Ambulatory follow-up of patients with lupus in a systemic autoimmune disease unit

Objetivos: Describir los síntomas referidos por los pacientes con lupus eritematoso sistémico (LES) durante su seguimiento ambulatorio en una Unidad de Enfermedades Autoinmunes Sistémicas (UEAS), la relación de éstos con el propio LES o con otras patologías y la necesidad de derivación a otros especialistas. Material y Métodos: Se realizó un análisis descriptivo prospectivo durante 5 meses que incluyó a 112 pacientes con LES en seguimiento ambulatorio por una UEAS. Se valoró la sintomatología padecida desde la última revisión, tuviera o no relación con el LES y la prevalencia de pacientes derivados a otros especialistas. Resultados: Ochenta (71.4%) pacientes presentaron sintomatología no explicable por el LES, destacando la artralgias por artrosis y el síndrome ansioso-depresivo. Presentaron síntomas asociados al LES 32 (23.5%) pacientes, siendo el brote articular en 10 (8.3%) pacientes, el brote renal en 8 (7.1%) y el brote cutáneo en 5 (4.4%) los más frecuentes. Por último, fueron derivados a otros especialistas 10 (8.3%) pacientes. Conclusiones: Durante el seguimiento ambulatorio en una UEAS de los pacientes con LES, la prevalencia de consultas por síntomas y enfermedades no relacionadas con el LES podría ser superior a aquellas atribuibles al propio LES, subrayando la necesidad de una visión global y multidisciplinar en el manejo de estos pacientes.Objectives: To describe the symptoms referred by the patients with systemic lupus erythematosus (SLE) during their ambulatory follow-up by an Autoinmune Disease Unit (ADU), the relationship between them and SLE itself or with other clinic entities and the need to refer lupus patients to other specialists. Methods: We performed a descriptive analysis during 5 months that included 112 patients with SLE with ambulatory follow-up by an ADU. We assessed the symptomatology suffered by the patients since the last visit, related or not to SLE, and the prevalence of patients referred to other specialists. Results: Eighty (71.4%) patients had symptoms no explainable by SLE, mainly due to arthralgias secondary to osteoarthrosis and anxiety-depressive syndrome. Thirty-two (23.5%) patients had symptoms related to SLE, the most frequent of which were articular flare in 10 (8.3%) patients, lupus nephritis in 8 (7.1%) and skin flare in 5 (4.4%). Finally, ten (8.3%) patients were referred to other specialists. Conclusions: During the ambulatory follow-up of patients with SLE in an ADU, the frequency of consultations for symptoms and illnesses no related to SLE may be higher than those secondary to SLE, highlighting the need of a global and multidisciplinary management of these patients

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

BACKGROUND AND AIMS Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH AND RESULTS C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. CONCLUSIONS Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.This work was supported by grants from Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for Jorge Simon and Maria Luz Martinez-Chantar); Ministerio de Economía, Industria y Competitividad, Retos a la Sociedad AGL2017- 86927R (for F.M.); Instituto de Salud Carlos III, Proyectos de Investigación en Salud DTS20/00138 and DTS21/00094 (for Jorge Simon and Maria Luz Martinez-Chantar, and Asis Palazon. respectively); Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-founded by European Regional Development Fund/European Social Fund, “Investing in your future” PI19/00819, “Una manera de hacer Europa” FIS PI20/00765, and PI21/01067 (for Jose J. G. Marin., Pau Sancho-Bru,. and Mario F. Fraga respectively); Departamento de Industria del Gobierno Vasco (for Maria Luz Martinez-Chantar); Asturias Government (PCTI) co-funding 2018-2023/ FEDER IDI/2021/000077 (for Mario F. Fraga.); Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00, CEX2021-001136-S PID2020-117941RB-I00, PID2020-11827RB-I00 and PID2019-107956RA-100 integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova and Asis Palazon); Ayudas Ramón y Cajal de la Agencia Estatal de Investigación RY2013-13666 and RYC2018- 024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research Foundation SFB/TRR57/P04, SFB1382-403224013/ A02 and DFG NE 2128/2-1 (for Francisco J Cubero and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism (NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru); Junta de Castilla y León SA074P20 (for Jose J. G. Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for Franz Martin); CIBERER Acciones Cooperativas y Complementarias Intramurales ACCI20-35 (for Mario F. Fraga); Ministerio de Educación, Cultura y Deporte FPU17/04992 (for Silvia Ariño); Fundació Marato TV3 201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is a fellow of the University of the Basque Country (UPV/ EHU); BIOEF (Basque Foundation for Innovation and Health Research); Asociación Española contra el Cáncer (Maria Luz Martinez-Chantar and Teresa C. Delgado.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa Foundation Program (for Maria Luz Martinez-Chantar); Proyecto Desarrollo Tecnologico CIBERehd (for Maria Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.S

High ACSL5 Transcript Levels Associate with Systemic Lupus Erythematosus and Apoptosis in Jurkat T Lymphocytes and Peripheral Blood Cells

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease in which increased apoptosis and decreased apoptotic cells removal has been described as most relevant in the pathogenesis. Long-chain acyl-coenzyme A synthetases (ACSLs) have been involved in the immunological dysfunction of mouse models of lupus-like autoimmunity and apoptosis in different in vitro cell systems. The aim of this work was to assess among the ACSL isoforms the involvement of ACSL2, ACSL4 and ACSL5 in SLE pathogenesis. Findings With this end, we determined the ACSL2, ACSL4 and ACSL5 transcript levels in peripheral blood mononuclear cells (PBMCs) of 45 SLE patients and 49 healthy controls by quantitative real time-PCR (q-PCR). We found that patients with SLE had higher ACSL5 transcript levels than healthy controls [median (range), healthy controls = 16.5 (12.3–18.0) vs. SLE = 26.5 (17.8–41.7), P = 3.9×10 E-5] but no differences were found for ACSL2 and ACSL4. In in vitro experiments, ACSL5 mRNA expression was greatly increased when inducing apoptosis in Jurkat T cells and PBMCs by Phorbol-Myristate-Acetate plus Ionomycin (PMA+Io). On the other hand, short interference RNA (siRNA)-mediated silencing of ACSL5 decreased induced apoptosis in Jurkat T cells up to the control levels as well as decreased mRNA expression of FAS, FASLG and TNF. Conclusions These findings indicate that ACSL5 may play a role in the apoptosis that takes place in SLE. Our results point to ACSL5 as a potential novel functional marker of pathogenesis and a possible therapeutic target in SLE.Financial support for the study was provided by the Ministerio de Ciencia e Innovación-Fondos Feder (PN-SAF2009-11491) and Junta de Andalucía (P07-CVI-02551) to A. Alcina and Fondo de Investigación Sanitaria (FIS PI081636, CP10/00526) to F. Matesanz. M. Fedetz and D. Ndagire are holders of a fellowship from Fundación Española de Esclerosis Múltiple (FEDEM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Graphical representation of the meta-analysis (A) Forest plot for the meta-analysis of the <i>UBASH3a</i> rs2277798 polymorphism in SLE in two Caucasian cohorts.

<p>(<b>B</b>) Forest plot for the meta-analysis of the <i>UBASH3a</i> rs9976767 polymorphism in SLE in two Caucasian cohorts.</p

Conditional logistic regression analysis for two <i>UBASH3a</i> SNPs located in SLE considering the two European populations as covariate.

<p>Conditional logistic regression analysis for two <i>UBASH3a</i> SNPs located in SLE considering the two European populations as covariate.</p

Meta-analysis of two <i>UBASH3a</i> genetic variants within Spanish and German SLE populations.

*<p>All P-values have been calculated for the allelic model. **Benjamini & Hochberg (1995) step-up FDR control. ***Odds ratio for the minor allele.</p

Genotype and minor allele frequencies of <i>UBASH3a</i> SNPs located in Caucasian SLE patients and healthy controls from Spain, the discovery cohort.

*<p>All P-values have been calculated for the allelic model. ** Pc = 0.248 Benjamini & Hochberg (1995). ***Pc = 9.9E-03 Benjamini & Hochberg (1995) step-up FDR control. ****Odds ratio for the minor allele.</p

Genotype and minor allele frequencies of <i>UBASH3a</i> SNPs located in Caucasian SLE patients and healthy controls from Germany.

*<p>All P-values have been calculated for the allelic model. ** Benjamini & Hochberg (1995) step-up FDR control. ***Odds ratio for the minor allele.</p