The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation ...are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess the relationship between circulating levels of cytokines, hepatic expression of toll-like receptors (TLRs), and degrees of NAFLD, and to investigate whether these levels could serve as noninvasive biomarkers of NASH. The present study assessed plasma levels of cytokines in 29 normal-weight women and 82 women with morbid obesity (MO) (subclassified: normal liver (
= 29), simple steatosis (
= 32), and NASH (
= 21)). We used enzyme-linked immunosorbent assays (ELISAs) to quantify cytokine and TLR4 levels and RTqPCR to assess TLRs hepatic expression. IL-1β, IL-8, IL-10, TNF-α, tPAI-1, and MCP-1 levels were increased, and adiponectin levels were decreased in women with MO. IL-8 was significantly higher in MO with NASH than in NL. To sum up, high levels of IL-8 were associated with the diagnosis of NASH in a cohort of women with morbid obesity. Moreover, a positive correlation between TLR2 hepatic expression and IL-8 circulating levels was found.
The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to ...choose the best personalized therapy for their patients.
To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice.
We designed a real-life study with 2 years of follow-up (TRAZELGA GEE-ELI-2017-01) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant.
Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy.
In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.
This is the first Spanish multicentric inception lupus cohort, formed by SLE patients attending Spanish Internal Medicine Services since January 2009. We aimed to analyse drug therapy during the ...first year of follow-up according to disease severity.
223 patients who had at least one year of follow-up were enrolled upon diagnosis of SLE. Therapy with prednisone, pulse methyl-prednisolone, hydroxychloroquine, immunosuppressives and calcium/vitamin D was analysed.
Prednisone was given to 65% patients, at a mean (SD) daily dose of 11 (10) mg/d. 38% patients received average doses >7.5 mg/d during the first year. Patients with nephritis and with a SLEDAI ≥6 were treated with higher doses of prednisone. 81% of patients were treated with hydroxychloroquine, with higher frequency among those with a SLEDAI ≥6 (88% vs. 68%, p<0.001). The use of immunosuppressive drugs and methyl-prednisolone pulses was higher in patients with a baseline SLEDAI ≥6, however, differences were no longer significant when patients with lupus nephritis were excluded. The use of calcium/vitamin D increased with the dose of prednisone, however, 43% of patients on medium-high doses of prednisone did not take any calcium or vitamin D.
This study gives a real-world view of the current therapeutic approach to early lupus in Spain. The generalised use of hydroxychloroquine is well consolidated. There is still a tendency to use prednisone at medium to high doses. Pulse methyl-prednisolone and immunosuppressive drugs were used in more severe cases, but not as steroid sparing agents. Vitamin D use was suboptimal.
IgG4-related disease (IgG4-RD) is a rare entity consisting of inflammation and fibrosis that has been described in multiple organs. Concrete diagnostic criteria have been established recently and ...there is a lack of large series of patients.To describe the clinical presentation, histopathological characteristics, treatment and evolution of a series of IgG4-RD Spanish patients.A retrospective multicenter study was performed. Twelve hospitals across Spain included patients meeting the current 2012 consensus criteria on IgG4-RD diagnosis.Fifty-five patients were included in the study, 38 of whom (69.1%) were male. Median age at diagnosis was 53 years. Thirty (54.5%) patients were included in the Histologically Highly Suggestive IgG4-RD group and 25 (45.5%) in the probable IgG4-RD group. Twenty-six (47.3%) patients had more than 1 organ affected at presentation. The most frequently affected organs were: retroperitoneum, orbital pseudotumor, pancreas, salivary and lachrymal glands, and maxillary sinuses.Corticosteroids were the mainstay of treatment (46 patients, 83.6%). Eighteen patients (32.7%) required additional immunosuppressive agents. Twenty-four (43.6%) patients achieved a complete response and 26 (43.7%) presented a partial response (<50% of regression) after 22 months of follow-up. No deaths were attributed directly to IgG4-RD and malignancy was infrequent.This is the largest IgG4-RD series reported in Europe. Patients were middle-aged males, with histologically probable IgG4-RD. The systemic form of the disease was frequent, involving mainly sites of the head and abdomen. Corticosteroids were an effective first line treatment, sometimes combined with immunosuppressive agents. Neither fatalities nor malignancies were attributed to IgG4-RD.
TESI DOCTORALEl trabajo de tesis que se presenta consta de dos estudios sobre procesos que tienen en común la presencia de bacteriemia persistente. El primero, un estudio sobre la bacteriemia de ...brecha, analiza las asociaciones etiológicas y microbiológicas, así como su valor pronóstico. El segundo expone las características de una serie de endocarditis infecciosa en un hospital docente que no dispone de cirugía cardiaca, y analiza el efecto del establecimiento de un grupo de trabajo multidisciplinar sobre endocarditis bacteriana. El primer estudio tiene por objetivo determinar el significado clínico y el pronóstico de la bacteriemia de brecha. El estudio consiste en un análisis retrospectivo de los casos recogidos prospectivamente del hospital Clínic de Barcelona y del hospital Universitari Joan XXIII de Tarragona. Se incluyeron los pacientes mayores de 14 años con bacteriemia de brecha y se analizaron las características demográficas, enfermedades subyacentes, origen nosocomial, focos infecciosos, microorganismos, pronóstico de la enfermedad de base y la mortalidad. La bacteriemia de brecha se evidenció en 392 de 6324 episodios (6,2%). El 80% fueron nosocomiales. El foco infeccioso más frecuente fue el endovascular. Los microorganismos aislados más frecuentes fueron Staphylococcus coagulasa negativa, S. aureus y P. aeruginosa. Fueron predictores de bacteriemia de brecha determinados focos (catéter venoso central, endocarditis y otros focos endovasculares); enfermedades subyacentes como neutropenia, politraumatismo, transplante de médula ósea alogénica y transplante de riñón; microorganismos como S. aureus, P aeruginosa y la infección polimicrobiana. La mortalidad cruda fue mayor en los pacientes con bacteriemia de brecha que en los que tenían bacteriemia no de brecha y esta condición fue predictor independiente de mortalidad. Se concluye que la bacteriemia de brecha es un predictor de mortalidad y su presencia supone una alta probabilidad de un foco endovascular. El objetivo del segundo estudio es analizar las características clínicas, el tratamiento de la endocarditis infecciosa en un hospital docente que no dispone de cirugía cardiaca.El estudio es descriptivo, de tendencias, y de casos y controles. Los casos se recogieron de los pacientes mayores de 14 años diagnosticados de endocarditis infecciosa en el hospital Universitario Joan XXIII. Se analizaron los factores de riesgo, las complicaciones, la indicación de cirugía cardiaca y la mortalidad. Se comparó con otras series procedentes de hospitales de tercer nivel y se analizó el papel sobre el pronóstico de un grupo multidisciplinar sobre endocarditis infecciosa. Se recogieron 120 casos con una edad de 50,8 ± 17,8 años (67,6%, varones). La incidencia se mantuvo estable a lo largo del estudio. La distribución por categorías fue: población general no seleccionada, 55%; asociada a drogadicción parenteral, 25%, y nosocomial, 20%. S. aureus fue el aislamiento más frecuente. Un 83% de pacientes presentó alguna complicación grave. La mortalidad intrahospitalaria fue del 19,2%. La insuficiencia renal aguda y el absceso perivalvular fueron predictores independientes de muerte. La disponibilidad del grupo de trabajo multidisciplinario sobre endocarditis infecciosa se asoció con un aumento significativo de la indicación de tratamiento quirúrgico y no se observaron cambios en la mortalidad intrahospitalaria .Se concluye que la insuficiencia renal aguda y el absceso perivalvular en el curso de una endocarditis infecciosa son factores de mal pronóstico. Un enfoque multidisciplinario de la endocarditis infecciosa ha comportado cambios en su tratamiento y ha incrementado la indicación de cirugía cardiaca.Publicaciones realizadas: Lopez Dupla M, Martínez JA, Vidal F, Almela M, López J, Marco F, Soriano A, Richart C, Mensa J. Clinical characterization of breakthrough bacteremia: a survey of 392 episodes. J Intern Med 2005; 258: 172-180.López-Dupla M, Hernández S, Olona M, Mercé J, Lorenzo A, Tapiol J, Gómez F, Santamaría J, García R, Auguet T, Richart C, Castells E, Bardají A, Vidal F. Características clínicas y evolución de la endocarditis infecciosa en una población general no seleccionada, atendida en un hospital docente que no dispone de cirugía cardiaca. Estudio de 120 casos. Rev Esp Cardiol 2006; 59: 1131-9.
OF THE THESISThe thesis presented is a made up of two works that have as a common characteristic to be both a report about persistent bacteremia. The first study analyses aetiology, microbiological associations and prognosis of breakthrough bacteraemia. The second one states the characteristics of a series of infective endocarditis in a teaching hospital without cardiac surgery facilities and analyses the effect of a multidisciplinary group working at infective endocarditis. The objective of the first study is to determine the clinical significance and outcome of a large series of breakthrough bacteremia. It is a retrospective analysis of a prospectively collected database from two hospitals, hospital Clínic of Barcelona and hospital Universitari Joan XXIII of Tarragona. Patients higher than 14 years diagnosed of breakthrough bacteremia were included. Demographic characteristics, underlying diseases, origin of infection, sources of infection, microorganisms isolated, prognosis of underlying disease and mortality were analysed. Breakthrough bacteremia was detected in 392 of 6324 episodes (6,2%) of bacteremia. Eighty percent of them were nosocomial and the most frequent source of infection was endovascular. Coagulase-negative staphylococcus, S. aureus, and P. aeruginosa were the most significant microorganisms involved. The conditions independently associated with an increased risk for developing breakthrough bacteraemia were nosocomial acquisition, selected sources (central venous catheter, endocarditis and other endovascular foci), underlying conditions (neutropenia, polytraumatism, allogenic bone marrow and kidney transplantation), and some particular microbial aetiologies (S. aureus, P. aeruginosa and polymicrobial). Crude mortality rate was greater in patients with breakthrough bacteraemia, and this condition was an independent predictor of death.In conclusion, breakthrough bacteremia is an independent predictor of death and when it occurs it is mandatory to search for an endovascular focus . The objective of the second study is to assess the clinical characteristics and management of infective endocarditis at a teaching hospital without cardiac surgery facilities, before and after the introduction of a specialized team involved in the treatment of endocarditis. The study is descriptive case-control study looking at trends. The cases were collected form the hospital Universitari Joan XXIII of Tarragona. Risk factors, the rate of complications, the rate of referral for cardiac surgery, and the mortality rate were assessed, and compared with those of other tertiary hospital with cardiac surgery. The study included 120 patients, with a mean age of 50.8±17.8 years (67.6% men). Disease incidence did not change throughout the study. Fifty-five percent of infective endocarditis cases occurred in the ordinary general population, 25% were in intravenous drug users, and 20% were of nosocomial origin. The most commonly isolated microorganism was Staphylococcus aureus. Up to 83% of patients presented with a severe complication. The in-hospital mortality rate was 19.2%. Acute renal failure and perivalvular abscess were independent predictors of death. The introduction in 2002 of a multidisciplinary team involved in the diagnosis, treatment and follow-up of infective endocarditis that included a consultant cardiac surgeon, was associated with a significant increase in referrals for surgery, though in-hospital mortality was not significantly altered. In conclusion, the occurrence of acute renal failure and perivalvular abscess worsen the prognosis of infective endocarditis. The introduction of a multidisciplinary team involved in the treatment of infective endocarditis modified the management of the disease and increased referrals for cardiac surgery.Publications: Lopez Dupla M, Martínez JA, Vidal F, Almela M, López J, Marco F, Soriano A, Richart C, Mensa J. Clinical characterization of breakthrough bacteremia: a survey of 392 episodes. J Intern Med 2005; 258: 172-180.López-Dupla M, Hernández S, Olona M, Mercé J, Lorenzo A, Tapiol J, Gómez F, Santamaría J, García R, Auguet T, Richart C, Castells E, Bardají A, Vidal F. Características clínicas y evolución de la endocarditis infecciosa en una población general no seleccionada, atendida en un hospital docente que no dispone de cirugía cardiaca. Estudio de 120 casos. Rev Esp Cardiol 2006; 59: 1131-9.
Objective
To compare the accuracy of the Birmingham Vasculitis Activity Score (BVAS), version 3, and the Five Factor Score (FFS), version 1996 and version 2009, to assess survival in antineutrophil ...cytoplasmic antibody–associated vasculitis (AAV).
Methods
A total of 550 patients with AAV (41.1% with granulomatosis with polyangiitis, 37.3% with microscopic polyangiitis, and 21.6% with eosinophilic granulomatosis with polyangiitis), diagnosed between 1990 and 2016, were analyzed. Receiver operating characteristic (ROC) curves and multivariable Cox analysis were used to assess the relationships between the outcome and the different scores.
Results
Overall mortality was 33.1%. The mean ± SD BVAS at diagnosis was 17.96 ± 7.82 and was significantly higher in nonsurvivors than in survivors (mean ± SD 20.0 ± 8.14 versus 16.95 ± 7.47, respectively; P < 0.001). The mean ± SD 1996 FFS and 2009 FFS were 0.81 ± 0.94 and 1.47 ± 1.16, respectively, and were significantly higher in nonsurvivors than in survivors (mean ± SD 1996 FFS 1.17 ± 1.07 versus 0.63 ± 0.81 P < 0.001 and 2009 FFS 2.13 ± 1.09 versus 1.15 ± 1.05 P < 0.001, respectively). Mortality rates increased according to the different 1996 FFS and 2009 FFS categories. In multivariate analysis, BVAS, 1996 FFS, and 2009 FFS were significantly related to death (P = 0.007, P = 0.020, P < 0.001, respectively), but the stronger predictor was the 2009 FFS (hazard ratio 2.9 95% confidence interval 2.4–3.6). When the accuracy of BVAS, 1996 FFS, and 2009 FFS to predict survival was compared in the global cohort, ROC analysis yielded area under the curve values of 0.60, 0.65, and 0.74, respectively, indicating that 2009 FFS had the best performance. Similar results were obtained when comparing these scores in patients diagnosed before and after 2001 and when assessing the 1‐year, 5‐year, and long‐term mortality. Correlation among BVAS and 1996 FFS was modest (r = 0.49; P < 0.001) but higher than between BVAS and the 2009 FFS (r = 0.28; P < 0.001).
Conclusion
BVAS and FFS are useful to predict survival in AAV, but the 2009 FFS has the best prognostic accuracy at any point of the disease course.
▪
Gaucher disase(GD), the most studied lysosomal rare disorder, is characterized by an inflammatory status involved in the high incidence of complications, immune impairment and comorbidities ...(infections, bone, pulmonary involvement, gammapathies and parkinsonism). The role of cytokines in this inflammatory state is partially known, and the modifications in this profile in GD patients under enzymatic replacement therapy have not been reported and neither included in clinical trial. Our group has reported some changes on the cytokine profile in patients with severe bone involvement and some inflammatory biomarkers of macrophage activation related to the iron profile. (Gervas 2015, Medrano 2015). However there are not specific studies related to different therapies.
Here we are presenting the final outcomes of a multicentre prospective non interventional study to explore the changes in the biomarkers of immune response in a cohort of Spanish type 1 Gaucher disease patients after one year on Velaglucerase alfa therapy.
Patients and Methods: A total of 17 type 1 GD from 15 centers, were included in a prospective protocol following these criteria: symptomatic patients of both sexes, aged older than 4 years, naïve or previously treated but without ERT at least one month previous to be included. The study was approval by ethical committees and designed according Helsinki declaration rules; every one patient signed the informed consent and commitment to complete all study. Current recommendation for ERT with Velaglucerase alfa were followed in every centre.
The study included hematological parameters, goals of therapy assessment, bone disease assessment were carried out in every visit and bone marrow MRI evaluated by Spanish-MRI score (Roca et al 2004) and densitometry were performed at baseline and in the final visit according the availability in each centre. GD biomarkers (Chitotriosidase, CCL18/PARC), proinflammatory biomarkers (ferritin level, serum protein electrophoresis and gammapathy profile including free light chain analysis) and the following cytokine profile: IL-10, IL-13, IL-4, IL-6, IL-7, Mip1a, Mip1b,TNFa, performed at baseline and 12 months after therapy.
Results: General characteristics: 9 males, 8 females, mean age: 37.5 years (9-72). 3 splenectomized patients (17.6%); genotype: 3 N370S homozygous one heterozygous for N370S/L444P and the rest heterozygous for N370S/other. Seven patients (41.2%) have previous history of bone disease complications. All patients received velaglucerase alfa (30U/kg-60U/kg) iv every two weeks for 1 year in every day clinical practice, and achieving an bjective response on goals of disease (hemoglobine, platelets count, spleen reduction and clinically asymptomatic),bone marrow burden decrease and stabilization were registered by MRI in 14 patients, bone mineral density improvement were reported during the year of therapy in those patients. No infusion reactions were reported, neither antibodies against velaglucerase alfa; concerning to biomarkers, a reduction or stabilization of CT activity and CCL/18PARC concentration were significantly reduced (p=0.011; p=0.041 respectively), no modification in the ferritin concentration were registered, no monoclonal gammopathy were found but polyclonal gammopathy were observed in the majority of patients, a tendency of normalization were detected. The cytokine profile showed a decrease in all inflammatory cytokines tested however for Mip1a (p=0.017) and TNFa (p=0.023) a significant reduction were achieved. Table 1
Conclusion: Velaglucerase alfa is a well-tolerated therapy in every day clinical practice, with a positive impact in the immune response with a significant decrease on the inflammatory state reflected through the cytokine reduction and preventing development of bone complications in this cohort independently of previous therapies.
Acknowledgments: This work was partially supported by a grant from Shire and FIS: PS12/01219
Table 1Comparative reduction of cytokines between baseline and 12 monthsIL10IL13IL4IL6IL7Mip 1aMip 1bTNF aChi X23.4150.0002.6681.6061.5458.1593.3084.263grade22222222significance0.1811.0000.2630.4480.4620.0170.1910.023
A significant decrease on Mip1a (p=0.017) and TNFa (p=0.023) and the end of study
No relevant conflicts of interest to declare.
to compare the accuracy of Birmingham Vasculitis score (BVAS) v.3, and Five Factors Score (FFS) v.1996 and v.2009, to assess survival in ANCA-associated Vasculitis (AAV).
550 patients with AAV (41.1% ...GPA, 37.3% MPA, 21.6% EGPA) diagnosed between 1990-2016 were analyzed. ROC curves and multivariable Cox analysis were used to assess the relationships between the outcome and the different scores.
Overall mortality was 33.1%. The mean BVAS at diagnosis was 17.96±7.82, and was significantly higher in non-survivors than in survivors (20.0±8.14 vs. 16.95±7.47, p<0.001). The mean 1996FFS and 2009FFS were 0.81±0.94 and 1.47±1.16, respectively, and were significantly higher in non-survivors than in survivors (1.17±1.07 vs. 0.63±0.81, p<0.001; 2.13±1.09 vs. 1.15±1.05, p<0.001). Mortality rates increased accordingly to the different 1996FFS and 2009FFS categories. In multivariate analysis BVAS, 1996FFS and 2009FFS were significantly related to death (p=0.007, p=0.020, p<0.001), but the stronger predictor was the 2009FFS (HR 2.9, 2.4-3.6). When the accuracy of BVAS, 1996FFS and 2009FFS to predict survival was compared in the global cohort, ROC analysis yielded AUC values of 0.60, 0.65 and 0.74, respectively, indicating that 2009FFS had the best performance. Similar results were obtained when comparing these scores in patients diagnosed before and after 2001, and assessing the 1-year, 5-years and long-term mortality. Correlation among BVAS and 1996FFS was modest (r=0.49, p<0.001), but higher than between BVAS and 2009FFS (r=0.28, p<0.001).
BVAS and FFS are useful to predict survival in AAV, but 2009FFS has the best prognostic accuracy at any point of the disease course.
This is the first study comparing the BVAS, 1996FFS and 2009FFS accuracy to assess survival in patients with AAV, and the first to validate 2009FFS in these patients. This article is protected by copyright. All rights reserved.
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