Publications by authors named "Eva Balada"

31 Publications

Clinical features of systemic sclerosis patients with anti-RNA polymerase III antibody in a single centre in Spain.

Clin Exp Rheumatol 2019 Jul-Aug;37 Suppl 119(4):41-48. Epub 2019 Feb 11.

Unit of Systemic Autoimmune Diseases, Institut de Recerca Vall d'Hebron, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.

Objectives: To evaluate the clinical features and survival of patients with positive anti-RNA polymerase III (anti-RNAP III) in a Spanish single centre.

Methods: We analysed 221 patients with SSc according to LeRoy and Medsger criteria. Twenty-six patients with positivity for anti-RNAP III antibodies were compared with 195 negative patients. Epidemiological, clinical, immunological features and survival were analysed.

Results: In patients with anti-RNAP III positivity diffuse cutaneous SSc (dcSSc) subset was the most prevalent (20, 76.9% vs. 35, 17.9%, p < 0.001), with shorter diagnosis delay (4.11 ± 7.34 years vs. 6.77 ± 9.22 years, p = 0.005). Patients with anti-RNAP III antibodies had higher frequency of arterial hypertension (13, 50% vs. 55, 28.2%, p = 0.024), scleroderma renal crisis (SRC) (3, 11.5% vs. 3, 1.5%, p = 0.023), arthritis (9, 34.6% vs. 35, 17.9%, p = 0.046), tendon friction rubs (4, 15.4% vs. 1, 0.5%, p = 0.001) and contractures (5, 19.2% vs. 10, 5.1%, p = 0.02). There were no differences found in the presence of cancer or in global survival. In the multivariate survival analysis, severe interstitial lung disease (ILD) (HR: 8.61, 95%CI 3.40 - 21.81), pulmonary arterial hypertension (PAH) (HR: 4.05, 95%CI 1.42 - 11.61) and SRC (HR: 17.27, 95%CI 3.36 - 88.97) were the only factors associated with poor prognosis.

Conclusions: In this cohort anti-RNAP III antibodies are related with dcSSc subset, shorter diagnostic delay and higher prevalence of musculoskeletal involvement, arterial hypertension and SRC. ILD, PAH and SRC were independent prognostic factors.
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October 2019

Tumour TIF1 mutations and loss of heterozygosity related to cancer-associated myositis.

Rheumatology (Oxford) 2018 02;57(2):388-396

Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Objectives: To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM).

Methods: Paired blood and tumour DNA samples from patients with anti-TIF1γ-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIF1γ expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score.

Results: From seven patients with anti-TIF1γ-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIF1γ-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1γ staining was more intense in tumours from anti-TIF1γ-positive patients (H-score 255 vs 196; P = 0.01). Also, TIF1γ staining in muscle was slightly more intense in anti-TIF1γ-positive than in anti-TIF1γ-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1γ staining was detected in the skin of both myositis and control patients.

Conclusion: Tumours from paraneoplastic anti-TIF1γ-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIF1γ in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis.
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http://dx.doi.org/10.1093/rheumatology/kex413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850766PMC
February 2018

Autoantibodies to types I and IV collagen and heart valve disease in systemic lupus erythematosus/antiphospholipid syndrome.

Clin Rheumatol 2017 Jun 10;36(6):1401-1406. Epub 2017 Mar 10.

Department of Internal Medicine, Autoimmune Diseases Unit, Vall Hebrón University Hospital, Universidad Autonoma de Barcelona, Pg. Vall d'Hebrón 119-129, 08035, Barcelona, Spain.

Introduction/objectives autoantibodies to types I and IV collagen have been described in rheumatic fever and infective endocarditis. We tried to elucidate if an autoimmune response against collagens I and IV exists, associated with heart valve disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). A cohort of 172 patients with SLE (n = 79), primary APS (PAPS, n = 83), and secondary APS (n = 10) were assessed for valvulopathy by transthoracic echocardiograms. Autoantibodies to types I and IV collagen were assessed in patients and 50 controls, setting autoantibody positivity at two standard deviations above the mean antibody level of controls. Positive anticollagen IV antibody rate was significantly higher in SLE patients (17.7%) in respect to the rest of groups (PAPS 2.4%, controls 2%; P = 0.001). Percentage of positive autoantibodies to collagen I was similar in SLE and APS cohort of patients with and without valvular disease (48.4 vs 51.6%, respectively; P = 0.45). Percentage of positive autoantibodies to collagen IV was increased but not significantly in SLE and APS cohort of patients with respect to those without valvular disease (62.5 vs 37.5%, respectively; P = 0.08). Mean (standard deviation) levels of positive anticollagen I and IV antibodies did not differ between patients with and without valvular disease (85.6 ± 55 vs 81 ± 85 U/ml, respectively; P = 0.86 for anticollagen I) (0.05 ± 0.02 vs 0.12 ± 0.16 U/ml, respectively; P = 0.34 for anticollagen IV). Our data indicate a lack of association of autoantibodies to types I and IV collagen with heart valve disease in SLE and APS.
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http://dx.doi.org/10.1007/s10067-017-3594-9DOI Listing
June 2017

Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis.

J Immunol Res 2014 4;2014:290797. Epub 2014 Feb 4.

Immunology Department, Hospital de La Santa Creu I Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.

A new myositis-specific autoantibody directed against melanoma differentiation-associated gene 5 (anti-MDA5) has been described in patients with dermatomyositis (DM). We report the clinical characteristics of patients with anti-MDA5 in a large Mediterranean cohort of DM patients from a single center, and analyze the feasibility of detecting this autoantibody in patient sera using new assays with commercially available recombinant MDA5. The study included 117 white adult patients with DM, 15 (13%) of them classified as clinically amyopathic dermatomyositis (CADM). Clinical manifestations were analyzed, with special focus on interstitial lung disease and its severity. Determination of anti-MDA5 antibodies was performed by a new ELISA and immunoblot technique. In sera, from 14 (12%) DM patients (8 CADM), MDA5 was recognized by ELISA, and confirmed by immunoblot. Eight of the 14 anti-MDA5-positive patients (57.14%) presented rapidly-progressive interstitial lung disease (RP-ILD) versus 3 of 103 anti-MDA5-negative patients (2.91%) (P < 0.05; OR: 44.4, 95% CI 9.3-212). The cumulative survival rate was significantly lower in anti-MDA5-positive patients than in the remainder of the series (P < 0.05). Patients with anti-MDA5-associated ILD presented significantly lower 70-month cumulative survival than antisynthetase-associated ILD patients. Among the cutaneous manifestations, only panniculitis was significantly associated with the presence of anti-MDA5 antibodies (P < 0.05; OR: 3.85, 95% CI 1.11-13.27). These findings support the reliability of using commercially available recombinant MDA5 for detecting anti-MDA5 antibodies and confirm the association of these antibodies with RP-ILD in a large series of Mediterranean patients with DM.
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http://dx.doi.org/10.1155/2014/290797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987881PMC
January 2015

Clinical and serological findings associated with the expression of ITGAL, PRF1, and CD70 in systemic lupus erythematosus.

Clin Exp Rheumatol 2014 Jan-Feb;32(1):113-6. Epub 2013 Nov 15.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain.

We determined the expression of Integrin alpha L chain (ITGAL), Perforin 1 (PRF1), and CD70 and studied the associations with laboratory and clinical parameters. CD4+ T cells were isolated from 35 SLE patients and 30 healthy controls. The transcript levels of ITGAL, PRF1, and CD70 were quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). The SLE patients had significantly elevated transcript levels of ITGAL (18.61±22.17 vs. 7.33±9.17, p=0.042), PRF1 (21.67±26.34 vs. 10.67±11.65, p=0.039), and CD70 (1.45±1.63 vs. 0.67± 0.28, p=0.011). Patients with anti-microsomal and/or anti-thyroglobulin antibodies showed high levels of ITGAL (33.41±30.14 vs. 13.58±16.43, p=0.044; and 34.01±27.66 vs. 11.90±16.17, p=0.007, respectively). No association was seen either for the typical antibodies of SLE or for the disease activity. Although ITGAL, PRF1, and CD70 are overexpressed in SLE CD4+ T cells, their expression is not linked to the typical clinical and serological parameters associated with the disease. The role that ITGAL may play in autoimmune thyroiditis deserves further investigation.
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October 2014

Soluble CD40 ligand in morbidly obese patients: effect of body mass index on recovery to normal levels after gastric bypass surgery.

JAMA Surg 2013 Feb;148(2):151-6

Surgery Unit, Hospital Universitari Arnau de Vilanova, Lleida, Spain.

Importance: In recent years, the CD40/CD40L system has been implicated in the pathophysiology of severe chronic inflammatory diseases. Recently, obesity has been described as a low chronic inflammatory disease, so this system could also be involved in the inflammatory process.

Objective: To study soluble CD40 ligand (sCD40L) and other factors implicated in coagulation (plasminogen activator inhibitor 1, antithrombin III, and fibrinogen) and inflammation (C-reactive protein) in patients with morbid obesity and different body mass indexes (BMIs) (calculated as weight in kilograms divided by height in meters squared), before and after weight loss induced by bariatric surgery.

Design: Plasma samples were obtained before and after a bariatric surgery intervention. Several inflammatory markers were then studied (sCD40L, plasminogen activator inhibitor 1, antithrombin III, and C-reactive protein). The values obtained were compared with a control group of nonobese persons.

Participants: Thirty-four morbidly obese patients undergoing gastric bypass surgery and 22 normal-weight controls matched for age and sex.

Interventions: A Roux-en-Y gastric bypass was performed in morbidly obese patients.

Main Outcome Measures: Levels of sCD40L, plasminogen activator inhibitor 1, antithrombin III, fibrinogen, and C-reactive protein 12 months after bariatric surgery.

Results: Obese men showed a tendency for decreased plasma sCD40L levels 1 year after surgery (mean [SEM], 246.5 [70.4] pg/mL before vs 82.2 [23.2] pg/mL after surgery; P < .05), whereas there were not any significant changes in obese women (285.9 [67.5] pg/mL before vs 287.0 [56.9] pg/mL after surgery). Levels of the other markers studied decreased significantly with weight loss in both sexes. However, all other studied markers tend to have higher concentrations in patients with higher BMIs, except for sCD40L, which tended to have lower concentrations in patients with BMIs higher than 55. The decreases with weight loss were lower with higher BMIs for all measurements, except for antithrombin III.

Conclusions And Relevance: Increased BMI, but not sex, influences recovery to normal levels for the markers studied, possibly indicating a worse prognosis.
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http://dx.doi.org/10.1001/jamasurgery.2013.419DOI Listing
February 2013

Further evidence of subphenotype association with systemic lupus erythematosus susceptibility loci: a European cases only study.

PLoS One 2012 26;7(9):e45356. Epub 2012 Sep 26.

Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.

Introduction: Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question.

Methods: European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication.

Results: THERE WERE THREE NEW ASSOCIATIONS: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR=0.76 and 1.30, P(corr) =0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci.

Conclusion: Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458859PMC
April 2013

Associations between the expression of epigenetically regulated genes and the expression of DNMTs and MBDs in systemic lupus erythematosus.

PLoS One 2012 21;7(9):e45897. Epub 2012 Sep 21.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona, Spain.

Objectives: We determined the expression of ITGAL, PRF1, KIR2DL4, CD70, and CD40LG in patients with SLE and performed correlations with the global DNA methylation status and the levels of three DNA methylation enzymes and two methyl CpG-binding domain (MBD) proteins.

Patients And Methods: CD4(+) T cells were isolated from 35 SLE patients and 30 healthy controls. DNA deoxymethylcytosine content was measured by an enzyme-linked immunosorbent assay (ELISA). Transcript levels of ITGAL, PRF1, KIR2DL4, CD70, CD40LG, DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 were quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR).

Results: SLE patients had significantly elevated transcript levels of ITGAL (18.61±22.17 vs. 7.33±9.17, p = 0.042), PRF1 (21.67±26.34 vs. 10.67±11.65, p = 0.039), and CD70 (1.45±1.63 vs. 0.67±0.28, p = 0.011). A positive correlation was observed between transcript levels of CD40LG and ITGAL (r = 0.477, p = 0.004) as well as between CD40LG and PRF1 (r = 0.557, p = 0.001). Transcript levels of KIR2DL4 were higher than controls' but it did not reach statistical significance (1.36±3.52 vs. 0.22±0.79, p = 0.560). A tight relationship with global DNA hypomethylation as well as with the expression of most of the DNA methylation-related genes was observed, especially for ITGAL, PRF1, and CD40LG.

Conclusions: ITGAL, PRF1, and CD70 are overexpressed in SLE CD4(+) T cells. The tight association of CD40LG with ITGAL and PRF1 leads us to infer that it probably contributes to the pathogenesis of the disease. The apparent simultaneous regulation between their expression and the global DNA hypomethylation as well as with the transcription of many DNA methylation-related enzymes, reinforces the idea that epigenetic mechanisms are responsible for the deregulation of ITGAL, PRF1, and CD40LG.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045897PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448686PMC
February 2013

Anti-TIF1γ antibodies (anti-p155) in adult patients with dermatomyositis: comparison of different diagnostic assays.

Ann Rheum Dis 2012 Jun 30;71(6):993-6. Epub 2012 Jan 30.

Department of Internal Medicine, Vall d’Hebron General Hospital. Universitat Autonoma de Barcelona, Barcelona, Spain.

Background: A new myositis-specific autoantibody (anti-p155) directed against transcriptional intermediary factor 1 γ (TIF1γ) has been described as a good marker of cancer-associated myositis (CAM).

Objective: To analyse the feasibility of detecting this autoantibody in patient serum samples using new assays with commercially available recombinant TIF1γ.

Methods: The study included 90 Spanish patients with dermatomyositis (DM), classified as clinically amyopathic DM, CAM, or DM without cancer. Anti-TIF1γ antibodies were detected by ELISA and immunoblot techniques and compared with anti-p155 antibody detection by protein immunoprecipitation assays with radiolabelled HeLa cells. The κ coefficient was used to compare the agreement between the different tests.

Results: Serum samples from 23 (25.6%) and 20 (22.2%) patients with DM recognised TIF1γ by ELISA and immunoblot, respectively. ELISA (κ=0.91) and immunoblot (κ=0.88) showed excellent agreement with immunoprecipitation analysis (anti-p155). Good concordance (κ=0.91) was also seen between ELISA and immunoblot.

Conclusions: Excellent agreement was found between anti-p155 detected by immunoprecipitation and anti-TIF1γ detected by ELISA or immunoblot. These data indicate that identification of this autoantibody can be reliably performed in a standard laboratory setting, with potential application in clinical practice for cancer screening in adult patients with DM.
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http://dx.doi.org/10.1136/annrheumdis-2011-200871DOI Listing
June 2012

Xenotropic murine leukemia virus-related virus (XMRV) in patients with systemic lupus erythematosus.

J Clin Immunol 2011 Aug 21;31(4):584-7. Epub 2011 Apr 21.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Vall d'Hebron Hospital, Autonomous University of Barcelona, Barcelona, Spain.

Objectives: Xenotropic murine leukemia virus-related virus (XMRV)-specific proviral DNA has been recently detected in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. Since chronic fatigue is commonly reported in patients with systemic lupus erythematosus (SLE) we aimed at testing the presence of this virus in these patients.

Methods: Ninety-five SLE patients, 45 of whom had a Fatigue Severity Scale score higher than 3, were included. Molecular analyses were performed by PCR from DNA obtained from the whole blood of both SLE patients and 50 healthy controls.

Results: None of the 145 samples analyzed yielded the specific XMRV PCR product.

Conclusions: We conclude that XMRV is not detected in blood neither from SLE patients nor from healthy controls. It leads to infer that other environmental and biological triggers (different from XMRV) may account for the increased levels of fatigue over the course of SLE.
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http://dx.doi.org/10.1007/s10875-011-9535-5DOI Listing
August 2011

Enhanced transcript levels of CD48 in CD4⁺ T cells from systemic lupus erythematosus patients.

Immunobiology 2011 Sep 12;216(9):1034-7. Epub 2011 Mar 12.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.

It is known that CD48 regulates T-cell activation. We evaluated the transcriptional expression of CD48 in CD4⁺ T cells from 30 SLE patients and 30 healthy controls. CD48 mRNA levels were considerably higher in the patients group: 1.80 ± 1.41 versus 1.10 ± 0.50 (p=0.023). An inverse correlation was obtained with respect to CD48 mRNA levels and age in the control group (r= -0.478, p=0.007). None association was found between CD48 mRNA expression and levels of anti-dsDNA, complement, or lymphocyte counts. Alternatively, a statistically significant positive correlation was observed between CD48 transcript levels and SLEDAI values (r=0.372, p=0.042). The higher CD48 mRNA levels observed in CD4⁺ T cells from SLE patients and the positive correlation found with SLEDAI lead us to infer that an overexpression of the protein coded by this gene may have important consequences on the development of SLE.
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http://dx.doi.org/10.1016/j.imbio.2011.03.004DOI Listing
September 2011

Implication of human endogenous retroviruses in the development of autoimmune diseases.

Int Rev Immunol 2010 Aug;29(4):351-70

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Barcelona, Spain.

Retroviruses can exist in an endogenous form, in which viral sequences are integrated into the human germ line and are vertically transmitted in a Mendelian fashion. Human endogenous retroviruses (HERVs), probably representing footprints of ancient germ-cell retroviral infections, occupy about 1% of the human genome. Some HERVs emerged in the genome over 25 million years ago, while others have appeared rather recently, at about the time of hominid and ape lineages divergence. Although some of these elements show mutations and deletions, some HERVs are transcriptionally active and produce functional proteins. Some medical conditions, such as cancer and autoimmune diseases, are linked to the transcription of some of the HERVs genes, to the expression of HERVs proteins (that may act as superantigens, for example), and/or to the development of antibodies against them that might cross-react with our own proteins. Their genetic sequences may also be, totally or partially, integrated into genes that regulate the immune response. These mechanisms could give rise to autoimmune diseases, such as lupus erythematosus, insulin-dependent diabetes mellitus, multiple sclerosis, Sjögren's syndrome, and rheumatoid arthritis, among others. This review is aimed at discussing evidence for a possible role of HERVs in the etiopathogenesis of different autoimmune diseases.
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http://dx.doi.org/10.3109/08830185.2010.485333DOI Listing
August 2010

Systemic lupus erythematosus as a first presentation of common variable immunodeficiency associated with infrequent mannose-binding lectin gene polymorphisms.

Rheumatol Int 2011 Apr 23;31(4):537-41. Epub 2009 Oct 23.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospitals Vall d'Hebron, Passeig Vall d'hebron 119-129, 08035 Barcelona, Spain.

The association of common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE) is infrequent. Mannose-binding lectin (MBL) has been shown to play a role in CVID and SLE. The purpose of this study is to describe two cases of CVID who presented as SLE and also evaluate the presence of MBL polymorphisms and MBL serum levels in those patients. In both patients, SLE was the first manifestation of CVID. In these patients the SLE immunological markers and disease activity disappeared after the development of CVID. They carried the very infrequent MBL haplotype 4Q-57Glu. One of them had a homozygous genotype, whereas the other patient was heterozygous and also presented the haplotype 4P-57Glu that had never been previously detected. Interestingly, this last patient was presenting frequent respiratory tract infections, developed bronchiectasis and had low levels of circulating MBL. These results may support the role of MBL in the development of autoimmunity in CVID. Further genetic studies are needed to clarify the role of the MBL polymorphisms in the development of autoimmunity in CVID.
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http://dx.doi.org/10.1007/s00296-009-1209-8DOI Listing
April 2011

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy.

Rheumatol Int 2010 Nov 21;30(12):1601-4. Epub 2009 Oct 21.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.

The objective of the study is to determine whether the activity of DNase1 is associated to the presence of nephropathy in patients with SLE. Forty-five patients affected with SLE and renal involvement were analyzed. The type of renal involvement was type III or IV glomerulonephritis. At least two serum samples were withdrawn from each patient, one obtained in a renal flare and the other obtained in a period of clinical stability. C3 and C4 complement levels and anti-DNA antibodies were determined. DNase1 activity was measured using a radial enzyme-diffusion method. Results suggest that when comparison of DNase1 activity was established between samples obtained during a phase of active renal involvement and those obtained in the clinically stable phase, we did not find statistically significant differences. When the comparison was performed with matched samples of the same patient, DNase1 activity was lower when patients had active renal involvement than when samples were taken in clinically stable phase (21.21 μg/ml ± 16.47 vs. 25.62 μg/ml ± 18.81, p < 0.05). No difference in DNase1 activity was observed between samples positive or negative for anti-DNA antibodies. No difference in DNase1 activity was found in patients with normal or decreased levels of C3 (25.09 μg/ml ± 17.78 vs. 20.01 μg/ml ± 16.15, p = 0.073) or C4 (23.52 μm/ml ± 16.60 vs. 19.62 μg/ml ± 17.54, p = 0.060). We conclude that low DNase1 activity is associated to the active phase of type III or IV nephropathy. Therefore, it is possible that this enzyme plays an important role in the development of SLE nephropathy.
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http://dx.doi.org/10.1007/s00296-009-1199-6DOI Listing
November 2010

Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity.

Rev Med Virol 2009 Sep;19(5):273-86

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Barcelona, Spain.

Eight per cent of the human genome is derived from the integration of retroviral sequences that were incorporated in our DNA more than 25 million years ago. Although some of these elements show mutations and deletions, some HERVs are transcriptionally active and produce functional proteins. Different mechanisms have been described which link HERVs to some chronic diseases such as several cancers, nervous system diseases and autoimmune rheumatic and connective tissue diseases. They could cause disease because of their capacity for being moved and inserted next to certain genes whose expression would be consequentially altered. Another way in which disease could potentially arise is when HERV-encoded proteins are expressed. These proteins would be considered as [foreign] and they could trigger B-cells to produce antibodies against them, which, in turn, might cross-react with other proteins of our bodies. This mechanism could give rise to autoimmune diseases such as rheumatoid arthritis (RA), lupus erythematosus, Sjögren's syndrome (SJS), mixed connective tissue diseases and inflammatory neurological disease. Furthermore, it should be pointed out that HERV-proteins may act as superantigens. Interestingly, some environmental agents seem to induce the expression of HERVs. Thus, ultraviolet light and several chemical agents could reactivate such sequences by altering their structure without modifying their nucleotide composition when the methylation pattern is changed. Therefore, the epigenetic changes observed in pathological conditions such as systemic lupus erythematosus (SLE) or cancer could be translated into an effect on the activation of some of the retroelements present in our genome which ultimately could have a direct or indirect role on the initiation and clinical evolution of certain chronic diseases.
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http://dx.doi.org/10.1002/rmv.622DOI Listing
September 2009

Genetic risk factors of thrombosis in the antiphospholipid syndrome.

Br J Haematol 2009 Nov 30;147(3):289-96. Epub 2009 Jul 30.

Autoimmune Diseases Research Laboratory, Vall d'Hebron University Hospital Research Institute, Barcelona, Spain.

The possibility of a genetic predisposition to develop antiphospholipid syndrome (APS) and to produce anticardiolipin antibodies and lupus anticoagulant has been addressed by family studies and population studies. Various studies suggest a familial occurrence of anticardiolipin antibodies and lupus anticoagulant, with or without clinical evidence of APS. This familial tendency could be genetically determined. Multiple human leucocyte antigen-DR or -DQ associations with antiphospholipid antibodies have been described. Genetic studies of a representative antigen, beta2-glycoprotein-I (beta(2)GPI), have been carried-out and a particular valine(247)/leucine polymorphism could be a genetic risk for presenting anti-beta(2)GPI antibodies and APS. Many other thrombosis-related genetic factors have been investigated in APS, but no additional risk for thrombosis has been indicated in affected patients. Although the mechanisms and pathophysiology of thrombosis in APS are highly heterogeneous and multifactorial, different genes and acquired factors seem to be involved. In this review, we will focus on those genetic variants that could contribute to the development of thrombosis in APS.
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http://dx.doi.org/10.1111/j.1365-2141.2009.07831.xDOI Listing
November 2009

Changes in lipid profile between flare and remission of patients with systemic lupus erythematosus: a prospective study.

J Rheumatol 2009 Aug 16;36(8):1639-45. Epub 2009 Jun 16.

Systemic Autoimmune Diseases Research Laboratory, Valld'Hebron Research Institute, Vall d'Hebron Hospital, Barcelona, Spain.

Objective: To determine the lipid profile of patients with systemic lupus erythematosus (SLE) according to the disease activity, and to calculate the percentage of patients that diverged from optimal values.

Methods: Serum was collected from 52 patients with SLE at flare and at remission. SLE disease activity was measured by using the SLE Disease Activity Index (SLEDAI). Clinical and biological measures were evaluated in both situations. Total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), and triglyceride (TG) levels were analyzed after overnight fasting. We also calculated the atherogenic ratios of TC/HDLC and LDLC/HDLC.

Results: SLE patients had significantly higher median TC/HDLC and LDLC/HDLC ratios at flare than during remission: 4.5 +/- 1.5 versus 3.9 +/- 1.0 (p = 0.007) and 2.7 +/- 1.1 versus 2.4 +/- 0.8 (p = 0.015), respectively. The differences persisted after adjustments based on kidney disease and treatment but not after adjusting by creatinine clearance < 60 ml/min/1.73 m(2) in remission. The variation between flare and remission of the percentage of SLE patients with high-risk levels of lipid profile to desirable values, and vice versa, was statistically significant for the LDLC/HDLC ratio (9 vs 1; p = 0.021).

Conclusion: Our results reflect a higher risk of atherosclerosis phenomena in SLE patients during flare than during clinical remission. This might explain the propensity to develop coronary heart disease in patients with SLE.
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http://dx.doi.org/10.3899/jrheum.081097DOI Listing
August 2009

Livedo racemosa as a marker of increased risk of recurrent thrombosis in patients with negative anti-phospholipid antibodies.

Med Clin (Barc) 2009 May 28;132(20):767-71. Epub 2009 Apr 28.

Research Unit in Systemic Autoimmune diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Barcelona, Spain.

Background And Objective: Livedo reticularis racemosa and cerebrovascular lesions characterize Sneddon's syndrome. We report 23 patients with livedo racemosa and describe the association with thrombotic events. Our objective was to determine whether livedo racemosa may be an independent clinical marker for the development of thrombotic events in patients who test negative for anti-phospholipid antibodies.

Methods: Twenty-three patients with widespread livedo racemosa were studied. None of the patients were positive for anti-phospholipid antibodies. The clinical protocol included a register of thrombotic events, fetal death or miscarriages, hypertension, and valvular heart disease. Cerebral MRI and echocardiography were systematically performed in all patients.

Results: Nineteen patients (82.60%) had thrombotic events. Fifteen (65.21%) had arterial thrombosis and eleven (47.82%) presented venous occlusions. Seven patients (30.43%) had both arterial and venous thrombosis. Fetal losses were recorded in seven cases (30.43%), with a total number of 33; five patients had 3 or more fetal losses. Eleven out of 23 patients (47.82%) had valvular heart disease. Arterial hypertension was detected in 16 (69.56%) patients. Four patients did not have thrombotic events but had other clinical manifestations. After anti-coagulation therapy was withdrawn, a new thrombotic event was observed in 9 out of the 14 treated patients (64.28%).

Conclusions: Livedo racemosa seems to be a good clinical marker for the detection of hypercoagulable states even in the absence of anti-phospholipid antibodies or other known biologic markers of thrombosis. Long-term anti-coagulation is probably warranted in patients with livedo racemosa and a previous thrombotic event.
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http://dx.doi.org/10.1016/j.medcli.2008.09.044DOI Listing
May 2009

Serum levels of soluble CD40 ligand at flare and at remission in patients with systemic lupus erythematosus.

J Rheumatol 2009 May 30;36(5):953-60. Epub 2009 Mar 30.

Systemic Autoimmune Diseases Research Laboratory, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Barcelona, Spain.

Objective: To perform a prospective evaluation of soluble CD40 ligand (sCD40L) levels according to the activity of systemic lupus erythematosus (SLE).

Methods: Two serum samples were taken from 53 patients with SLE: at flare and at remission. Clinical and biological measures (sCD40L levels were measured by a commercial ELISA) were evaluated in both situations.

Results: Patients with SLE had significantly lower median levels of sCD40L during flare than during remission [3365 (6157) vs 7125 (4122) pg/ml; p < 0.001]. The multivariate analysis to explain those patients with lower values of sCD40L during flare than during remission included 3 variables: 2 related to flare (prednisone dose received 192,000 x 10(6)/l) and one related to lower changes in SLE Disease Activity Index (SLEDAI) score. We regrouped patients with the 2 characteristics related to flare as Group 4, and the others were Group 123. All patients with low SLEDAI scores at flare had statistically significant lower sCD40L levels during flare than during remission. When flare SLEDAI scores were higher than the 50th percentile, patients of Group 123 showed the same behavior and even more diminished levels of sCD40L during flare than patients of Group 123 with low SLEDAI scores (p = 0.023); and patients of Group 4 showed no differences in the values of sCD40L between flare and remission (p = 0.241).

Conclusion: sCD40L plays a biologically active role, with decreased levels at flare at low SLEDAI scores. At high SLEDAI scores there are mechanisms that involve platelets and that are inhibited by high doses of prednisone that lead to increased serum values of sCD40L at flare.
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http://dx.doi.org/10.3899/jrheum.080978DOI Listing
May 2009

DNase 1 and systemic lupus erythematosus.

Autoimmun Rev 2008 May 10;7(5):359-63. Epub 2008 Mar 10.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, Barcelona, Spain.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology with a complex genetic basis that includes many susceptibility genes on multiple chromosomes. As many complex human diseases, SLE involves multiple, interacting genetic and environmental determinants, and identifying genes and enzymes for complex traits is challenging and has had limited success so far. DNase1 has been implicated in the pathophysiology of SLE since the 1950s. The importance of DNase1 has grown up since the description that apoptotic cells can be the source of self-antigens in SLE. Many articles have focused in disturbed apoptosis and in the defects of the apoptotic cell debris as the origin of nucleosomes against which the immune response can be induced. The enzyme DNase1 plays a role in the clearance of apoptotic debris, and is therefore of capital interest in this process. In this review we highlight the current findings in the pathophysiology, genetics, and therapeutical role of DNase1 in SLE.
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http://dx.doi.org/10.1016/j.autrev.2008.02.002DOI Listing
May 2008

The complex immunogenetic basis of systemic lupus erythematosus.

Autoimmun Rev 2008 May 1;7(5):345-51. Epub 2008 Feb 1.

Autoimmune Diseases Research Laboratory, Vall d'Hebron Research Institute, Passeig Vall d'Hebron 119-129, Barcelona, Spain.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology with a complex genetic basis that includes many susceptibility genes on multiple chromosomes. As complex human diseases like SLE involve multiple, interacting genetic and environmental determinants, identifying genes for complex traits is challenging and has had limited success so far. Several key approaches that are necessary to identify disease susceptibility genes in common diseases such as SLE are now available. Collectively, these approaches will allow the prioritization of candidate genes based on available knowledge of map position and biologic relevance. They will also allow us to obtain the genomic structure of these genes as well as to study sequence variants that will facilitate the identification of genes that are important in the development and expression (severity) of lupus and associated phenotypes. Although it is still a labor-intensive and expensive project to identify susceptibility genes in common diseases such as SLE, the new techniques that are now being used will undoubtedly improve gene mapping in such a kind of diseases. In this review we highlight the current findings in the genetics of human SLE after using these approaches.
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http://dx.doi.org/10.1016/j.autrev.2008.01.001DOI Listing
May 2008

Transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in CD4+ T cells from patients with systemic lupus erythematosus.

Immunology 2008 Jul 11;124(3):339-47. Epub 2008 Jan 11.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Barcelona, Spain.

Global DNA hypomethylation in CD4(+) T cells has been detected in systemic lupus erythematosus (SLE) and it seems to be linked to its pathogenesis. We investigated the relationship between overall DNA methylation and the expression of three DNA (cytosine-5) methyltransferases involved in the DNA methylation process. The DNA deoxymethylcytosine (dmC) content of purified CD4(+) T cells from 29 SLE patients and 30 healthy controls was measured by means of an enzyme-linked immunosorbent assay (ELISA). The transcript levels of DNA cytosine-5-methyltransferase 1 (DNMT1), DNA cytosine-5-methyltransferase 3A (DNMT3A) and DNA cytosine-5-methyltransferase 3B (DNMT3B) were quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR). Association studies were also carried out with several laboratory parameters, as well as with the patients' clinical manifestations. SLE patients had a significantly lower CD4(+) T-cell DNA dmC content than controls (0.802 +/- 0.134 versus 0.901 +/- 0.133) (P = 0.007). No differences in transcript levels were observed for DNMT1, DNMT3A and DNMT3B between patients and controls. The simultaneous association of low complement counts with lymphopenia, high titres of anti-double-stranded DNA (anti-dsDNA), or an SLE disease activity index (SLEDAI) of > 5, resulted in the increase of at least one of the three DNA methyltransferases. It is possible that patients were reacting indirectly to an underlying DNA hypomethylation status by increasing the mRNA levels of DNA methyltransferases when the disease was being definitely active.
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http://dx.doi.org/10.1111/j.1365-2567.2007.02771.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440828PMC
July 2008

DNA methylation and systemic lupus erythematosus.

Ann N Y Acad Sci 2007 Jun;1108:127-36

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Barcelona, Spain.

Several studies have indicated the importance of DNA hypomethylation in the etiology of systemic lupus erythematosus (SLE). Different enzymes linked to the DNA methylation process have been described. The identification of all these enzymes means that cells have the capacity to modify their methylation patterns. Therefore, to obtain a deeper understanding of the role this epigenetic mechanism may have on SLE, the enzymes involved in the DNA methylation mechanism must be thoughtfully analyzed. In fact, studies of enzymes (other than DNMT1) in this autoimmune disease are still lacking. We have recently investigated the simultaneous gene expression of DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 in SLE patients. Here we review some of the studies that focus on the relationship between DNA methylation and SLE as well as we report our recent findings in this field. We suggest some alternative hypothesis that could help to understand the causes of the global DNA hypomethylation observed in the CD4+ T cells of these patients.
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http://dx.doi.org/10.1196/annals.1422.015DOI Listing
June 2007

Protein Z levels and anti-protein Z antibodies in patients with arterial and venous thrombosis.

Thromb Res 2008 14;121(6):727-34. Epub 2007 Sep 14.

Department of Internal Medicine, Research Unit for Autoimmune Diseases, Vall d'Hebrón University Hospital, Barcelona, Spain.

Introduction: The thrombotic risk associated with protein Z (PZ) deficiency is unclear. Anti-protein Z (anti-PZ) has been described as a risk factor in unexplained embryo demise. The aim of our study was to evaluate a possible PZ deficiency and presence of anti-PZ antibodies on thrombotic diseases.

Material And Methods: We performed a case-control study on 114 patients with preexisting arterial or venous thrombosis (50 and 64, respectively). Thrombosis was studied based on etiology (creating factor risk subgroups) and on specific thrombotic disease.

Results: PZ levels of patients were significantly lower compared to controls (1709+-761.3 ng/mL vs. 2437+-964.7 ng/mL P=0.001). The high arterial risk factor subgroup showed the lowest PZ level (1267.5+-609 ng/mL) whereas the rest of arterial and venous etiological subgroups presented similar PZ levels. Patients with peripheral artery disease had the lowest PZ level (1022+-966 ng/mL). The rest of arterial and venous thrombotic diseases presented similar PZ levels. A significant increased risk for arterial and venous thrombosis for the lowest (<1685 ng/mL) quartile of PZ has been founded (OR:52, P=0.001 and OR:18, P=0.007, respectively). Anti-PZ antibodies were negative in the majority of patients, although mean anti-PZ IgG antibody levels in the arterial thrombosis group were significantly higher compared to venous thrombosis and control groups (P=0.05 and P=0.005, respectively).

Conclusions: The results suggest that both arterial and venous thrombotic events are related to low PZ levels and that low PZ concentrations are associated with thrombosis in our study. In arterial thrombosis our findings strengthen previous studies that related low PZ levels to atherosclerotic disease. Anti-PZ antibodies do not seem to play a potent role in thrombosis.
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http://dx.doi.org/10.1016/j.thromres.2007.07.009DOI Listing
October 2008

Transcript overexpression of the MBD2 and MBD4 genes in CD4+ T cells from systemic lupus erythematosus patients.

J Leukoc Biol 2007 Jun 14;81(6):1609-16. Epub 2007 Mar 14.

Research Unit in Systemic Autoimmune Diseases, Vall d'Hebron Research Institute, Hospital Vall d'Hebron, Barcelona, Spain.

Global DNA hypomethylation in CD4+ T cells has been detected in systemic lupus erythematosus (SLE), and it seems to be linked to its pathogenesis. We investigated the relationship between overall DNA methylation and the expression of two methyl CpG-binding domain (MBD) proteins. DNA deoxymethylcytosine (d(m)C) content of purified CD4(+) T cells from 29 SLE patients and 30 healthy controls was measured by means of an ELISA. Transcript levels of two methyl CpG-binding proteins (MBD2 and MBD4) were quantified by real-time RT-PCR. Association studies were also carried out with several laboratory parameters, as well as with the patients' clinical manifestations. SLE patients had significantly less CD4+ T cell DNA d(m)C content than controls (0.802+/-0.134 vs. 0.901+/-0.133; P=0.007). MBD2 and MBD4 mRNA levels were considerably higher in the patients' group: 0.975 +/- 0683 versus 0.604 +/- 0.614 (P=0.004) and 0.359 +/- 0.330 versus 0.092 +/- 0.169, respectively (P<0.0005). It is interesting that SLE patients showed a negative correlation between methylation indices and MBD2 (r=-0.609, P<0.0005) and MBD4 (r=-0.395, P=0.034) transcript levels. MBD2 and MBD4 transcript overexpression and inverse correlations with DNA methylation indices indicate that both enzymes may really have a direct and active role on the genome-wide DNA hypomethylation observed in CD4+ T cells from SLE patients.
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http://dx.doi.org/10.1189/jlb.0107064DOI Listing
June 2007

Mutations of activin-receptor-like kinase 1 (ALK-1) are not found in patients with pulmonary hypertension and underlying connective tissue disease.

Clin Rheumatol 2007 Jun 29;26(6):947-9. Epub 2006 Aug 29.

Internal Medicine Department, Vall D'Hebron General Hospital, Barcelona, Spain.

Pulmonary arterial hypertension is a recognized clinical component of systemic autoimmune diseases, especially systemic sclerosis. Mutations in the bone morphogenetic protein receptor 2 gene reported in sporadic and familial primary pulmonary arterial hypertension have failed to be detected in patients with either scleroderma spectrum disease or underlying connective tissue diseases. Activin receptor-like kinase 1 (ALK-1) gene has recently been linked to the pathogenesis of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia, which has some resemblance with the CREST syndrome. The presence of mutations in the ALK-1 gene in ten patients with underlying connective tissue diseases was investigated.
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http://dx.doi.org/10.1007/s10067-006-0388-xDOI Listing
June 2007

Acquired haemophilia A: successful treatment with immunosuppression, methylprednisolone pulses and oral cyclosporin.

Thromb Haemost 2006 Apr;95(4):735-7

Department of Internal Medicine, Vall d'Hebrón General Hospital, Universidad Autónoma of Barcelona, Spain.

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April 2006

Antihistone and anti-double-stranded deoxyribonucleic acid antibodies are associated with renal disease in systemic lupus erythematosus.

Am J Med 2004 Feb;116(3):165-73

Internal Medicine, Vall d'Hebron Hospitals, Barcelona, Spain.

Purpose: We sought to assess the nephritogenic antibody profile of patients with systemic lupus erythematosus (SLE), and to determine which antibodies were most useful in identifying patients at risk of nephritis.

Methods: We studied 199 patients with SLE, 78 of whom had lupus nephritis. We assayed serum samples for antibodies against chromatin components (double-stranded deoxyribonucleic acid [dsDNA], nucleosome, and histone), C1q, basement membrane components (laminin, fibronectin, and type IV collagen), ribonucleoprotein, and phospholipids. Correlations of these antibodies with disease activity (SLE Disease Activity Index) and nephropathy were assessed. Patients with no initial evidence of nephropathy were followed prospectively for 6 years.

Results: Antibodies against dsDNA, nucleosomes, histone, C1q, and basement membrane components were associated with disease activity (P <0.05). In a multivariate analysis, anti-dsDNA antibodies (odds ratio [OR] = 6; 95% confidence interval [CI]: 2 to 24) and antihistone antibodies (OR = 9.4; 95% CI: 4 to 26) were associated with the presence of proliferative glomerulonephritis. In the prospective study, 7 (6%) of the 121 patients developed proliferative lupus glomerulonephritis after a mean of 6 years of follow-up. Patients with initial antihistone (26% [5/19] vs. 2% [2/95], P = 0.0004) and anti-dsDNA reactivity (6% [2/33] vs. 0% [0/67], P = 0.048) had a greater risk of developing proliferative glomerulonephritis than patients without these autoantibodies.

Conclusion: In addition to routine anti-dsDNA antibody assay, antihistone antibody measurement may be useful for identifying patients at increased risk of proliferative glomerulonephritis.
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http://dx.doi.org/10.1016/j.amjmed.2003.08.034DOI Listing
February 2004

[Atherosclerosis and anti-oxidized low density lipoprotein antibodies in an elderly population].

Med Clin (Barc) 2002 Jul;119(5):161-5

Research Unit in Systemic Autoimmune Diseases, Internal Medicine Department, Hospital Vall d'Hebron, Barcelona, Spain.

Background: Antibodies to oxidized LDL (anti-OxLDL) have been found to be associated with atherosclerosis. The aim of the study was to evaluate the relationship between anti-OxLDL antibodies and atherosclerosis in the elderly.

Patients And Method: We studied several risk factors and different clinical manifestations of atherosclerosis in 100 people older than 65 years and in 48 healthy blood donor controls (age range: 20 to 55 years). Anti-OxLDL antibodies were measured by ELISA.

Results: Thirty-one percent of the patients tested positive for anti-OxLDL. This percentage increased in the group of subjects without any risk factor or clinical manifestation (66.6%) as it was the case of the mean optical density (O.D.) value (O.D. = 0.671 vs. 0.357 in our general geriatric population). Most of those with a proven atherosclerotic event tested negative for anti-OxLDL antibodies and a statistically significant difference was shown for those with a calcified aortic arch (P = 0.041, 95% CI 0.15-0.97). Mean value of risk factors and clinical manifestations was 3.50 among anti-OxLDL-negative patients, whereas it was 2.51 in the anti-OxLDL-positive group (P = 0.035, 95% CI 0.07-1.91). Actually, when more adverse effects were present, patients' trend to test negative for anti-OxLDL antibodies was higher. An inverse correlation was observed between anti-OxLDL titers and the relative risk of coronary heart disease (P = 0.020).

Conclusions: The cause of the decrease of free anti-OxLDL antibodies in situations that lead to an oxidative stress is unknown but it may be explained by the formation of immunocomplexes in an effort to ease the clearance of oxidized substrates.
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http://dx.doi.org/10.1016/s0025-7753(02)73351-4DOI Listing
July 2002