Archive for the 'Artículos'

Jueves 5 / noviembre / 2020

Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

Filed under: Artículos,Artículos científicos,reumatología,sindromes — José Pedro Martínez — noviembre 5th, 2020 — 10:39 PM



Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.


We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9–edited zebrafish were used as an in vivo model to assess gene function.


We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.


Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.)


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Domingo 26 / agosto / 2018

Reumatología 3.0

Filed under: Artículos,Artículos científicos — José Pedro Martínez — agosto 26th, 2018 — 9:55 AM


Nuevos criterios de clasificación de artritis reumatoide

¿Cómo hacer buen uso del metotrexato en artritis reumatoide?

Estudio por imagen del hombro doloroso

Miopatías inflamatorias. Dermatomiositis, polimiositis y miositis

con cuerpos de inclusión

Fibromialgia y fatiga crónica causada por sensibilidad al gluten no celíaca


Análisis de líquido sinovial

Utilización de tocilizumab en la esclerosis sistémica:breve revisión de la literatura

Dolores musculo esqueléticos. Radiculopatías. Afectación de partes blandas. Artritis aguda

Dolor neuropático


Anticuerpos antinucleares


Prescripción de antiinflamatorios no esteroideos y protectores gástricos en urgencias

Hiperparatiroidismo: ¿primario o secundario?

Análisis de sedimento urinario

Manejo de la hiperglucemia inducida por corticoides


La encuesta como técnica de investigación. Elaboración de cuestionarios y tratamiento estadístico de los datos (I) PDF

La encuesta como técnica de investigación. Elaboración de cuestionarios y tratamiento estadístico de los datos (II) PDF

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Lunes 12 / marzo / 2018

Phase I Clinical Trial with a Novel Altered Peptide Ligand Derived from Human Heat-Shock Protein 60 for Treatment of Rheumatoid Arthritis: Safety, Pharmacokinetics and Preliminary Therapeutic Effects

Filed under: Artículos,Artículos científicos,Centro de Reumatología — José Pedro Martínez — marzo 12th, 2018 — 10:43 AM

Dinorah Prada1, Jorge Gómez1, Norailys Lorenzo2, Oreste Corrales2, Ana López1, Evelio González2, Ania Cabrales2, Yusimy Reyes1, Yuliet Bermudez3, Yisel Avila3, Lina Pérez1, Claudio Molinero1, Osmel Martinez1, Leonardo Oramas2, Yaysel Miñoso4, Yassel Ramos2, Hilda Garay2, Ever Pérez2, Matilde López2, Osvaldo Reyes2, Yolanda Cruz4, Alfredo Hernández4, Cabal Carlos2, Vladimir Besada2, Luis Javier González2, Gabriel Padrón2 and Maria del Carmen Domínguez Horta2,*
1National Reference Center for Rheumatic Disease, 10 de Octubre, Havana, Cuba
2Center for Genetic Engineering and Biotechnology (CIGB), 6162, Havana, Cuba
3National Center for Clinical Trial (CENCEC), Miramar, Playa, CP 11300, Havana, Cuba
4Center for Surgical Medical Research (CIMEQ), Siboney, Playa, Havana, Cuba

*Corresponding author: Maria del Carmen Domínguez Horta, Center for Genetic Engineering and Biotechnology (CIGB), 6162, Havana, Cuba, Tel: +53-7-250-4397; Email:

Received date: January 29, 2018; Accepted date: February 08, 2018; Published date: February 12, 2018
Copyright: ©2018 Prada D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.



Background: CIGB 814 is an Altered Peptide Ligand (APL) from a CD4+ T-cell epitope of human heat shock
protein 60 (HSP60), an auto-antigen involved in the pathogenesis of rheumatoid arthritis (RA). It induced
mechanisms associated with restoration of peripheral tolerance in preclinical studies. This clinical trial was
conducted to assess safety and pharmacokinetics (PK) of CIGB-814 in patients with RA.
Method: 20 patients with moderated active RA were included in an open label trial. Sequential dose-escalation of
1, 2.5 and 5 mg of CIGB-814 was studied. Consecutive groups of six, five and nine patients received a
subcutaneous dose weekly of the peptide during the first month and one dose monthly during the next five months.
Clinical response in patients was evaluated according to the American College of Rheumatology (ACR) and Disease
Activity Score in 28 joints (DAS 28) criteria. Function and health-related quality of life, quantification of proinflammatory
cytokines and radiographic changes in patients by magnetic resonance imaging (MRI) were also
Result: The treatment was well tolerated at all doses. Only mild events were observed. PK study showed that
CIGB-814 reached the maximum concentration in plasma in 30 min and was cleared mostly after 4 h. CIGB-814
reduced disease activity and MRI score in patients. This effect was less marked with the dose of 5 mg. Five and
eleven out of 18 patients achieved ACR 50 and ACR 70 respectively at the end of the treatment. In addition, patients
showed decreases of DAS28 scores, during treatment and at the end of the follow-up. This therapy improved
function and health-related quality of life of patients. CIGB-814 significantly decreased interleukin (IL)-17 in patients
treated with 2.5 mg. Therapy with 1 mg and 2.5 mg of CIGB-814 led to significant reduction of interferon gamma
Conclusion: Phase I concluded showing safety of CIGB-814. The PK profile revealed that peptide is cleared
from plasma very rapidly. Results indicated preliminary evidences of clinical efficacy and support further clinical investigation of this peptide for treatment of RA.
Trial registration: RPCEC00000238.

Keywords: APL; HSP60; Rheumatoid arthritis; Clinical trial; Safety


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