Diseño e ingeniería de proteínas en biomedicina : posibles agonistas y antagonistas de la hepcidina

Los trastornos en el metabolismo del hierro pueden causar enfermedades tanto por defecto como por exceso del mismo en el organismo, no existiendo una cura actualmente para ninguno de ellos. Recientemente se ha descrito una proteína, la hepcidina, que es la encargada de regular la homeostasis de este metal, lo que abre todo un abanico de posibles terapias dirigidas contra esta diana. En este trabajo se hace un resumen de los nuevos fármacos que se han ido diseñando (aún no hay ninguno comercializado) y se proponen nuevas opciones terapéuticas utilizando la ingeniería de proteínas como herramienta para crear agonistas y antagonistas de la hepcidina.The iron metabolism disorders can cause both iron overload and iron deficiency diseases, for which there is no cure at this moment. Recently a new protein, hepcidin, has been described, and its function is to regulate the homeostasis of this metal, which opens a new bunch of possible therapies against this target. In this work there is a summary of the new drugs which have been designed (none of them is comercialized yet) and new therapeuitcal options are proposed using the protein engineering as a tool to create both agonists and antagonists of the hepcidin.Grado en Medicin

Diseño e ingeniería de proteínas en biomedicina : posibles agonistas y antagonistas de la hepcidina

[ES]: Los trastornos en el metabolismo del hierro pueden causar enfermedades tanto por defecto como por exceso del mismo en el organismo, no existiendo una cura actualmente para ninguno de ellos. Recientemente se ha descrito una proteína, la hepcidina, que es la encargada de regular la homeostasis de este metal, lo que abre todo un abanico de posibles terapias dirigidas contra esta diana. En este trabajo se hace un resumen de los nuevos fármacos que se han ido diseñando (aún no hay ninguno comercializado) y se proponen nuevas opciones terapéuticas utilizando la ingeniería de proteínas como herramienta para crear agonistas y antagonistas de la hepcidina.[EN]: The iron metabolism disorders can cause both iron overload and iron deficiency diseases, for which there is no cure at this moment. Recently a new protein, hepcidin, has been described, and its function is to regulate the homeostasis of this metal, which opens a new bunch of possible therapies against this target. In this work there is a summary of the new drugs which have been designed (none of them is comercialized yet) and new therapeuitcal options are proposed using the protein engineering as a tool to create both agonists and antagonists of the hepcidin.Peer Reviewe

Uveitis in psoriatic arthritis: study of 406 patients in a single university center and literature review

Background/purpose The manifestations of uveitis are well established in axial spondyloarthritis (ax-SpA), but not in psoriatic arthritis (PsA). We aimed to assess, in a large unselected series of PsA: (A) the frequency and clinical features of uveitis; (B) its association with PsA activity, the impact of disease and functional disability, and (C) its relationship with the biological treatment. In addition, a literature review was performed. Methods Retrospective longitudinal study of PsA patients from a single referral hospital. PsA was classified according to the CASPAR criteria, and uveitis was diagnosed by experienced ophthalmologists. Results We studied 406 patients with PsA (46.3±12.3 years). Uveitis was observed in 20 (4.9%). Uveitis was acute in all cases, anterior (80%), unilateral (80%) and recurrent (50%). Patients with uveitis had a higher prevalence of HLA-B27 (45% vs 7.5%, p<0.0001), sacroiliitis on MRI (25% vs 8.3% p=0.027), ocular surface pathology (10% vs 0.8%, p=0.021), and median PsA impact of Disease Score (5.9 (2.1–6.8) vs 1.25 (0.0–3.0), p=0.001) and Bath Ankylosing Spondylitis Functional Index (4 (1.6–5) vs 1.0 (0.0–3.5), p=0.01) than patients without uveitis. The exposure adjusted incidence rate (episodes/100 patients-year) of uveitis before versus after biological treatment decreased with anti-TNFα monoclonal antibodies (56.3 vs 9.4) and increased with etanercept (ETN) (6.03 vs 24.2) and secukinumab (SECU) (0 vs 50) (including only one patient treated in the last two cases). Conclusion The prevalence of uveitis in patients with PsA was about 5%. The pattern was similar to that observed in ax-SpA. Uveitis was associated with a worse quality of life and greater functional disability. The uveitis exposure adjusted incidence rate decreased with anti-TNFα monoclonal antibodies and increased with ETN and SECU

Factors associated with atherosclerosis in radiographic and non-radiographic axial spondyloarthritis. A multicenter study on 838 patients

Objectives: To identify disease-related factors associated with subclinical atherosclerosis and cardiovascular (CV) events in a large series of patients with axial spondyloarthritis (axSpA) and to identify possible differences in the effect of the potential pro-atherogenic factors between ankylosing spondylitis (AS) non-radiographic axSpA (nr-axSpA). Methods: This is a cross-sectional observational study of the AtheSpAin cohort, a Spanish multicenter cohort to study atherosclerosis in axSpA. Subclinical atherosclerosis determined by carotid ultrasound included assessment of carotid intima-media thickness (cIMT) and plaque detection. Results: 639 AS and 167 nr-axSpA patients were recruited. CV risk factors (CRF) and several disease-related factors showed a statistically significant association with subclinical atherosclerosis in the crude analysis. After adjustment for age, sex, and smoking (model 1), associations remained statistically significant for spinal mobility, inflammatory bowel disease, use of prednisone, and Disease-modifying antirheumatic drugs (DMARD) when assessing carotid plaques and for acute phase reactants (APR) at diagnosis, use of prednisone, DMARD, and TNF-inhibitors when measuring cIMT. In model 2, which also included classic CRF as confounding factors to identify axSpA features with a potential independent pro-atherogenic effect, the functional status was the only variable significantly associated with plaques and the use of prednisone and APR at diagnosis with cIMT. No association differences were found between both subtypes of patients. Besides, APR at diagnosis were also associated with subsequent development of CV events that had occurred in 33 patients. Conclusion: Apart from CRF, atherosclerotic disease in AxSpA is associated with disease-related factors such as inflammatory response and disease severity, with no differences between AS and nr-axSpA

Irisin as a Novel Biomarker of Subclinical Atherosclerosis, Cardiovascular Risk and Severe Disease in Axial Spondyloarthritis.

Patients with axial spondyloarthritis (axSpA) have a high disease burden mainly due to the rheumatic disease itself, and also exhibit accelerated atherosclerosis, that leads to a higher incidence of cardiovascular (CV) disease. Accordingly, the identification of biomarkers of CV risk and inflammation in axSpA patients is clinically relevant. In this sense, given the beneficial functions exerted by the adipomyokine irisin in processes related to CV disease and inflammation, our aim was to assess, for the first time, the role of irisin as a genetic and serological biomarker of subclinical atherosclerosis, CV risk and disease severity in axSpA patients. A large cohort of 725 Spanish patients with axSpA was included. Subclinical atherosclerosis (presence of plaques and abnormal carotid intima-media thickness values) was evaluated by carotid ultrasound. Four irisin polymorphisms (rs16835198 G/T, rs3480 A/G, rs726344 G/A, and rs1570569 G/T) were genotyped by TaqMan probes. Additionally, serum irisin levels were determined by ELISA. Low irisin levels were linked to the presence of plaques (p=0.002) and atherogenic index values ≥4 (p=0.01). Serum irisin were positively correlated with C-peptide levels (p2.1 (Odds Ratio (OR): 0.48 [0.28-0.83] and OR: 0.73 [0.57-0.92], respectively, p=0.01 in both cases). Additionally, the frequency of rs1570569 T allele was higher in these patients (OR: 1.46 [1.08-1.97], p=0.01). Furthermore, the GGGT haplotype was more frequent in patients with ASDAS values >2.1 (OR: 1.73 [1.13-2.66], p=0.01). Our results indicate that low serum irisin levels could be indicators of the presence of subclinical atherosclerosis, high CV risk and more severe disease in axSpA patients. In addition, irisin may also constitute a genetic biomarker of disease activity in axSpA