The role of biologics in the treatment of giant cell arteritis

ABSTRACT: Introduction: Giant cell arteritis is a vasculitis of large and middle-sized arteries that affects individuals older than 50 years. Although glucocorticoids remain the mainstay in the treatment of this vasculitis, other drugs are often required to achieve clinical remission and allow glucocorticoid discontinuation. Areas covered: The review summarizes the main biologic therapies used for the managements of GCA. Expert commentary: Although several biologic agents have been used in patients with GCA, the only biologic agent currently approved for this purpose is the recombinant humanized anti-IL-6 receptor antibody: tocilizumab. It has demonstrated efficacy to improve clinical symptoms, decrease the cumulative prednisone dose and reduce the frequency of relapses in clinical trials and real-life studies on patients with GCA. A trial showed that abatacept may be useful to maintain remission in GCA patients. An openlabel study suggested that ustekinumab could be useful for the treatment of patients with refractory GCA. However, further studies are required to confirm if both abatacept and ustekinumab are useful as an adjunctive therapy to reduce relapses or as a glucocorticoid sparing agent in GCA. Anakinra has been successfully used in a few patients with refractory GCA. In contrast, anti-tumor necrosis factor- α therapy yielded disappointing results in GCA

Anakinra for the treatment of adult-onset Still's disease

ABSTRACT: Introduction: Adult onset Still's disease (AOSD) is an uncommon systemic inflammatory disease on the clinical spectrum of autoinflammatory disorders. Its presentation and clinical course may result in several well-differentiated phenotypes: from a systemic and highly symptomatic pattern to a chronic articular pattern. Overproduction of numerous pro-inflammatory cytokines is observed in AOSD. Anakinra (ANK), a human interleukin (IL)-1R antagonist, has recently been approved in the EU for the treatment of AOSD. Areas covered: In this review, we discuss the main studies on the efficacy and safety on ANK for the treatment of AOSD. The vast majority of them are retrospective studies and case series. Expert commentary: Overall, ANK is an effective biologic agent for the treatment of AOSD, especially for the systemic pattern and also for those patients who have life-threatening complications, which frequently occur over the course of the disease. The initial dose usually indicated of ANK in adults is 100 mg/day subcutaneously, although dose reduction can be performed in some cases once the disease is under control. The safety profile of ANK is favorable and similar to that described in other rheumatic diseases. In conclusion, ANK is an effective and safe agent for the treatment of AOSD

The Peñalara Massif (Spanish Central System). Morphostructure and modelling

El Macizo de Peñalara se localiza en el sector central de la Sierra de Guadarrama (Sistema Central Español) y sus cimas sobrepasan en unos 200 m el nivel general de cumbres que presenta aquí 2100 m de cota media absoluta (Fig. 1). En la estructura de bloques (Block mountain) que caracteriza el relieve de esta montaña intraplaca de reactivación Alpina, el Macizo de Peñalara corresponde a una dovela flanqueada por bloques más deprimidos (Fig. 2). Los límites del Macizo están asociados a fallas y, dentro de ellas, destacan las pertenecientes a los sistemas NNE-SSW y NNW-SSE (Fig. 3). La litología dominante del zócalo son ortogneises glandulares (también hay algunos leucocráticos) de edad preordovícica. Localmente aparecen rocas plutónicas (leucogranitos aplíticos) y filonianas (Aplitas) del ciclo hercínico. Los sedimentos de las coberteras mesozoicas (del Cretácico) y cenozoicas (del Paleógeno y Mioceno) y los recubrimientos de mayor entidad (de origen fluvial) se localizan en la fosa o depresión intramontana aledaña de El Paular o Alto Lozoya (Fig. 4). En el Macizo, sin embargo, afloran los materiales del zócalo o aparece recubiertos por Formaciones Superficiales o depósitos reciente (cuaternarios) discontinuos y de poca entidad: es le caso de los depósitos fluvioglaciares y torrenciales de los fondos de las gargantas, los tills de los complejos morrénicos pleistocenos (Fig. 5), y los depósitos de vertiente (aglomerados de bloques o canchales y lenguas de solifluxión) debidos a la actividad periglaciar. En hombreras, rellanos, y planicies de las cimas o de los piedemontes, abundan las depresiones semi-endorreicas (navas, algunas de origen cárstico) donde se producen fenómenos de decantación de finos (limos, arcillas) y reducción (depósitos turbosos). En las cimas y tramos superiores de las laderas, en cotas que superan los 2000 m., hay formaciones de ambiente frío (nivación y ciclos de helada), con signos de actividad. Son surcos o canales de arroyada por fusión nival, flujo de derrubios (debris flow), pedreras de bloques con crestas de imbricación, y suelos estructurados (rosetas, guirnaldas, enlosados) con signos de flujo (Figs. 6 y 7). La magnitud e intensidad de dichos fenómenos, es un tema que se debe investigarse en profundidad y servirá para concretar la idoneidad o no de definir estas áreas como un verdadero ambiente o piso periglaciar.The Peñalara Massif is located in the central area of the Guadarrama Mountains (Spanish Central System), and it constitutes the highest terrains within this mountain range (Peñalara Peak, 2428 m). The mountain tops exceed here about 200 m the generalized level of summits, which in this area of the Central System reach 2100 metres above sea level on average (Fig. 1). These topographic characteristics, along with its northern and continental imprint, make possible to argue about the presence of a current periglacial environment in the Peñalara Massif. This environment would be equivalent to the cryo-Mediterranean vegetation layer (summit grasslands). For the morpho-structure of serialized blocks (block mountain) which characterizes this intra-plate –Alpine reactivated-type— mountain, the Peñalara massif represents the ‘keystone’, to which other down-thrown blocks are laterally attached (Fig. 2). The appearance or physiognomy formed by this structural arrangement is the so-called ‘stairway piedmont’ (piedmonttreppen). The massif boundaries are related to faults, within which two systems are predominant: NNE-SSW and NNWSSE (Fig. 3). The faults which define the boundaries of the front Massif with respect to its interior valleys (El Paular and Alto Eresma) belong to the first system. The faults which define the link between the summit plains and the slope shelves belong to the second system. Orthoderived metamorphic rocks (from pre-Hercynian/pre-Ordovician rocks) constitute the predominant lithology of the basement. They are mostly glandular gneisses, but also leuco-gneisses. Locally, they appear Hercynian and post-Ordovician plutonic (aplitic leuco-granite) and dyke (aplite) rocks. As far as the sedimentary cover is concerned, including recent deposits, they are preferably concentrated at the basis of the Massif, and also in its slopes (Fig. 4). Sedimentary cover is mainly represented by Mesozoic and Cenozoic formations, located at the bottom of the El Paular (or Alto Lozoya) Valley graben. They consist in Cretaceous carbonate (dolomites and marl) and detritic (sands and sandstone) rocks, and also Palaeogene (conglomerate and sands) and Neogene (conglomerate and arkoses of the Miocene) rocks. Piedmont and valley-filling surficial deposits have a major fluvio-torrential origin (alluvial fans and fluvial terraces), of a Pleistocene age. To a lesser extent, there are also channel deposits (alluvial sand, silt, gravel and pebbles) and almost-endorreic lowland sediments (some of them of karstic origin, filling sinkhole-type pits), where decanting of silt and clay –and reduction processes, with peat formation— occurs. Recent slope deposits, despite not being of a great entity in this massif, they have an interest for the interpretation of cold climate geomorphic processes—they are fluvio-glacial and torrential deposits in gorge bottoms, glacial tills and moraine deposits (Fig. 5) and hillslope sediments (scree, talus slope and solifluction lobes), originated by periglacial (cryogenic) activity. Within the summits and the highest zones of the slopes, almost always above 2000 m.a.s.l, there are surficial deposits with signs of current activity, which will be determining factors in order to establish the current magnitude of the cold climate geomorphic activity (snow and freeze-and-thaw processes). Examples of these surficial deposits and landforms are avalanche gullies and debris flow channels, imbricate stones and small ridges within talus slope deposits, and patterned grounds (stripes, garlands and stone pavements) with signs of current flow (Figs. 6 and 7). The magnitude and intensity of these cold climate processes is an issue that should be investigated deeply (a first step is the periglacial processes gauge at Dos Hermanas). This research will serve for defining or not these areas as a truly periglacial environment.Depto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasTRUEpu

Anatomía Comparada del Aparato Genital Masculino de Mamíferos Domésticos. Herramienta de Aprendizaje Virtual para Veterinarios, Biólogos y Médicos

Esta aplicación es una herramienta útil para estudiantes y profesores de diferentes campos. Permitirá conocer y estudiar el aparato genital masculino, señalando gráficamente la estructura a memorizar, ver su contenido teórico y autoevaluarse

The lp13.3 genomic region -rs599839- is associated with endothelial dysfunction in patients with rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is an inflammatory disease associated with accelerated atherosclerosis and high risk of cardiovascular (CV) disease. Since genome-wide association studies demonstrated association between rs599839 polymorphism and coronary artery disease, in the present study we assessed the potential association of this polymorphism with endothelial dysfunction, an early step in atherogenesis. Methods: A total of 128 RA patients without history of CV events were genotyped for rs599839 A/G polymorphism. The presence of endothelial dysfunction was assessed by brachial ultrasonography (brachial flow-mediated endothelium-dependent (FMD)). Results: Patients carrying the allele G exhibited more severe endothelial dysfunction (FMD%: 4.61 ± 3.94%) than those carrying the wild allele A (FMD%: 6.01 ± 5.15%) (P = 0.08). Adjustment for gender, age at the time of study, follow-up time and classic CV risk factors disclosed a significant association between the rs599839 polymorphism and FMD (G vs. A: P = 0.0062). Conclusions: Our results confirm an association of the rs599839 polymorphism with endothelial dysfunction in RA

Analysis of the Interferon Gamma (rs2430561, +874T/A) Functional Gene Variant in Relation to the Presence of Cardiovascular Events in Rheumatoid Arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) morbidity and mortality. Since interferon-gamma (IFN-γ) has a direct effect on inflammation, in this study we assessed the potential association of the IFNG functional gene variant rs2430561 with CV disease in patients with RA. METHODS: One thousand six hundred and thirty-five patients fulfilling the 1987 American College of Rheumatology classification criteria for RA were genotyped for the IFNG (rs2430561, +874T/A) gene polymorphism using TaqMan genotyping assay. Patients were stratified according to the presence of CV events or not. Logistic regression models to explain the presence of CV disease according to the IFNG rs2430561 allele distribution were performed. The potential influence of this variant in the development of subclinical atherosclerosis was also analyzed in a subgroup of patients with no history of CV events to determine carotid artery intima-media thickness (IMT) (n = 286) and presence of carotid plaques. Levels of the cytokine were determined in a subgroup of patients by ELISA. RESULTS: Adjusted logistic regression model disclosed that presence of the minor allele A was not associated with increased risk of suffering CV events in RA patients. Besides, differences did not achieve statistical significance regarding carotid IMT and presence of carotid plaques in RA patients carrying IFNG rs2430561 variant allele. Levels of IFN-γ were higher in patients who had suffered CV events compared to patients who did not. CONCLUSION: Our results do not support a role of IFNG rs2430561 (+874T/A) functional gene variant in the development of CV disease in RA patients

Vapor pressure deficit constrains transpiration and photosynthesis in holm oak: A comparison of three methods during summer drought.

High rates of vapor pressure deficit (VPD) can severely decrease plant productivity by reducing stomatal conductance, which might be exacerbated during Mediterranean summers due to soil water deficit. In this study, we monitored the response of holm oak, the archetype of Mediterranean trees, to changes in VPD during a summer drought period to evaluate the effects and consequences on gas exchange of the two water stresses (atmospheric and soil). Measurements were performed on trees growing in an experimental plantation over two summers with moderate drought stress by using three different methods: at the leaf level with an infrared gas analyzer, using a whole-plant chamber for short-term monitoring at the tree level, and measuring the canopy temperature for long-term monitoring. The three methods provided negative relationships between leaf conductance and VPD but with discrepancies probably associated with the measurement scale. Overall, the results showed that atmospheric and soil water stress had an additive effect. Under well-watered conditions, an increase in VPD was partially compensated by a reduction in stomatal conductance, resulting in a slight increase in the transpiration rates. With soil water deficit, the response to VPD resulted in a further decrease in stomatal conductance, reducing transpiration as a water saving strategy. The decrease in conductance in response to VPD was transitory, recovering to initial values as soon as the VPD decreased, both under well-watered and drought conditions. Due to this high sensitivity to atmospheric drought, the maximum carbon gain rates of holm oak were restricted to a short environmental window, which might modulate its physiological performance and natural distribution.Publishe

HCV-coinfection is related to an increased HIV-1 reservoir size in cART-treated HIV patients: a cross-sectional study

In HIV-1/HCV-coinfected patients, chronic HCV infection leads to an increased T-lymphocyte immune activation compared to HIV-monoinfected patients, thereby likely contributing to increase HIV-1 reservoir that is the major barrier for its eradication. Our objective was to evaluate the influence of HCV coinfection in HIV-1 viral reservoir size in resting (r) CD4+ T-cells (CD25-CD69-HLADR-). Multicenter cross-sectional study of 97 cART-treated HIV-1 patients, including 36 patients with HIV and HCV-chronic co-infection without anti-HCV treatment, 32 HIV patients with HCV spontaneous clearance and 29 HIV-monoinfected patients. rCD4+ T-cells were isolated and total DNA was extracted. HIV viral reservoir was measured by Alu-LTR qPCR. Differences between groups were calculated with a generalized linear model. Overall, 63.9% were men, median age of 41 years and Caucasian. Median CD4+ and CD8+ T-lymphocytes were 725 and 858 cells/mm 3 , respectively. CD4+ T nadir cells was 305 cells/mm 3 . Proviral HIV-1 DNA size was significantly increased in chronic HIV/HCV-coinfected compared to HIV-monoinfected patients (206.21 ± 47.38 vs. 87.34 ± 22.46, respectively; P = 0.009), as well as in spontaneously clarified HCV co-infected patients when compared to HIV-monoinfected individuals (136.20 ± 33.20; P = 0.009). HIV-1/HCV co-infected patients showed a larger HIV-1 reservoir size in comparison to HIV-monoinfected individuals. This increase could lead to a greater complexity in the elimination of HIV-1 reservoir in HIV-1/HCV-coinfected individuals, which should be considered in the current strategies for the elimination of HIV-1 reservoir.Financial support was provided by the Instituto de Salud Carlos III to VB (PI15CIII/00031), by the Spanish Ministry of Economy and Competitiveness to MC (SAF2016–78480-R) and The SPANISH AIDS Research Network RD16CIII/0002/0001, RD16CIII/0002/0002 and RD16/0025/0013 - ISCIII – FEDER. MRLP is supported by ISCIII - Subdirección General de Evaluacion and European Funding for Regional Development (FEDER) (PIE 13/00040 and RD12/0017/0017 RETIC de SIDA). C.P. is supported by the Portuguese Fundação para a Ciência e Tecnologia (FCT) (grant number SFRH/ BPD/77448/2011 is part of the EDCTP2 programme supported by the European Union). V.B., A.F.R. and N.R. are supported by the Miguel Servet programme from Fondo de Investigación Sanitaria (ISCIII) (grant number CP13/00098, CP14/CIII/00010 and CP14/00198, respectively)

Osteoprotegerin CGA Haplotype Protection against Cerebrovascular Complications in Anti-CCP Negative Patients with Rheumatoid Arthritis

INTRODUCTION: Rheumatoid arthritis is an inflammatory disease with high incidence of cardiovascular disease due to accelerated atherosclerosis. Osteoprotegerin (OPG) has been associated with increased risk of atherosclerotic disease in the general population. Several polymorphisms in the OPG gene with functional effects on cardiovascular disease in non-rheumatic individuals have been described. Therefore, we aimed to analyze the effect of three of these functional OPG polymorphisms on the risk of cardiovascular disease in a large and well-characterized cohort of Spanish patients with rheumatoid arthritis. METHODS: Three OPG gene variants (rs3134063, rs2073618 and rs3134069) were genotyped by TaqMan assays in 2027 Spanish patients with rheumatoid arthritis. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing was positive in 997 of 1714 tested. Also, 18.3% of the whole series had experienced cardiovascular events, including 5.4% with cerebrovascular accidents. The relationship between OPG variants and cardiovascular events was assessed using Cox regression. RESULTS: No association between OPG gene variants and cardiovascular disease was observed in the whole group of rheumatoid arthritis patients or in anti-CCP positive patients. Nevertheless, a protective effect of CGA haplotype on the risk of cardiovascular disease in general, and specifically in the risk of cerebrovascular complications after adjusting for sex, age at disease diagnosis and traditional cardiovascular risk factors was disclosed in anti-CCP negative patients (HR = 0.54; 95%CI: 0.31-0.95; p = 0.032 and HR = 0.17; 95%CI: 0.04-0.78; p = 0.022, respectively). CONCLUSION: Our results indicate a protective effect of the OPG CGA haplotype on cardiovascular risk, mainly due to a protective effect against cerebrovascular events in anti-CCP negative rheumatoid arthritis patients

Lack of Association between ABO, PPAP2B, ADAMST7, PIK3CG, and EDNRA and Carotid Intima-Media Thickness, Carotid Plaques, and Cardiovascular Disease in Patients with Rheumatoid Arthritis

Introduction. Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. Recent studies have identified the ABO rs579459, PPAP2B rs17114036, and ADAMTS7 rs3825807 polymorphisms as genetic variants associated with coronary artery disease and the PIK3CG rs17398575 and EDNRA rs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT) and presence/absence of carotid plaques) and CV disease in RA. Material and Methods. 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology. Results. No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders. Conclusion. Our results do not confirm association between ABO rs579459, PPAP2B rs17114036, ADAMTS7 rs3825807, PIK3CG rs17398575, and EDNRA rs1878406 and subclinical atherosclerosis and CV disease in RA