritis lúpica, los anti-Nu (OR= 92,9; p< 0,001) y el C3 bajo (OR= 7,1; p= 0,007), La sub-representación de los anti-RNP resultó un factor de riesgo para la recaída del LES y de la nefritis lúpica (OR= 0,023; p= 0,009 y OR= 0,1; p= 0,025). Conclusiones: los pacientes con LES positivos de anticuerpos anti-Nu, anti-DNAdc o niveles bajos del C3 presentaron un riesgo mayor de recaída del LES y de la nefritis lúpica en los próximos 12 meses, lo que señala la necesidad de estrechar su monitoreo clínico(AU)

Introduction: the research carried out have not been successful in finding serological biomarkers or sufficiently reliable biomarkers for predicting relapse in systemic lupus erythematosus (SLE). Objective: setermine the predictive value of specific antinuclear antibodies for relapse of SLE and lupus nephritis. Methods: an analytical, observational, longitudinal and prospective study was carried out in 120 adult patients with inactive SLE (SLEDAI-2K ≤ 5 points). The baseline presence of seven antinuclear specificities, low C3 and C4 were correlated with the occurrence of SLE relapse (increases in score SLEDAI-2K ≥ 4) and lupus nephritis by univariate analysis. The most valuable variables were further evaluated as predictors a multivariate logistic regression model to calculate the odds ratio (OR). Results: SLE and lupus nephritis relapses were observed in 51 (42.5 percent) and 29 (24.2 percent) patients, respectively. The presence of anti-Nu (OR= 1523.0, P < 0.001) antibodies and anti-dsDNA (OR= 12.1; p = 0.044) and lupus nephritis, anti-Nu (OR= 92.9; p < 0.001) and low C3 (OR= 7.1; p= 0.007) emerged as risk factors for relapse of SLE in multivariate analysis. The underrepresentation of anti-RNP was a risk factor for relapse of SLE and lupus nephritis (OR = 0.023; p= 0.009; OR = 0.1; p= 0.025). Conclusions: SLE patients with positive anti-Nu, anti-dsDNA and low levels of C3 had a higher risk of relapse of SLE and lupus nephritis in the succeeding 12 months, signaling the need for close clinical monitoring(AU)

Autoanticuerpos como biomarcadores de actividad de la enfermedad del lupus eritematoso sistémico / Autoantibodies as biomarkers of disease activity in systemic lupus erythematosus

Hay una necesidad urgente de biomarcadores que permitan identificar y predecir las fases de actividad del lupus eritematoso sistémico (LES) para optimizar el manejo clínico de los pacientes. De la centena de autoanticuerpos presentes en los pacientes con LES muy pocos son candidatos para biomarcadores de actividad clínica de la enfermedad y ninguno se ha establecido como criterio independiente para la toma de decisiones clínicas. Identificar las recaídas del LES es más arte que ciencia. Recientemente se ha señalado que la correlación positiva entre los niveles de autoanticuerpos y la actividad del LES puede estar subvertida por la presencia de autoanticuerpos protectores que se oponen al daño hístico que producen los autoanticuerpos patogénicos. Los anticuerpos anti-nucleosoma, anti-DNA de doble cadena y anti-C1q están asociados a la actividad de la enfermedad evaluada por varios sistemas de puntuación internacionales como el SLEDAI, ECLAM y BILAG, mayormente en estudios transversales. Estos biomarcadores resultan prometedores para el seguimiento clínico de pacientes con LES, pero aún necesitan la validación de estudios controlados multicéntricos de gran escala. Se hizo esta revisión para resumir los retos del descubrimiento y validación de los autoanticuerpos biomarcadores de actividad del LES en el marco de la complejidad funcional de los autoanticuerpos...

There is an urgent need for biomarkers to identify and predict activity phases of systemic lupus erythematosus (SLE) to optimize the patients clinical management. Out of hundreds of autoantibodies present in SLE patients, very few are candidates for biomarkers of clinical disease activity and none has been established as an independent criterion for clinical decision making. Identifying relapse of SLE is more art than science. It has recently been suggested that the positive correlation between autoantibody levels and SLE activity may be subverted by the presence of protective autoantibodies opposed to tissue damage produced by pathogenic autoantibodies. The anti-nucleosome, anti-dsDNA and anti-C1q antibodies are associated with disease activity assessed by several international rating systems such as the SLEDAI, BILAG ECLAM and, partly in cross-sectional studies. These biomarkers are promising for clinical monitoring of SLE patients, but they still need the validation of multi-scale controlled studies. This review was to summarize the challenges of discovery and validation of biomarkers of autoantibodies in SLE activity within the functional complexity of the autoantibodies...

Anti-nucleosome antibodies as a disease marker in systemic lupus erythematosus and its correlation with disease activity and other autoantibodies.

Background: Detection of anti-nucleosome antibodies (anti-nuc) in patients with systemic lupus erythematosus (SLE) has been well established and it is claimed that their presence is associated with disease activity. Aims: The aim of this study is to evaluate the incidence of anti-nuc antibodies and to correlate them with disease activity and its association with other autoantibodies like anti-nuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), anti-histone antibodies (AHA), as well as autoantibodies to histone subfractions like H1, (H2A-H4) complex, H2B, and H3. Methods: This cross-sectional study included 100 SLE patients referred from the Rheumatology, Dermatology, and Nephrology Departments. SLE disease activity was evaluated by using SLE-Disease Activity Index (SLEDAI) score. A patient was defined as having active SLE when the SLEDAI score was more than 5.0. Fifty normal controls were also tested as a healthy control group. Anti-nuc antibodies, anti-dsDNA, and AHA were tested by Enzyme-Linked Immunosorbent Assay (ELISA) and ANA was detected by an indirect immunofluorescence test. Results: All patients studied were in an active stage of disease and were untreated, of which 44 patients had renal biopsy-proven kidney involvement, which was categorized as lupus nephritis (LN) and 56 patients did not show any renal manifestations (SLE without LN). Anti-nuc antibodies were positive in 88%, anti-dsDNA in 80%, and AHA in 38% of the cases. ANA was positive in all SLE patients studied. None of the normal controls was found to be positive for these antibodies. Although a slightly higher incidence of autoantibodies were noted in LN, there was no statistical difference noted between LN and SLE without LN groups for anti-nuc and anti-dsDNA antibodies (p > 0.05). A higher incidence of autoantibodies to ANA specificities were noted in anti-nuc positive cases, but there was no statistical difference between anti-nuc positive and anti-nuc negative cases for ANA specificities among LN and SLE without nephritis groups (p > 0.05). Conclusions: Anti-nuc antibody detection could be a better tool for the diagnosis of SLE. Although there was no significant difference in LN and SLE without LN groups, this study suggests that anti-nuc detection can be useful as an additional disease activity marker to other laboratory tests.