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1. Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus

Author

Julius Lindblom, Lorenzo Beretta, Maria Orietta Borghi, PRECISESADS Clinical Consortium, Marta E. Alarcón-Riquelme, Ioannis Parodis, Barbara Vigone, Jacques-Olivier Pers, Alain Saraux, Valérie Devauchelle-Pensec, Divi Cornec, Sandrine Jousse-Joulin, Bernard Lauwerys, Julie Ducreux, Anne-Lise Maudoux, Carlos Vasconcelos, Ana Tavares, Esmeralda Neves, Raquel Faria, Mariana Brandão, Ana Campar, António Marinho, Farinha Fátima, Isabel Almeida, Angel Gonzalez-Gay Mantecón, Ricardo Blanco Alonso, Alfonso Corrales Martínez, Ricard Cervera, Ignasi Rodríguez-Pintó, Gerard Espinosa, Rik Lories, Ellen De Langhe, Nicolas Hunzelmann, Doreen Belz, Torsten Witte, Niklas Baerlecken, Georg Stummvoll, Michael Zauner, Michaela Lehner, Eduardo Collantes, Rafaela Ortega-Castro, MaAngeles Aguirre-Zamorano, Alejandro Escudero-Contreras, MaCarmen Castro-Villegas, Norberto Ortego, María Concepción Fernández Roldán, Enrique Raya, Inmaculada Jiménez Moleón, Enrique de Ramon, Isabel Díaz Quintero, Pier Luigi Meroni, Maria Gerosa, Tommaso Schioppo, Carolina Artusi, Carlo Chizzolini, Aleksandra Zuber, Donatienne Wynar, Laszló Kovács, Attila Balog, Magdolna Deák, Márta Bocskai, Sonja Dulic, Gabriella Kádár, Falk Hiepe, Velia Gerl, Silvia Thiel, Manuel Rodriguez Maresca, Antonio López-Berrio, Rocío Aguilar-Quesada, and Héctor Navarro-Linares.

Subjects
autoimmunity, systemic lupus erythematosus, antiphospholipid syndrome, diagnosis, biomarkers, cytokines, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionSystemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs).MethodsSerum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays.ResultsOf the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak.DiscussionOur findings suggest that, upon validation, CCL8, CXCL13, and IL-1RA could serve as promising serum biomarkers of activity in SLE.

Published
2023
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2. HLA class II DNA typing in a large series of European patients with systemic lupus erythematosus: correlations with clinical and autoantibody subsets

Author

Galeazzi, Mauro, Sebastiani, Gian Domenico, Morozzi, Gabriella, Carcassi, Carlo, Ferrara, Giovanni Battista, Scorza, Raffaella, Cervera, Ricard, Garrido, Enrique De Ramon, Fernandez-Nebro, Antonio, Houssiau, Frederic, Jedryka-Goral, Anna, Passiu, Giuseppe, Papasteriades, Chryssa, Piette, Jean-Charles, Smolen, Josef, Porciello, Giovanni, and Marcolongo, Roberto

Subjects
Systemic lupus erythematosus -- Genetic aspects, HLA class II antigens -- Physiological aspects
Published
2002

3. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial

Author

Frédéric A, Houssiau, David, D'Cruz, Shirish, Sangle, Philippe, Remy, Carlos, Vasconcelos, Radmila, Petrovic, Christoph, Fiehn, Enrique, de Ramon Garrido, Inge-Magrethe, Gilboe, Maria, Tektonidou, Daniel, Blockmans, Isabelle, Ravelingien, Véronique, le Guern, Geneviève, Depresseux, Loïc, Guillevin, Ricard, Cervera, René, Westhovens, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie

Subjects
Male, medicine.medical_treatment, 030232 urology & nephrology, Lupus nephritis, Azathioprine, Mycophenolate, Gastroenterology, Recurrence - prevention & control, Lupus Nephritis - drug therapy, 0302 clinical medicine, Secondary Prevention, Immunology and Allergy, Randomized Controlled Trials as Topic, Immunosuppression, Middle Aged, Lupus Nephritis, 3. Good health, Treatment Outcome, Prednisolone, Drug Therapy, Combination, Female, Azathioprine - adverse effects, therapeutic use, Nephritis, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, Cyclophosphamide - therapeutic use, Cyclophosphamide, Immunology, Article, General Biochemistry, Genetics and Molecular Biology, Mycophenolic acid, Young Adult, 03 medical and health sciences, Rheumatology, Internal medicine, Immunosuppressive Agents - adverse effects, therapeutic use, medicine, Humans, Glucocorticoids, Mycophenolic Acid - adverse effects, analogs & derivatives, therapeutic use, Glucocorticoids - therapeutic use, 030203 arthritis & rheumatology, business.industry, Clinical and Epidemiological Research, Mycophenolic Acid, Prednisolone - therapeutic use, medicine.disease, business, Follow-Up Studies
Abstract

BackgroundLong-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment.MethodsA total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months.ResultsThe baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out.ConclusionsFewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance.

Published
2010
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4. Combination therapy with interferon Beta-1b and azathioprine in secondary progressive multiple sclerosis

Author

Miguel Hervás, Enrique de Ramon, Oscar Fernández, Victoria Fernández, Antonio Capdevila, Cristobalina Mayorga, Miguel G. Guerrero, Luis Muñoz, G. Luque, and Antonio Leán

Subjects
medicine.medical_specialty, Chemotherapy, Expanded Disability Status Scale, Side effect, Combination therapy, business.industry, medicine.medical_treatment, Multiple sclerosis, Interferon beta-1b, Azathioprine, medicine.disease, Surgery, Neurology, Internal medicine, medicine, Neurology (clinical), business, Prospective cohort study, medicine.drug
Abstract

Combination therapy may benefit the subgroup of patients with secondary progressive multiple sclerosis (SPMS) who do not respond to interferon beta (IFNB). We performed a two-year study of azathioprine (AZA) combined with IFNB-1b in SPMS patients who had not responded well to IFNB-1b alone. Patients with SPMS were eligible for this non-controlled prospective study if they had two or more relapses requiring corticosteroid treatment or deteriorated by at least 0.5 points on the Expanded Disability Status Scale (EDSS) while on IFNB-1b in the year preceeding the study. Patients were to continue treatment with IFNB-1b (8 MIU qod, subcutaneous) and received AZA (50 mg tid, oral). Safety was assessed in terms of adverse reactions and laboratory measures graded according to the WHO toxicity scale. Efficacy was explored by changes in relapse rate, EDSS, 9-hole peg test (9-HPT), neuropsychological scores, and magnetic resonance imaging (MRI) results. Neutralizing antibodies (NAB) were measured. Ten SPMS patients (6 females) with a median EDSS score of 4.5 were enrolled. One patient withdrew because of gastrointestinal complaints, one was withdrawn owing to poor compliance, and 8 patients completed therapy. The only frequent side effect was lymphopenia, reported at least once in all patients. Annual relapse rate was reduced by approximately 50 % in the second year. There was a significant trend for EDSS increase. Total lesion load measured by MRI decreased at 12 and 24 months; only one patient had active lesions. No changes were seen in the 9-HPT. There was a significant improvement in neuropsychological tests after 24 months (p = 0.045). One patient tested positive for NAB throughout the study, and transient NAB were detected in 4 patients. In conclusion, combination therapy with IFNB-1b and AZA was safe and generally well tolerated in patients with SPMS. Strict clinical and laboratory monitoring is recommended during this combination therapy.

Published
2002
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5. Natural evolution of skin test sensitivity in patients allergic to β-lactam antibiotics

Author

A. Miranda, J. M. Vega, Carlos Juarez, Enrique de Ramon, María José Torres, Cristobalina Mayorga, Antonino Romano, Miguel Blanca, and Juan Jesus García

Subjects
Adult, Male, Allergy, Time Factors, medicine.drug_class, Immunology, Antibiotics, Physiology, Benzylpenicillin, Group B, Drug Hypersensitivity, Immunopathology, Ampicillin, Humans, Immunology and Allergy, Medicine, Aged, Skin Tests, business.industry, Amoxicillin, Middle Aged, medicine.disease, Survival Analysis, Anti-Bacterial Agents, Penicillin, Female, business, medicine.drug
Abstract

Background: Subjects with immediate reactions to penicillins and positive skin test responses may lose sensitivity if penicillin is avoided. The longer the interval between the reaction and the skin test, the greater the likelihood of having a negative result. Objective: We sought to study prospectively the evolution of skin test sensitivity in a group of subjects allergic to penicillin with positive skin test responses to different penicillin determinants. Methods: Skin tests were performed with major and minor determinants of benzylpenicillin (BPO/MDM), amoxicillin (AX), and ampicillin at the initial evaluation and repeated 1, 3, and 5 years later if the responses were still positive. Subjects were divided into 2 groups. Group A consisted of patients with a positive skin test response to benzylpenicilloyl or minor determinant mixture, and group B consisted of those with a selective response to amoxicillin and good tolerance to benzylpenicillin. Results: In group A (n = 31) after 1 year, 25 patients continued to have positive responses and 6 began to have negative responses; after 3 years, 18 continued to have positive responses, 5 began to have negative responses, and 2 were lost to follow-up; and after 5 years, 12 continued to have positive responses, 5 began to have negative responses, and 1 was lost to follow-up. In group B (n = 24) 12 had positive responses, and 12 had negative responses after 1 year; 6 had positive responses, 5 had negative responses, and 1 was lost to follow-up after 3 years; and no patients had positive responses, 5 had negative responses, and 1 was lost to follow-up after 5 years. Survival analysis showed significant differences between groups (log-rank test=12.8; P Conclusion: Patients with a selective response to amoxicillin tended to lose sensitivity faster than those who responded to several penicillin determinants, supporting the existence of at least 2 distinct types of IgE response in patients allergic to β-lactam. (J Allergy Clin Immunol 1999;103:918-24.)

Published
1999
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6. Determination of IgE antibodies to the benzylpenicilloyl determinant: A comparison of the sensitivity and specificity of three radio allergo sorbent test methods

Author

Javier Fernández, Cristobalina Mayorga, Enrique de Ramon, Miguel Blanca, F. Moreno, Carlos Juarez, Juan José García García, Antonino Romano, and J. M. Vega

Subjects
Adult, Male, Microbiology (medical), Intraclass correlation, Clinical Biochemistry, Immunoglobulin E, Sensitivity and Specificity, Benzylpenicillin, Antibodies, Drug Hypersensitivity, Radioallergosorbent Test, Radio allergo sorbent test, Clinical history, medicine, Humans, Immunology and Allergy, Aged, Skin Tests, biology, Receiver operating characteristic, Chemistry, Biochemistry (medical), Public Health, Environmental and Occupational Health, Penicillin G, Original Articles, Hematology, Middle Aged, Human serum albumin, Penicillin, Medical Laboratory Technology, ROC Curve, Immunology, biology.protein, Female, medicine.drug
Abstract

The quantitation of in vitro IgE antibodies to the benzylpenicilloyl determinant (BPO) is a useful tool for evaluating suspected penicillin allergic subjects. Although many different methods have been employed, few studies have compared their diagnostic specificity and sensitivity. In this study, the sensitivity and specificity of three different radio allergo sorbent test (RAST) methods for quantitating specific IgE antibodies to the BPO determinant were compared. Thirty positive control sera (serum samples from penicillin allergic subjects with a positive clinical history and a positive penicillin skin test) and 30 negative control sera (sera from subjects with no history of penicillin allergy and negative skin tests) were tested for BPO‐specific IgE antibodies by RAST using three different conjugates coupled to the solid phase: benzylpenicillin conjugated to polylysine (BPO‐PLL), benzylpenicillin conjugated to human serum albumin (BPO‐HSA), and benzylpenicillin conjugated to an aminospacer (BPO‐SP). Receiver operator control curves (ROC analysis) were carried out by determining different cut‐off points between positive and negative values. Contingence tables were constructed and sensitivity, specificity, negative predictive values (PV–), and positive predictive values (PV+) were calculated. Pearson correlation coefficients (r) and intraclass correlation coefficients (ICC) were determined and the differences between methods were compared by χ(2) analysis. Analysis of the areas defined by the ROC curves showed statistical differences among the three methods. When cut‐off points for optimal sensitivity and specificity were chosen, the BPO‐HSA assay was less sensitive and less specific and had a lower PV– and PV+ than the BPO‐PLL and BPO‐SP assays. Assessment of r and ICC indicated that the correlation was very high, but the concordance between the PLL and SP methods was higher than between the PLL and HSA or SP and HSA methods. We conclude that for quantitating IgE antibodies by RAST to the BPO determinant, BPO‐SP or BPO‐PLL conjugates offer advantages in sensitivity and specificity compared with BPO‐HSA. These results support and extend previous in vitro studies by our group and highlight the importance of the carrier for RAST assays. J. Clin. Lab. Anal. 11:251–257, 1997. © 1997 Wiley‐Liss, Inc.

Published
1997
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8. The efficacy of natalizumab in patients with multiple sclerosis according to level of disability: results of an observational study

Author

Jose Carlos López-Madrona, Begoña Oliver, G. Luque, Victoria Fernández, Enrique de Ramon, A. Alonso, Antonio León, Miguel Guerrero, Oscar Fernández, Laura Leyva, and Marcos Papais Alvarenga

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, Time Factors, Antibodies, Monoclonal, Humanized, Severity of Illness Index, Disability Evaluation, Young Adult, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, Predictive Value of Tests, Recurrence, Severity of illness, medicine, Humans, Immunologic Factors, Prospective Studies, Young adult, Prospective cohort study, Expanded Disability Status Scale, business.industry, Multiple sclerosis, Antibodies, Monoclonal, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, Treatment Outcome, Neurology, Spain, Predictive value of tests, Physical therapy, Observational study, Female, Neurology (clinical), business, medicine.drug
Abstract

Background: Little is known about how the level of disability at the start of treatment with natalizumab affects its efficacy. Objectives: The aim of this study was to investigate the effect of natalizumab on relapses in patients with different levels of baseline disability associated with MS. Methods: This single-centre observational study collected demographic data for patients followed prospectively and who were scheduled to start natalizumab therapy due to the presence of disease activity. The annualized relapse rate (ARR) and Kurtzke Expanded Disability Status Scale scores were analysed for the previous year, on starting treatment (baseline) and 1 year after starting therapy. Results: Seventy-seven patients (mean age: 39.0 years, mean disease duration: 12.4 years) were included. The difference between ARR before and after starting treatment was 0.92 for baseline Expanded Disability Status Scale ≤3.5 ( p Conclusions: The findings support the efficacy of natalizumab in reducing ARR in the year after starting treatment in patients with baseline Expanded Disability Status Scale ≤6.

Published
2010

9. Interferon receptor expression in multiple sclerosis patients

Author

Cristobalina Mayorga, Begoña Oliver, Juan C. López, Laura Leyva, Antonio León, Oscar Fernández, Enrique de Ramon, G. Luque, María Jesús Pinto-Medel, Eva Blanco, Victoria Fernández, A. Alonso, and Jose A. Tamayo

Subjects
Adult, Male, Treatment response, Multiple Sclerosis, Immunology, Gene expression, Immunology and Allergy, Medicine, Humans, In patient, RNA, Messenger, Receptor, Receptors, Interferon, Regulation of gene expression, Interferon receptor, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Multiple sclerosis, Interferon-beta, Middle Aged, medicine.disease, Response to treatment, Neurology, Gene Expression Regulation, Female, Neurology (clinical), business
Abstract

To determine the gene expression of IFNAR1, IFNAR2 and MxA protein and the association with IFNbeta treatment response in MS patients. MS patients treated with IFNbeta had a significant decrease in IFNAR1 and IFNAR2 expression, and a significant increase in MxA compared to non-treated patients and healthy controls. Also, those patients who had a good response to treatment had a significant decrease in IFNAR1 and IFNAR2 expression compared to non-responders, non-treated patients and healthy controls. IFNbeta influences the expression of its receptors, and is greater in patients who respond to IFNbeta treatment. This down-regulation could be indicative of the response to IFNbeta.

Published
2006

10. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: Results from the MAINTAIN Nephritis Trial

Author

Houssiau, Frédéric, D'Cruz, David, Sangle, Shirish, Remy, Philippe, Vasconcelos, Carlos, Petrovic, Radmila, Fiehn, Christoph, Garrido, Enrique De Ramon, Gilboe, Inge-Magrethe, Tektonidou, Maria, Blockmans, Daniel, Ravelingien, Isabelle, Le Guern, Véronique, Depresseux, Geneviève, Guillevin, Loïc, Cervera, Ricard, Abramowicz, Daniel, Atzeni, Fabiola, Danieli, Maria Giovanna, De Clercq, Luc, De Keyser, Filip, Delahousse, Michel, Espinosa, Gerard, Golstein, Marc, Hirsch, Marco, Karras, Alexandre, Lang, Philippe, Marchal, Martine, Marinho, António, Max, Regina, Peeters, Patrick, Petera, Peter, Quémeneur, Thomas, Raeman, Frank, Sarzi-Puttini, Piercarlo, De Santis, Lucia Valiente, Verresen, Luc, Weiss, Laurence, Westhovens, René, Houssiau, Frédéric, D'Cruz, David, Sangle, Shirish, Remy, Philippe, Vasconcelos, Carlos, Petrovic, Radmila, Fiehn, Christoph, Garrido, Enrique De Ramon, Gilboe, Inge-Magrethe, Tektonidou, Maria, Blockmans, Daniel, Ravelingien, Isabelle, Le Guern, Véronique, Depresseux, Geneviève, Guillevin, Loïc, Cervera, Ricard, Abramowicz, Daniel, Atzeni, Fabiola, Danieli, Maria Giovanna, De Clercq, Luc, De Keyser, Filip, Delahousse, Michel, Espinosa, Gerard, Golstein, Marc, Hirsch, Marco, Karras, Alexandre, Lang, Philippe, Marchal, Martine, Marinho, António, Max, Regina, Peeters, Patrick, Petera, Peter, Quémeneur, Thomas, Raeman, Frank, Sarzi-Puttini, Piercarlo, De Santis, Lucia Valiente, Verresen, Luc, Weiss, Laurence, and Westhovens, René

Abstract

Background: Long-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment. Methods: A total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months. Results: The baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out. Conclusions: Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2010

11. Anti-cofactor autoantibodies in systemic lupus erythematosus: Prevalence, clinical and HLA class II associations

Author

UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service de rhumatologie, Sebastiani, Gian Domenico, Morozzi, Gabriella, Bellisai, Francesca, Fineschi, Irene, Bacarelli, Maria Romana, Simpatico, Antonella, Font, Josep, Cervera, Ricard, Houssiau, Frédéric, Fernandez-Nebro, Antonio, Garrido, Enrique De Ramon, De Pita, Ornella, Smolen, Josef, Galeazzi, Mauro, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service de rhumatologie, Sebastiani, Gian Domenico, Morozzi, Gabriella, Bellisai, Francesca, Fineschi, Irene, Bacarelli, Maria Romana, Simpatico, Antonella, Font, Josep, Cervera, Ricard, Houssiau, Frédéric, Fernandez-Nebro, Antonio, Garrido, Enrique De Ramon, De Pita, Ornella, Smolen, Josef, and Galeazzi, Mauro

Abstract

The aim of our study was to evaluate the clinical and HLA-class II allele associations of some anti-cofactor antibodies in a homogeneous group of European patients with SLE. One hundred thirty-six patients with SLE, fulfilling four or more of the ACR 1997 revised criteria for the classification of the disease, coming from 7 European countries, were enrolled consecutively. Anti-prothrombin (anti-PT), anti-annexin V (anti-AnnV), anti-protein C (anti-Cprot) and anti-protein S (anti-Sprot) were determined by using commercial ELISA kits. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1, DQB1 and DPB1 loci was performed by using PCR-SSOP method, carried out using digoxygenin (DIG) labeled probes. The prevalence of anti-AnnV, anti-PT, anti-Cprot and anti-Sprot was 19%, 10.4%, 4.4% and 8.1%, respectively. Twenty-seven % of anti-AnnV positive patients reported migraine vs 5.5% of anti-AnnV negatives (p = 0.003, but p not significant, odds ratio (OR) = 6.4, 95% confidence interval (CI) = 2-21). Anti-PT, anti-AnnV and anti-Sprot were positively associated with some HLA alleles, but pc was not significant. In this study we have shown that some HLA alleles carry the risk to produce antibodies against phospholipid-binding proteins, but these association need confirmation in other studies, because they have never been reported and appear to be weak associations.

Published
2008

12. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.

Author

UCL - MD/MINT - Département de médecine interne, UCL - MD/MNOP - Département de morphologie normale et pathologique, UCL - (SLuc) Service de rhumatologie, UCL - (SLuc) Service d'anatomie pathologique, Houssiau, Frédéric, Vasconcelos, Carlos, D'Cruz, David, Sebastiani, Gian Domenico, Garrido Ed, Enrique de Ramon, Danieli, Maria Giovanna, Abramovicz, Daniel, Blockmans, Daniel, Mathieu, Alessandro, Direskeneli, Haner, Galeazzi, Mauro, Gül, Ahmet, Levy, Yair, Petera, Peter, Popovic, Rajko, Petrovic, Radmila, Sinico, Renato Alberto, Cattaneo, Roberto, Font, Josep, Depresseux, Geneviève, Cosyns, Jean-Pierre, Cervera, Ricard, UCL - MD/MINT - Département de médecine interne, UCL - MD/MNOP - Département de morphologie normale et pathologique, UCL - (SLuc) Service de rhumatologie, UCL - (SLuc) Service d'anatomie pathologique, Houssiau, Frédéric, Vasconcelos, Carlos, D'Cruz, David, Sebastiani, Gian Domenico, Garrido Ed, Enrique de Ramon, Danieli, Maria Giovanna, Abramovicz, Daniel, Blockmans, Daniel, Mathieu, Alessandro, Direskeneli, Haner, Galeazzi, Mauro, Gül, Ahmet, Levy, Yair, Petera, Peter, Popovic, Rajko, Petrovic, Radmila, Sinico, Renato Alberto, Cattaneo, Roberto, Font, Josep, Depresseux, Geneviève, Cosyns, Jean-Pierre, and Cervera, Ricard

Abstract

OBJECTIVE: Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment. METHODS: In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed. RESULTS: Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant. CONCLUSION: The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen.

Published
2002

13. HLA class II DNA typing in a large series of European patients with systemic lupus erythematosus - Correlations with clinical and autoantibody subsets

Author

UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service de rhumatologie, Galeazzi, Mauro, Sebastiani, Gian Domenico, Morozzi, Gabriella, Carcassi, Carlo, Ferrara, Giovanni Battista, Scorza, Raffaella, Cervera, Ricard, Garrido, Enrique de Ramon, Fernandez-Nebro, Antonio, Houssiau, Frédéric, Jedryka-Goral, Anna, Passiu, Giuseppe, Papasteriades, Chryssa, Piette, Jean-Charles, Smolen, Josef, Porciello, Giovanni, Marcolongo, Roberto, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service de rhumatologie, Galeazzi, Mauro, Sebastiani, Gian Domenico, Morozzi, Gabriella, Carcassi, Carlo, Ferrara, Giovanni Battista, Scorza, Raffaella, Cervera, Ricard, Garrido, Enrique de Ramon, Fernandez-Nebro, Antonio, Houssiau, Frédéric, Jedryka-Goral, Anna, Passiu, Giuseppe, Papasteriades, Chryssa, Piette, Jean-Charles, Smolen, Josef, Porciello, Giovanni, and Marcolongo, Roberto

Published
2002

14. Immunosuppressive therapy in lupus nephritis: The Euro‐Lupus Nephritis Trial, a randomized trial of low‐dose versus high‐dose intravenous cyclophosphamide

Author

Houssiau, Frédéric A., primary, Vasconcelos, Carlos, additional, D'Cruz, David, additional, Sebastiani, Gian Domenico, additional, Garrido, Enrique de Ramon, additional, Danieli, Maria Giovanna, additional, Abramovicz, Daniel, additional, Blockmans, Daniel, additional, Mathieu, Alessandro, additional, Direskeneli, Haner, additional, Galeazzi, Mauro, additional, Gül, Ahmet, additional, Levy, Yair, additional, Petera, Peter, additional, Popovic, Rajko, additional, Petrovic, Radmila, additional, Sinico, Renato Alberto, additional, Cattaneo, Roberto, additional, Font, Josep, additional, Depresseux, Geneviève, additional, Cosyns, Jean‐Pierre, additional, and Cervera, Ricard, additional

Published
2002
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15. Anticardiolipin and anti-ß2GPI antibodies in a large series of European patients with systemic lupus erythematosus: Prevalence and clinical associations

Author

Sebastiani, Gian Domenico, primary, Galeazzi, Mauro, additional, Tincani, Angela, additional, Piette, Jean-Charles, additional, Font, Josep, additional, Allegri, Flavio, additional, Mathieu, Alessandro, additional, Smolen, Josef, additional, Garrido, Enrique de Ramon, additional, Fernandez-Nebro, Antonio, additional, Jedryka-Goral, Anna, additional, Papasteriades, Chryssa, additional, Morozzi, Gabriella, additional, Bellisai, Francesca, additional, De Pita, Ornella, additional, and Marcolongo, Roberto, additional

Published
1999
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16. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: Lessons from long‐term followup of patients in the Euro‐Lupus Nephritis Trial.

Author

Frédéric A. Houssiau, Carlos Vasconcelos, David D'Cruz, Gian Domenico Sebastiani, Enrique de Ramon Garrido, Maria Giovanna Danieli, Daniel Abramovicz, Daniel Blockmans, Alessandro Mathieu, Haner Direskeneli, Mauro Galeazzi, Ahmet Gül, Yair Levy, Peter Petera, Rajko Popovic, Radmila Petrovic, Renato Alberto Sinico, Roberto Cattaneo, Josep Font, and Geneviève Depresseux

Subjects
LUPUS nephritis, IMMUNOREGULATION, PROGNOSIS, RESEARCH methodology, PREDICTION models
Abstract

In the Euro‐Lupus Nephritis Trial (ELNT), 90 patients with lupus nephritis were randomly assigned to a high‐dose intravenous cyclophosphamide (IV CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or a low‐dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks), each of which was followed by azathioprine (AZA). After a median followup of 41 months, a difference in efficacy between the 2 regimens was not observed. The present analysis was undertaken to extend the followup and to identify prognostic factors. Renal function was prospectively assessed quarterly in all 90 patients except 5 who were lost to followup. Survival curves were derived using the Kaplan‐Meier method. After a median followup of 73 months, there was no significant difference in the cumulative probability of end‐stage renal disease or doubling of the serum creatinine level in patients who received the low‐dose IV CYC regimen versus those who received the high‐dose regimen. At long‐term followup, 18 patients (8 receiving low‐dose and 10 receiving high‐dose treatment) had developed permanent renal impairment and were classified as having poor long‐term renal outcome. We demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 gm/24 hours) was the best predictor of good long‐term renal outcome. Long‐term followup of patients from the ELNT confirms that, in lupus nephritis, a remission‐inducing regimen of low‐dose IV CYC followed by AZA achieves clinical results comparable with those obtained with a high‐dose regimen. Early response to therapy is predictive of good long‐term renal outcome. [ABSTRACT FROM AUTHOR]

Published
2004
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17. Desarrollo de panuveítis por tuberculosis en paciente con esclerosis múltiple tratado con interferón beta

Author

Lucía Echevarría Lucas, Rosa Bellido Muñoz, Olga Villena Irigoyen, Trinidad Nievas Gómez, María José del Río Pardo, and Enrique de Ramón Garrido

Subjects
Tuberculosis ocular, Panuveítis, Esclerosis múltiple, Corticoides, Interferón beta, Ophthalmology, RE1-994
Abstract

Presentamos el caso de un ex toxicómano de 50 años que acudió a consulta de oftalmología con visión borrosa bilateral. En la anamnesis refería su desintoxicación 20 años atrás, con abstinencia total desde entonces y buena reinserción social. Su historia clínica reflejaba serología de hepatitis B+ y C+, pero VIH− y recientemente comenzó con esclerosis múltiple, controlada con interferón beta. Señalaba haber padecido últimamente un resfriado invernal prolongado. En la exploración oftalmológica se apreciaba una uveítis bilateral con precipitados queráticos. En funduscopia del ojo derecho destacaban múltiples granulomas coroideos y zonas de vasculitis periférica, activas y cicatriciales. La funduscopia del ojo izquierdo era normal. Tras diversas pruebas diagnósticas, como radiografía torácica y TAC pulmonar, se detectaron varios nódulos pulmonares. Asimismo, se realizó una prueba de Mantoux que resultó fuertemente positiva. La analítica mostraba neutropenia y linfopenia importantes. Por todo ello se hizo un diagnóstico de presunción de panuveítis secundaria a tuberculosis sistémica. Se administraron fármacos antituberculosos y corticoides sistémicos, con buena respuesta clínica sistémica y ocular. El interferón beta 1b es un inmunomodulador apropiado para la esclerosis múltiple, pero sus principales efectos secundarios son alteraciones analíticas como leucopenia, linfocitopenia y trombocitopenia. Los linfocitos CD4+ T, leucocitos, macrófagos y granulocitos, con la producción de sus mediadores interferón gamma, IL-12 o TNF-α son fundamentales para controlar al Mycobacterium tuberculosis. Por ello, antes de introducir Interferón beta 1b, convendría realizar técnicas de screening, como la prueba de Mantoux o el interferon gamma release assay–(quantiferon-TB) para detectar posibles tuberculosis latentes potencialmente activables.

Published
2016
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18. Estado de salud y utilización de recursos sanitarios de una población de ancianos atendidos en domicilio Health conditions and use of social care resources in a population of the elderly taken care at home

Author

Carmen Gálvez-Romero, Araceli González-Valentín, and Enrique de Ramón Garrido

Subjects
Atención domiciliaria, dependencia funcional, ancianos, percepción de salud y utilización de servicios sanitarios, Home care, functional dependence, elderly, perception of health, use of health care resources, Nursing, RT1-120
Abstract

La población de personas mayores, respecto a la población general en España, representa un 15,4%, proporción que aumentará en el futuro, sobre todo en mayores de 80 años. La atención domiciliaria de esta población es alternativa a su institucionalización, por lo que interesa conocer sus características sociodemográficas, clínicas y de utilización de recursos sanitarios para responder a sus necesidades reales. Se realizó un estudio de corte transversal en pacientes incluidos en un programa de incapacitados. Se estudiaron variables sociodemográficas y clínicas, capacidad funcional y cognitiva, y utilización de recursos sociosanitarios. Nuestros pacientes son una población mayor, presentan deterioro cognitivo importante, nivel elevado de dependencia y comorbilidad. Una quinta parte considera su estado de salud como malo. Utilizan con frecuencia los servicios de urgencia y, en menor medida, ingresan en el hospital. Algunas características sociodemográficas de estos pacientes determinan su nivel de audición y estado mental, tales como la edad, ocupación en su etapa laboral e ingresos económicos. Se mostraron determinantes de la utilización de los servicios sanitarios las patologías crónicas, la polifarmacia, escasamente las incapacidades funcionales y los ingresos económicos.Older persons represent 15,4% of the population of Spain. This proportion will increase in the future, especially for persons older than 80 years of age. As home care for this population is an alternative to their institutionalization, it is necessary to determine their sociodemographic and clinical characteristics, as well as their use of health care resources, in order to respond to their true needs. We undertook a cross-sectional study of patients included in an Incapacity Program. Variables studied included sociodemographic and clinical factors, functional and cognitive capacity, and the use of health and social care resources. The patients were older, with important cognitive worsening, and a high level of dependence and accompanying disease. One fifth considered their health status as poor. They often used the emergency services, and less often were admitted to hospital. Certain sociodemographic characteristics of these patients determined their level of hearing and mental status, such as age, occupation during their working life, and financial income. Factors determining their use of the health services were chronic disease, polypharmacy, slight functional incapacity and financial income.

Published
2007

19. Analysis of ancestral and functionally relevant CD5 variants in systemic lupus erythematosus patients.

Author

Maria Carmen Cenit, Mario Martínez-Florensa, Marta Consuegra, Lizette Bonet, Elena Carnero-Montoro, Noelia Armiger, Miguel Caballero-Baños, Maria Teresa Arias, Daniel Benitez, Norberto Ortego-Centeno, Enrique de Ramón, José Mario Sabio, Francisco J García-Hernández, Carles Tolosa, Ana Suárez, Miguel A González-Gay, Elena Bosch, Javier Martín, and Francisco Lozano

Subjects
Medicine, Science
Abstract

ObjectiveCD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis.MethodsThe CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed.ResultsT-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis.ConclusionThe ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.

Published
2014
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20. No evidence of association between common autoimmunity STAT4 and IL23R risk polymorphisms and non-anterior uveitis.

Author

María Carmen Cénit, Ana Márquez, Miguel Cordero-Coma, Marina Begoña Gorroño-Echebarría, Alejandro Fonollosa, Alfredo Adán, Agustín Martínez-Berriotxoa, David Díaz Valle, Esperanza Pato, Ricardo Blanco, Joaquín Cañal, Manuel Díaz-Llopis, José Luis García Serrano, Enrique de Ramón, María José Del Rio, José Manuel Martín-Villa, Blanca Molins, Norberto Ortego-Centeno, and Javier Martín

Subjects
Medicine, Science
Abstract

ObjectiveSTAT4 and IL23R loci represent common susceptibility genetic factors in autoimmunity. We decided to investigate for the first time the possible role of different STAT4/IL23R autoimmune disease-associated polymorphisms on the susceptibility to develop non-anterior uveitis and its main clinical phenotypes.MethodsFour functional polymorphisms (rs3821236, rs7574865, rs7574070, and rs897200) located within STAT4 gene as well as three independent polymorphisms (rs7517847, rs11209026, and rs1495965) located within IL23R were genotyped using TaqMan® allelic discrimination in a total of 206 patients with non-anterior uveitis and 1553 healthy controls from Spain.ResultsNo statistically significant differences were found when allele and genotype distributions were compared between non-anterior uveitis patients and controls for any STAT4 (rs3821236: P=0.39, OR=1.12, CI 95%=0.87-1.43; rs7574865: P=0.59 OR=1.07, CI 95%=0.84-1.37; rs7574070: P=0.26, OR=0.89, CI 95%=0.72-1.10; rs897200: P=0.22, OR=0.88, CI 95%=0.71-1.08;) or IL23R polymorphisms (rs7517847: P=0.49, OR=1.08, CI 95%=0.87-1.33; rs11209026: P=0.26, OR=0.78, CI 95%=0.51-1.21; rs1495965: P=0.51, OR=0.93, CI 95%=0.76-1.15).ConclusionOur results do not support a relevant role, similar to that described for other autoimmune diseases, of IL23R and STAT4 polymorphisms in the non-anterior uveitis genetic predisposition. Further studies are needed to discard a possible weak effect of the studied variant.

Published
2013
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21. Evidence of new risk genetic factor to systemic lupus erythematosus: the UBASH3A gene.

Author

Lina-Marcela Diaz-Gallo, Elena Sánchez, Norberto Ortego-Centeno, Jose Mario Sabio, Francisco J García-Hernández, Enrique de Ramón, Miguel A González-Gay, Torsten Witte, Hans-Joachim Anders, María F González-Escribano, and Javier Martin

Subjects
Medicine, Science
Abstract

The ubiquitin associated and Src-homology 3 (SH3) domain containing A (UBASH3a) is a suppressor of T-cell receptor signaling, underscoring antigen presentation to T-cells as a critical shared mechanism of diseases pathogenesis. The aim of the present study was to determine whether the UBASH3a gene influence the susceptibility to systemic lupus erythematosus (SLE) in Caucasian populations. We evaluated five UBASH3a polymorphisms (rs2277798, rs2277800, rs9976767, rs13048049 and rs17114930), using TaqMan® allelic discrimination assays, in a discovery cohort that included 906 SLE patients and 1165 healthy controls from Spain. The SNPs that exhibit statistical significance difference were evaluated in a German replication cohort of 360 SLE patients and 379 healthy controls. The case-control analysis in the Spanish population showed a significant association between the rs9976767 and SLE (Pc = 9.9E-03 OR = 1.21 95%CI = 1.07-1.37) and a trend of association for the rs2277798 analysis (P = 0.09 OR = 0.9 95%CI = 0.79-1.02). The replication in a German cohort and the meta-analysis confirmed that the rs9976767 (Pc = 0.02; Pc = 2.4E-04, for German cohort and meta-analysis, respectively) and rs2277798 (Pc = 0.013; Pc = 4.7E-03, for German cohort and meta-analysis, respectively) UBASH3a variants are susceptibility factors for SLE. Finally, a conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs9976767 polymorphism. Our results suggest that UBASH3a gene plays a role in the susceptibility to SLE. Moreover, our study indicates that UBASH3a can be considered as a common genetic factor in autoimmune diseases.

Published
2013
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22. Two functional variants of IRF5 influence the development of macular edema in patients with non-anterior uveitis.

Author

Ana Márquez, María Carmen Cénit, Miguel Cordero-Coma, Norberto Ortego-Centeno, Alfredo Adán, Alejandro Fonollosa, David Díaz Valle, Esperanza Pato, Ricardo Blanco, Joaquín Cañal, Manuel Díaz-Llopis, Enrique de Ramón, María José Del Rio, José Luis García Serrano, Joseba Artaraz, José Manuel Martín-Villa, Víctor Llorenç, Marina Begoña Gorroño-Echebarría, and Javier Martín

Subjects
Medicine, Science
Abstract

OBJECTIVE:Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated IRF5 genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes. METHODS:Three IRF5 polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin. RESULTS:A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (P FDR =5.07E-03, OR=1.48, CI 95%=1.14-1.92 and P FDR =3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: P=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: P=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both IRF5 genetic variants are specifically associated with the lack of macular edema in uveitis patients. CONCLUSION:Our results clearly showed for the first time that two functional genetic variants of IRF5 may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies.

Published
2013
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23. Estado de salud y utilización de recursos sanitarios de una población de ancianos atendidos en domicilio

Author

Carmen Gálvez-Romero, Araceli González-Valentín, and Enrique de Ramón Garrido

Subjects
Atención domiciliaria, dependencia funcional, ancianos, percepción de salud y utilización de servicios sanitarios, Nursing, RT1-120
Abstract

La población de personas mayores, respecto a la población general en España, representa un 15,4%, proporción que aumentará en el futuro, sobre todo en mayores de 80 años. La atención domiciliaria de esta población es alternativa a su institucionalización, por lo que interesa conocer sus características sociodemográficas, clínicas y de utilización de recursos sanitarios para responder a sus necesidades reales. Se realizó un estudio de corte transversal en pacientes incluidos en un programa de incapacitados. Se estudiaron variables sociodemográficas y clínicas, capacidad funcional y cognitiva, y utilización de recursos sociosanitarios. Nuestros pacientes son una población mayor, presentan deterioro cognitivo importante, nivel elevado de dependencia y comorbilidad. Una quinta parte considera su estado de salud como malo. Utilizan con frecuencia los servicios de urgencia y, en menor medida, ingresan en el hospital. Algunas características sociodemográficas de estos pacientes determinan su nivel de audición y estado mental, tales como la edad, ocupación en su etapa laboral e ingresos económicos. Se mostraron determinantes de la utilización de los servicios sanitarios las patologías crónicas, la polifarmacia, escasamente las incapacidades funcionales y los ingresos económicos.

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