Búsqueda de biomarcadores y mecanismos de respuesta a ocrelizumab en pacientes con esclerosis múltiple primariamente progresiva

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 13-01-2023La esclerosis múltiple (EM) es una enfermedad autoinmune crónica del sistema nervioso central que induce desmielinización, inflamación y daño axonal. Es una enfermedad heterogénea con gran variabilidad clínica, cuya etiología se desconoce, aunque se han identificado diferentes factores ambientales que favorecen la aparición de la enfermedad en individuos predispuestos genéticamente. Aproximadamente un 15% de los pacientes debutan con la forma primariamente progresiva (EMPP), caracterizada por la progresión continua de la disfunción neurológica desde el comienzo de la enfermedad. Aunque en las últimas décadas ha aumentado exponencialmente el número de opciones terapéuticas disponibles en la EM, éstas no han logrado modificar con éxito el curso de la EMPP. En el momento actual, ocrelizumab, un anticuerpo monoclonal anti-CD20, es el único tratamiento aprobado para pacientes con esta forma clínica de la enfermedad, gracias a unos buenos perfiles de seguridad y eficacia demostrados en el ensayo clínico ORATORIO. Sin embargo, se desconocen los efectos del fármaco sobre el sistema inmunitario, por lo que resulta imprescindible entender el impacto que tiene sobre las diferentes poblaciones inmunológicas y su posible asociación con la respuesta al tratamiento. Además, no se sabe si ocrelizumab actúa diferencialmente en función del estado inflamatorio basal de los pacientes...Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that induces demyelination, inflammation and axonal damage. MS is a heterogeneous disease with great clinical variability whose etiology is unknown, although different environmental factors have been identified promoting disease onset in genetically predisposed individuals. Approximately 15% of patients debut with primary progressive MS (PPMS), a clinical form characterized by continuous progression of neurological dysfunction since disease´s onset.Although number of therapeutic options in MS has increased exponentially in recent decades, they have failed to successfully modify the course of PPMS. At present, ocrelizumab, an anti-CD20 monoclonal antibody, is the only approved drug for patients with this clinical form of the disease, with good safety and efficacy profiles demonstrated in the ORATORIO clinical trial.However, the effects of the drug on the immune system are unknown, so it is essential to understand its impact on different immune subsets and its possible association with response to treatment. Furthermore, it is not known whether the effect of ocrelizumab depends on the baseline inflammatory status of the patients...Fac. de MedicinaTRUEunpu

Effect of sex in systemic psoriasis therapy: Differences in prescription, effectiveness and safety in the BIOBADADERM prospective cohort

The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be pre-scribed biologics. There were no differences between men and women in effectiveness of therapy, measur-ed in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness.The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall)

Effect of alemtuzumab over sNfL and sGFAP levels in multiple sclerosis

IntroductionAlemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS).AimTo evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years.MethodsThis prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison.ResultsThe study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7–42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56–10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1–3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7–52.7] pg/ml and 158.9 [IQR, 126.9–255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03–8.54] pg/ml and 91.0 [72.6–109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values.ConclusionAlemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values

Results obtained from the multiple geodetic observations at Lorca (Murcia, Spain) subsidence area

Trabajo presentado en el AGU (American Geophysical Union) Fall Meeting: Advancing Earth and Space Science, celebrado en Washington D.C. (Estados Unidos), del 10 al 14 de diciembre de 2018The Lorca region, located in the Alto Guadalentín Basin, southern Spain, shows the highest subsidence rates recorded in Europe (about 10 cm/yr). It is produced by a long-term aquifer exploitation (González and Fernández, 2011; Bonì et al., 2014). This process has been studied in various works using interferometric synthetic aperture radar (InSAR) with images acquired from different satellites (ERS and ENVISAT radar data spanning the 1992 – 2007 period; ALOS PALSAR data for the period 2007–2010; and COSMO-SkyMed data for the period 2011–2012). González et al. (2012) established a relationship between the crustal unloading produced by the groundwater overexploitation and the stress change on the regional active tectonic faults in relation with the May 2008 Lorca earthquake. Those previous studies, based on InSAR and using either ascending or descending acquisitions, assumed that the surface displacement direction is entirely vertical. However, it is important to obtain the complete 3D motion field in order to perform a correct interpretation of the observations, as well as to carry out an advanced numerical model of the aquifer evolution, to be considered for sustainable management plans of groundwater resources and hazard assessments. To achieve this goal, GNSS surveys have been carried out from 2015 to 2018, showing the regional 3D displacement field associated to the exploitation of the aquifer (Prieto et al., 2016; Fernández et al. 2017). Also, simultaneous ascending and descending InSAR observations have been used, along with structural gravimetry (Camacho et al., 2015) and microgravity to study the subsidence area in a more complete geodetic way. We present the results obtained from all those techniques, their comparison, and the interpretation results using different inversion techniques (Tiampo et al., 2011; Camacho et al., 2011, 2015; Cannavò et al., 2015).Peer reviewe

Herpesvirus Antibodies, Vitamin D and Short-Chain Fatty Acids: Their Correlation with Cell Subsets in Multiple Sclerosis Patients and Healthy Controls

Although the etiology of multiple sclerosis (MS) is still unknown, it is commonly accepted that environmental factors could contribute to the disease. The objective of this study was to analyze the humoral response to Epstein-Barr virus, human herpesvirus 6A/B and cytomegalovirus, and the levels of 25-hydroxyvitamin D (25(OH)D) and the three main short-chain fatty acids (SCFA), propionate (PA), butyrate (BA) and acetate (AA), in MS patients and healthy controls (HC) to understand how they could contribute to the pathogenesis of the disease. With this purpose, we analyzed the correlations among them and with different clinical variables and a wide panel of cell subsets. We found statistically significant differences for most of the environmental factors analyzed when we compared MS patients and HC, supporting their possible involvement in the disease. The strongest correlations with the clinical variables and the cell subsets analyzed were found for 25(OH)D and SCFAs levels. A correlation was also found between 25(OH)D and PA/AA ratio, and the interaction between these factors negatively correlated with interleukin 17 (IL-17)-producing CD4+ and CD8+ T cells in untreated MS patients. Therapies that simultaneously increase vitamin D levels and modify the proportion of SCFA could be evaluated in the future

Connected Insulin Pens and Caps : An Expert's Recommendation from the Area of Diabetes of the Spanish Endocrinology and Nutrition Society (SEEN)

Undoubtedly, technological advances have revolutionised diabetes management in recent years. The development of advanced closed hybrid loop insulin pumps or continuous glucose monitoring (CGM) systems, among others, have increased the quality of life and improved glycaemic control of people with diabetes. However, only some patients have access to such technology, and only some want to use it. CGM has become much more widespread, but in terms of insulin delivery, most people with type 1 diabetes (T1D) and almost all people with type 2 diabetes (T2D) on insulin therapy are treated with multiple-dose insulin injections (MDI) rather than an insulin pump. For these patients, using connected insulin pens or caps has shown benefits in reducing missed insulin injections and promoting correct administration over time. In addition, using these devices improves the quality of life and user satisfaction. The integration of insulin injection and CGM data facilitates both users and the healthcare team to analyse glucose control and implement appropriate therapeutic changes, reducing therapeutic inertia. This expert's recommendation reviews the characteristics of the devices marketed or in the process of being marketed and their available scientific evidence. Finally, it suggests the profile of users and professionals who would benefit most, the barriers to its generalisation and the changes in the care model that implementing these devices can bring with it

Overview of recent TJ-II stellarator results

The main results obtained in the TJ-II stellarator in the last two years are reported. The most important topics investigated have been modelling and validation of impurity transport, validation of gyrokinetic simulations, turbulence characterisation, effect of magnetic configuration on transport, fuelling with pellet injection, fast particles and liquid metal plasma facing components. As regards impurity transport research, a number of working lines exploring several recently discovered effects have been developed: the effect of tangential drifts on stellarator neoclassical transport, the impurity flux driven by electric fields tangent to magnetic surfaces and attempts of experimental validation with Doppler reflectometry of the variation of the radial electric field on the flux surface. Concerning gyrokinetic simulations, two validation activities have been performed, the comparison with measurements of zonal flow relaxation in pellet-induced fast transients and the comparison with experimental poloidal variation of fluctuations amplitude. The impact of radial electric fields on turbulence spreading in the edge and scrape-off layer has been also experimentally characterized using a 2D Langmuir probe array. Another remarkable piece of work has been the investigation of the radial propagation of small temperature perturbations using transfer entropy. Research on the physics and modelling of plasma core fuelling with pellet and tracer-encapsulated solid-pellet injection has produced also relevant results. Neutral beam injection driven Alfvénic activity and its possible control by electron cyclotron current drive has been examined as well in TJ-II. Finally, recent results on alternative plasma facing components based on liquid metals are also presentedThis work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014–2018 under Grant Agreement No. 633053. It has been partially funded by the Ministerio de Ciencia, Inovación y Universidades of Spain under projects ENE2013-48109-P, ENE2015-70142-P and FIS2017-88892-P. It has also received funds from the Spanish Government via mobility grant PRX17/00425. The authors thankfully acknowledge the computer resources at MareNostrum and the technical support provided by the Barcelona S.C. It has been supported as well by The Science and Technology Center in Ukraine (STCU), Project P-507F

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 +/- 20.6% vs 93.6 +/- 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 +/- 5.2 mm vs 19.9 +/- 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P &lt; 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P &lt; 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P &lt; 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P &lt; 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment