Publications by authors named "Norberto Ortego-Centeno"

224 Publications

Role of the IL33 and IL1RL1 pathway in the pathogenesis of Immunoglobulin A vasculitis.

Sci Rep 2021 08 9;11(1):16163. Epub 2021 Aug 9.

Research Group On Genetic Epidemiology and Atherosclerosis in Systemic Diseases and in Metabolic Bone Diseases of the Musculoskeletal System, IDIVAL, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, Avenida Cardenal Herrera Oria s/n, 39011, Santander, Spain.

Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.
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http://dx.doi.org/10.1038/s41598-021-95762-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352942PMC
August 2021

Clinical and serological associations of autoantibodies in patients with systemic lupus erythematosus.

J Investig Med 2021 Jun 28. Epub 2021 Jun 28.

Institute for Biosanitary Research of Granada (ibs.GRANADA), Granada, Spain.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the formation of antigen-antibody complexes which trigger an immune response. We investigate certain autoantibodies including nucleosome, double-stranded DNA (dsDNA), Smith, ribonucleoprotein, and Sjögren's syndrome-related antigens, and examine their associations with disease activity, damage accrual, and SLE-related clinical and serological manifestations in patients with SLE. We conducted a cross-sectional study with a total 293 patients (90.4% female, mean age 46.87±12.94 years) and used the Systemic Lupus Erythematosus Disease Activity Index 2000 and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) to evaluate disease activity and disease-related damage, respectively. Systemic Lupus Erythematosus Disease Activity Index scores were significantly higher in anti-nucleosome-positive (3.87±2.72 vs 2.52±2.76, p=0.004) and anti-dsDNA-positive (3.08±2.91 vs 2.04±2.48, p=0.010) patients compared with patients without these antibodies. SDI scores were also significantly higher in anti-nucleosome-positive patients (1.61±1.99 vs 0.89±1.06, p=0.004). The presence of antinucleosome (p=0.019) and anti-dsDNA antibodies (p=0.001) both correlated significantly with the incidence of nephritis; anti-La antibodies were associated with arthritis (p=0.022), and we also observed a relationship between the presence of antinucleosome antibodies and leukopenia (p=0.011). Patients with antinucleosome or anti-dsDNA antibodies had a higher disease activity and were likely to have nephritis. Antinucleosome was also associated with more damage accrual. A greater understanding of these autoantibodies could lead to the development of new approaches to more accurate assessments of SLE.
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http://dx.doi.org/10.1136/jim-2021-001887DOI Listing
June 2021

Imaging findings of sarcoidosis.

Med Clin (Barc) 2021 Jun 21. Epub 2021 Jun 21.

Unidad de Enfermedades Sistémicas, Servicio de Medicina Interna, Hospital San Cecilio, Granada, España.

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http://dx.doi.org/10.1016/j.medcli.2021.04.008DOI Listing
June 2021

Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes.

Ann Rheum Dis 2021 Apr 1. Epub 2021 Apr 1.

Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Andalucía, Spain.

Objective: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes.

Methods: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA).

Results: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with and , and revealed a novel association of . Stratified analyses showed specific associations of with lcSSc, and an exclusive association of with dcSSc. Similarly, private associations were detected in and confirmed the previously reported association of with ACA-positive patients, as opposed to the and alleles associated with ATA presentation.

Conclusions: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.
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http://dx.doi.org/10.1136/annrheumdis-2021-219884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292594PMC
April 2021

BAFF, APRIL and BAFFR on the pathogenesis of Immunoglobulin-A vasculitis.

Sci Rep 2021 06 1;11(1):11510. Epub 2021 Jun 1.

Research Group on Genetic Epidemiology and Atherosclerosis in Systemic Diseases and in Metabolic Bone Diseases of the Musculoskeletal System, IDIVAL, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, Avenida Cardenal Herrera Oria s/n, 39011, Santander, Spain.

BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.
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http://dx.doi.org/10.1038/s41598-021-91055-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169776PMC
June 2021

Immune thrombocytopenia and COVID-19: Case report and review of literature.

Lupus 2021 Aug 30;30(9):1515-1521. Epub 2021 May 30.

Faculty of Medicine, University of Granada, Granada, Spain.

Immune thrombocytopenia, also known as immune thrombocytopenic purpura (ITP), has been reported as an important complication related to COVID-19.We present a 49-year-old male patient with systemic lupus erythematosus with lupus nephritis, antiphospholipid syndrome and history of ITP who developed an ITP flare in the context of COVID-19. He had no bleeding manifestations and had a good response to prednisone treatment.We review the characteristics of the cases reported to date in the literature, with an analysis of 57 patients. Mean age was 56 years (±19.6 SD), and 50.9% were male. This was the first episode of ITP in most of the patients (86.05%), with SARS-CoV-2 acting as the initial trigger. We found that ITP flares may appear in both mild and severe COVID-19 cases. They also appeared at any time during the course of the disease, 48.2% of patients developed it during hospitalization, while it was diagnosed at admission in the rest of the cases. Platelet counts were significantly lower than other ITP series, with a median nadir platelet count of 8 × 10/L (IQR 2-17.75 × 10/L). These patients show a higher bleeding rate (61.4%) compared with other ITP series. They also show a better response to treatment, with good response to the first line therapies in 76.9% of them. The most common first-line treatment was intravenous immunoglobulin (IVIG), used alone or combined with corticosteroids in 40.4% and 32.7% of cases respectively, while 25% of patients received only corticosteroids.Our review suggests that COVID-19-related ITP can be seen even in previously healthy patients. Clinicians must be aware that ITP may appear both in mild and severe COVID-19, at any time during its course. Given that this kind of ITP seems to be associated with a higher bleeding risk, its diagnosis in a clinical scenario such as COVID-19, where anticoagulant therapy is frequently used, may be critical. Treatment with IVIG and/or corticoids is often effective.
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http://dx.doi.org/10.1177/09612033211021161DOI Listing
August 2021

Identification of a shared genetic risk locus for Kawasaki disease and IgA vasculitis by a cross-phenotype meta-analysis.

Rheumatology (Oxford) 2021 05 16. Epub 2021 May 16.

Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain.

Objectives: Combination of genomic data of different pathologies as a single phenotype has emerged as a useful strategy to identify genetic risk loci shared among immune-mediated diseases. Our study aimed to increase our knowledge of the genetic contribution to Kawasaki disease (kDa) and IgA vasculitis (IgAV) by performing the first comprehensive large-scale analysis on the genetic overlap between both pediatric vasculitis.

Methods: A total of 1,190 vasculitis patients and 11 302 healthy controls were analyzed. First, in the discovery phase, genome-wide data of 405 kDa patients and 6,252 controls and 215 IgAV patients and 1,324 controls, all of European origin, were combined using an inverse variance meta-analysis. Second, the top associated polymorphisms were selected for replication in additional independent cohorts (570 cases and 3,726 controls). Polymorphisms with p-values ≤ 5x1 0 -8 in the global IgAV-kDa meta-analysis were considered as shared genetic risk loci.

Results: A genetic variant, rs3743841, located in an intron of the NAGPA gene, reached genome-wide significance in the cross-disease meta-analysis (p= 8.06x10-10). Additionally, when IgAV was individually analyzed, a strong association between rs3743841 and this vasculitis was also evident (p= 1.25x10-7; OR (95% CI)=1.47 (1.27-1.69)). In silico functional annotation showed that this polymorphism acts as a regulatory variant modulating the expression levels of the NAGPA and SEC14L5 genes.

Conclusion: We have identified a new risk locus with pleiotropic effects on the two vasculitis of childhood analyzed. This locus represents the strongest non-HLA signal described for IgAV to date.
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http://dx.doi.org/10.1093/rheumatology/keab443DOI Listing
May 2021

Anti-Polymyositis/Scl Antibodies in Systemic Sclerosis: Clinical Associations in a Multicentric Spanish Cohort and Review of the Literature.

J Clin Rheumatol 2021 Apr 28. Epub 2021 Apr 28.

From the Department of Autoimmune Diseases, Institut Clinic de Medicina i Dermatologia, Hospital Clínic, Barcelona, Catalonia, Spain Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Catalonia, Spain Department of Internal Medicine, Corporación Sanitaria Universitaria Parc Taulí, Sabadell, Barcelona, Catalonia Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Asturias Department of Internal Medicine, Hospital Universitario Cruces, Barakaldo, Vizcaya Department of Internal Medicine, Hospital Universitario Miguel Servet, Zaragoza Department of Internal Medicine, Hospital Campus de la Salud, Complejo Universitario de Granada Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada Department of Internal Medicine, Hospital Universitario de Bellvitge, L'Hospitalet de Llobregat, Barcelona Department of Internal Medicine, Hospital Clínico Universitario de Santiago, Santiago de Compostela, A Coruña Department of Internal Medicine, Hospital La Paz, Madrid Department of Internal Medicine, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Catalonia Department of Internal Medicine, Hospital de Cabueñes, Gijón, Asturias, Spain.

Objectives: To assess the clinical profile of patients with anti-polymyositis/Scl (PM/Scl) antibodies in a cohort of Spanish patients with systemic sclerosis.

Methods: From the Spanish Scleroderma Study Group database, we selected patients in whom PM/Scl antibodies had been tested. We compared demographic, clinical, laboratory, and survival data between patients with and without PM/Scl antibodies.

Results: Seventy-two of 947 patients (7.6%) tested positive for PM/Scl antibodies. Patients with PM/Scl antibodies presented initially with more puffy fingers and arthralgias but less Raynaud phenomenon. Regarding cumulative manifestations, myositis and arthritis were more prevalent in patients with PM/Scl antibodies, as well as pulmonary fibrosis. On the contrary, patients with PM/Scl antibodies had less pulmonary hypertension. No difference in terms of survival at 5 and 10 years was noticed between the 2 groups.

Conclusions: In Spanish systemic sclerosis patients, PM/Scl antibodies are associated with a distinct clinical profile. However, PM/Scl antibodies did not influence survival.
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http://dx.doi.org/10.1097/RHU.0000000000001676DOI Listing
April 2021

Relative Handgrip Strength as Marker of Cardiometabolic Risk in Women with Systemic Lupus Erythematosus.

Int J Environ Res Public Health 2021 04 27;18(9). Epub 2021 Apr 27.

Department of Education, Faculty of Education Sciences, University of Almería, 04120 Almería, Spain.

This study aimed to examine the association of relative handgrip strength (rHGS) with cardiometabolic disease risk factors in women with systemic lupus erythematosus (SLE).

Methods: Seventy-seven women with SLE (mean age 43.2, SD 13.8) and clinical stability during the previous six months were included. Handgrip strength was assessed with a digital dynamometer and rHGS was defined as absolute handgrip strength (aHGS) divided by body mass index (BMI). We measured blood pressure, markers of lipid and glucose metabolism, inflammation (high sensitivity C-reactive protein [hs-CRP]), arterial stiffness (pulse wave velocity [PWV]), and renal function. A clustered cardiometabolic risk index (z-score) was computed.

Results: Pearson's bivariate correlations revealed that higher rHGS was associated with lower systolic blood pressure (SBP), triglycerides, hs-CRP, PWV, and lower clustered cardiometabolic risk (r = from -0.43 to -0.23; all < 0.05). Multivariable linear regression analyses adjusted for age, disease activity (SLEDAI), and accrual damage (SDI) confirmed these results (all < 0.05) except for triglycerides.

Conclusions: The findings suggest that higher rHGS is significantly associated with lower cardiometabolic risk in women with SLE.
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http://dx.doi.org/10.3390/ijerph18094630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123887PMC
April 2021

Disease Damage Accrual and Low Bone Mineral Density in Female Patients with Systemic Lupus Erythematosus.

Biol Res Nurs 2021 Oct 31;23(4):575-583. Epub 2021 Mar 31.

Biohealth Research Institute in Granada (ibs.GRANADA), Pabellón de consultas externas 2, Granada, Spain.

Osteoporosis is a common comorbidity in patients with systemic lupus erythematosus (SLE), but the potential contribution of disease-associated factors to bone status in SLE is not well known because the reported risk factors from different studies differ greatly. We aimed to examine frequency of reduced bone mass in women with SLE, and determine their potential associations with disease activity, damage accrual and SLE-related clinical markers. A cross-sectional study including 121 Caucasian pre-menopausal and postmenopausal women was conducted (mean age 49.2 ± 12.4 years). The SLE Disease Activity Index (SLEDAI-2 K) and the SDI Damage Index were used to assess disease activity and disease-related damage, respectively. Bone mineral density (BMD) of the left femoral neck and lumbar spine (L2-L4) were measured by dual-energy X-ray absorptiometry. Ten patients (8.3%) had osteoporosis, 63 (52.1%) patients had osteopenia and 6.8% of women had history of previous fracture. Patients with low bone mass had a significantly higher mean SDI (1.3 ± 1.2 versus 0.7 ± 1.0 0.003). T-score at lumbar spine was inversely correlated with SDI score (r = -0.222, 0.014) and complement C3 level ( = -0.206, .024). SDI scores were significantly different between patients with osteoporosis, osteopenia, and normal BMD after adjusting for covariates ( .004). There is a high prevalence of low BMD in Caucasian women with SLE, and this status was associated with higher damage accrual scores, supporting that disease damage may itself be a major contributor to the low BMD. Women with SLE with organ damage require regular bone status monitoring to prevent further musculoskeletal damage.
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http://dx.doi.org/10.1177/10998004211005550DOI Listing
October 2021

Effect of COVID-19 confinement on the mental status of patients with systemic lupus erythematosus.

Med Clin (Engl Ed) 2021 Apr 18;156(8):379-385. Epub 2021 Mar 18.

Centro de Investigación Mente, Cerebro, y Comportamiento (CIMCYC), Departamento de Personalidad, Evaluación y Tratamiento Psicológico, Universidad de Granada, Granada, Spain.

Background And Objective: Patients with systemic lupus erythematosus (SLE) are more vulnerable to higher levels of stress and psychopathological symptoms than the general healthy population. Therefore, the COVID-19 outbreak could alter their psychological state. The objective was to analyze the psychological impact of the pandemic and confinement on stress levels and psychopathological symptoms in patients with SLE.

Patients And Method: In this cross-sectional study, stress levels were compared with the Perceived Stress Scale, the Stress Vulnerability Inventory and psychopathological symptoms of the SCL-90-R Symptom Inventory in patients with SLE during the period of confinement (group 1; n = 276) in comparison to patients with SLE evaluated in a period before the pandemic (group 2; n = 152).

Results: The comparison between both groups showed there were statistically significant differences in vulnerability to stress ( < 0.0001), depression ( ≤ 0.05), anxiety ( ≤ 0.05), phobic anxiety ( < 0.0001), interpersonal sensitivity ( ≤ 0.043), and psychoticism ( ≤ 0.023). In these variables, the group of patients with lupus in confinement obtained higher scores.

Conclusions: The confinement and threat of the COVID-19 outbreak had important repercussions on the psychological state of patients with SLE with high levels of stress, anxiety, and depression. These findings show their vulnerability to a public health alert and indicate the need to carry out a psychological approach to these patients while the state of health emergency lasts as well as to possible outbreaks of the virus.
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http://dx.doi.org/10.1016/j.medcle.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969859PMC
April 2021

The presence of both HLA-DRB1*04:01 and HLA-B*15:01 increases the susceptibility to cranial and extracranial giant cell arteritis.

Clin Exp Rheumatol 2021 Mar-Apr;39 Suppl 129(2):21-26. Epub 2021 Mar 18.

Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, Santander; Research Group on Genetic Epidemiology and Atherosclerosis in Systemic Diseases and in Metabolic Bone Diseases of the Musculoskeletal System, IDIVAL, Santander; School of Medicine, Universidad de Cantabria, Santander, Spain; and Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Objectives: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes.

Methods: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups.

Results: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA.

Conclusions: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.
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May 2021

[Effect of COVID-19 confinement on the mental status of patients with systemic lupus erythematosus].

Med Clin (Barc) 2021 04 29;156(8):379-385. Epub 2021 Jan 29.

Centro de Investigación Mente, Cerebro, y Comportamiento (CIMCYC), Departamento de Personalidad, Evaluación y Tratamiento Psicológico, Universidad de Granada. Granada, España.

Background And Objective: Patients with systemic lupus erythematosus (SLE) are more vulnerable to higher levels of stress and psychopathological symptoms than the general healthy population. Therefore, the COVID-19 outbreak could alter their psychological state. The objective was to analyze the psychological impact of the pandemic and confinement on stress levels and psychopathological symptoms in patients with SLE.

Patients And Method: In this cross-sectional study, stress levels were compared with the Perceived Stress Scale, the Stress Vulnerability Inventory and psychopathological symptoms of the SCL-90-R Symptom Inventory in patients with SLE during the period of confinement (group 1; n=276) in comparison to patients with SLE evaluated in a period before the pandemic (group 2; n=152).

Results: The comparison between both groups showed there were statistically significant differences in vulnerability to stress (P<.0001), depression (P≤.05), anxiety (P≤.05), phobic anxiety (P<.0001), interpersonal sensitivity (P≤.043), and psychoticism (P≤.023). In these variables, the group of patients with lupus in confinement obtained higher scores.

Conclusions: The confinement and threat of the COVID-19 outbreak had important repercussions on the psychological state of patients with SLE with high levels of stress, anxiety, and depression. These findings show their vulnerability to a public health alert and indicate the need to carry out a psychological approach to these patients while the state of health emergency lasts as well as to possible outbreaks of the virus.
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http://dx.doi.org/10.1016/j.medcli.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846210PMC
April 2021

[Reply].

Med Clin (Barc) 2021 04 8;156(7):361. Epub 2021 Jan 8.

Unidad de Enfermedades Sistémicas, Hospital San Cecilio, Granada, España.

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http://dx.doi.org/10.1016/j.medcli.2020.08.015DOI Listing
April 2021

Role of fibroblast growth factor-23 in calcinosis in women with systemic sclerosis.

Acta Reumatol Port 2020 Oct-Dec;45(4):259-264

Objective: Systemic sclerosis (SSc) is a complex disorder of unknown etiology. The purpose of this study was to evaluate fibroblast growth factor-23 (FGF-23) serum levels in women with SSc compared with healthy controls and to examine a possible association between FGF-23 serum levels with the presence of calcinosis in SSc patients.

Methods: This cross-sectional study was performed in San Cecilio Hospital, Granada (Spain) from November 2017 to May 2019. Sixty-two women with SSc and 62 age and sex matched healthy controls were included in this study. FGF-23 serum concentration was evaluated by indirect enzyme-linked immunosorbent assay (ELISA).

Results: There was no significant difference in FGF-23 levels between SSc patients and healthy controls (78.2 ± 60.5 vs. 80.3 ± 56.3 pg/mL, p= 0.662). Regarding the characteristics of the disease, we found a relationship between the values of FGF-23 and the presence of calcinosis. The levels of FGF-23 are higher in patients suffering from calcinosis (p= 0.028).

Conclusion: We observed the presence of higher levels of serum FGF-23 in SSc female patients with calcinosis. Therefore, FGF-23 could be a possible therapeutic target for future treatments.
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January 2021

Vitamin D Levels are Associated with Disease Activity and Damage Accrual in Systemic Lupus Erythematosus Patients.

Biol Res Nurs 2021 07 30;23(3):455-463. Epub 2020 Dec 30.

Instituto de Investigación Biosanitaria, IBS, Granada, Spain.

Vitamin D has immunosuppressive properties and is considered a therapeutic option, although there is controversy about the role of this vitamin in the pathogenesis of systemic lupus erythematosus (SLE). We aimed to determine the prevalence of vitamin D insufficiency and deficiency and their potential association with disease activity, damage accrual, SLE-related clinical manifestations, and cardiovascular risk factors in SLE patients. A cross-sectional study of 264 patients was conducted (89.4% females; mean age 46.7 ± 12.9 years). The SLE Disease Activity Index (SLEDAI-2 K) and the SDI Damage Index were used to assess disease activity and disease-related damage, respectively. The mean 25(OH)D value was 25.1 ± 13.0 ng/ml. Eleven patients (4.2%) had 25(OH)D <10 (deficiency) and 178 patients (70.6%) had 25(OH)D <30 (insufficiency). In the 25(OH)D deficiency group, SLEDAI was significantly higher than the insufficiency ( = 0.001) and normal groups ( < 0.001). Also, patients with vitamin D deficiency presented significantly higher SDI scores than patients with 25(OH)D insufficiency ( = 0.033) and 25(OH)D normal levels ( = 0.029). There is a high prevalence of both vitamin D deficiency and insufficiency in Caucasian SLE patients and this status was associated with higher SLEDAI and SDI scores, supporting the impact of vitamin D levels on disease activity and damage accrual in SLE patients. Longitudinal studies on the relationship between vitamin D status and disease activity and progression are therefore required.
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http://dx.doi.org/10.1177/1099800420983596DOI Listing
July 2021

HLA association with the susceptibility to anti-synthetase syndrome.

Joint Bone Spine 2021 05 7;88(3):105115. Epub 2020 Dec 7.

Department of Systemic Autoimmune Diseases, Hospital Universitario Valle de Hebron, Barcelona, Spain.

Objective: To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD).

Methods: We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing.

Results: A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P=1.56E-09, odds ratio-OR [95% confidence interval-CI]=2.54 [1.84-3.50] and 21.4% versus 5.5%, P=18.95E-18, OR [95% CI]=4.73 [3.18-7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P=0.0003, OR [95% CI]=0.48 [0.31-0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P=0.001, OR [95% CI]=2.54 [1.39-4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed.

Conclusions: Our results support the association of the HLA complex with the susceptibility to ASSD.
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http://dx.doi.org/10.1016/j.jbspin.2020.105115DOI Listing
May 2021

Genomic Risk Score impact on susceptibility to systemic sclerosis.

Ann Rheum Dis 2021 01 1;80(1):118-127. Epub 2020 Oct 1.

Instituto de Parasitologia y Biomedicina Lopez-Neyra, Granada, Andalucía, Spain

Objectives: Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time.

Methods: Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model.

Results: The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693.

Conclusions: GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc.
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http://dx.doi.org/10.1136/annrheumdis-2020-218558DOI Listing
January 2021

Association between homocysteine levels and arterial stiffness in women with systemic sclerosis.

Clin Exp Rheumatol 2020 May-Jun;38 Suppl 125(3):92-97. Epub 2020 Aug 26.

Systemic Autoimmune Diseases Unit, Hospital Universitario San Cecilio, Granada; School of Medicine, University of Granada; and Instituto de Investigación Biosanitaria, IBS, Granada, Spain.

Objectives: The purpose of this study was to evaluate homocysteine (Hcy) serum levels in women with systemic sclerosis (SSc) compared with healthy controls and to examine possible associations between Hcy and markers of arterial stiffness.

Methods: A cross-sectional study was performed at a single hospital between November 2017 and May 2019: 62 women with SSc and 62 age- and sex-matched healthy controls were enrolled. Pulse wave velocity (PWV) was measured non-invasively along the carotid-femoral arterial segment. Serum Hcy was analysed using immunonephelo-metric method.

Results: There was a significant difference in Hcy serum levels between SSc female patients and healthy controls (11.9±3.3 vs. 10.3±2.3 μmol/ml, p=0.002). Serum levels of Hcy were positively correlated with PWV (r=0.28, p<0.05), brain natriuretic peptide (BNP) (r=0.36, p<0.05) and disease duration (r=0.38, p<0.05), within the SSc group. In addition, in the linear regression model, higher Hcy concentrations were associated with higher PWV [β=0.74 95% CI (0.085, 1.394); p=0.027], BNP [β=0.04 95% CI (0.014, 0.072); p=0.004] and disease duration [β=0.18 95% CI (0.070, 0.300); p=0.002]. In multiple linear regression model adjusting for covariants, Hcy remained positively related to the PWV [β=0.033 95% CI (0.003, 0.062); p=0.031].

Conclusions: Our findings revealed a positive correlation between Hcy serum levels and PWV, which indicates that high levels of Hcy may predispose to the development of vascular stiffness in patients with SSc.
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September 2020

The incidence rate of pulmonary arterial hypertension and scleroderma renal crisis in systemic sclerosis patients with digital ulcers on endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i).

Rheumatology (Oxford) 2021 02;60(2):872-880

Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Universitario Vall d'Hebron, Barcelona, Spain.

Introduction: Endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i) are beneficial in pulmonary arterial hypertension (PAH) and digital ulcers (DU) and prevent from DU recurrences. Our study aimed to determine the difference in the incidence rate of PAH and scleroderma renal crisis (SRC) in patients with SSc and DU (SSc-DU) under ERAs/PDE5i or without treatment.

Methods: We conducted a retrospective cohort study including SSc-DU patients from the Spanish Scleroderma Registry (RESCLE). The primary outcome was the incidence rate of PAH and SRC in patients under ERAs/PDE5i or not.

Results: Some 544 patients out of 1817 (29.9%) in the RESCLE database had DU, 221 (40.6%) under ERAs/PDE5i and 323 (59.4%) not. The incidence rate (95% CI) difference between patients under treatment or not under did not reach statistical significance in PAH [-0.1 (-4.8, 4.69), P = 0.988] or in SRC [0.7 (-2.2, 3.7), P = 0.620]. However, the time from the first DU to the diagnosis of SRC was delayed in treated patients [mean (s.d.) 7.6 (5.8) years vs 2.9  (5.3); P = 0.021]. The dcSSc subset was more prevalent in the treatment group (36 vs 26%; P = 0.018), along with anti-topoisomerase I antibodies (34 vs 18%; P < 0.001) and tendon friction rubs (12 vs 6%; P = 0.038), whereas the lcSSc subset was more prevalent in the no-treatment group (57 vs 66%; P = 0.031) along with ACA (37 vs 46%; P = 0.031).

Conclusion: There was no difference in the incidence rate of PAH and SRC between groups. However, treatment with ERAs and/or PDE5i appeared to delay the occurrence of SRC.
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http://dx.doi.org/10.1093/rheumatology/keaa401DOI Listing
February 2021

One world, one health: The novel coronavirus COVID-19 epidemic.

Med Clin (Engl Ed) 2020 Sep 23;155(6):272. Epub 2020 Jul 23.

Unidad de Enfermedades Sistémicas, Servicio de Medicina Interna, Hospital San Cecilio, Granada, Spain.

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http://dx.doi.org/10.1016/j.medcle.2020.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377713PMC
September 2020

Effectiveness of corticoid pulses in patients with cytokine storm syndrome induced by SARS-CoV-2 infection.

Med Clin (Engl Ed) 2020 Aug 10;155(4):159-161. Epub 2020 Jul 10.

Unidad de Enfermedades Sistémicas, Servicio de Medicina Interna, Hospital Universitario Clínico San Cecilio, Granada, Spain.

Introduction: Cytokine storm syndrome (CSS) is a serious complication of COVID-19 patients. Treatment is tocilizumab. The use of glucocorticoids (GC) is controversial. In other very similar CSS, such as macrophage activation syndrome (MAS) and hemophagocytic syndrome (HFS), the main treatment are corticosteroids. Our objective is to evaluate the efficacy of GC in the CSS by COVID-19.

Patients: We included 92 patients with CSS associated to COVID-19 who received GC, GC, and tocilizumab and only tocilizumab. We determine CSS markers. We evaluated mortality, intubation, and a combined variable.

Results: In all cases the percentages of events were lower in the group of patients with GC was administered. The hazard ratio of the final variables with GC versus the group in which only tocilizumab was administered was lower as CGs were considered, with statistical significance for survival.

Discussion: The early use of GC pulses could control SLC, with a lower requirement to use tocilizumab and a decrease in events such as intubation and death.
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http://dx.doi.org/10.1016/j.medcle.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351423PMC
August 2020

Biologic Therapy in Refractory Non-Multiple Sclerosis Optic Neuritis Isolated or Associated to Immune-Mediated Inflammatory Diseases. A Multicenter Study.

J Clin Med 2020 Aug 11;9(8). Epub 2020 Aug 11.

Rheumatology, Ophtalmology and Internal Medicine, Hospital Universitario Marqués de Valdecilla, Av. de Valdecilla, 25, 39008 Santander, Spain.

We aimed to assess the efficacy of biologic therapy in refractory non-Multiple Sclerosis (MS) Optic Neuritis (ON), a condition more infrequent, chronic and severe than MS ON. This was an open-label multicenter study of patients with non-MS ON refractory to systemic corticosteroids and at least one conventional immunosuppressive drug. The main outcomes were Best Corrected Visual Acuity (BCVA) and both Macular Thickness (MT) and Retinal Nerve Fiber Layer (RNFL) using Optical Coherence Tomography (OCT). These outcome variables were assessed at baseline, 1 week, and 1, 3, 6 and 12 months after biologic therapy initiation. Remission was defined as the absence of ON symptoms and signs that lasted longer than 24 h, with or without an associated new lesion on magnetic resonance imaging with gadolinium contrast agents for at least 3 months. We studied 19 patients (11 women/8 men; mean age, 34.8 ± 13.9 years). The underlying diseases were Bechet's disease ( = 5), neuromyelitis optica ( = 3), systemic lupus erythematosus ( = 2), sarcoidosis ( = 1), relapsing polychondritis ( = 1) and anti-neutrophil cytoplasmic antibody -associated vasculitis ( = 1). It was idiopathic in 6 patients. The first biologic agent used in each patient was: adalimumab ( = 6), rituximab ( = 6), infliximab ( = 5) and tocilizumab ( = 2). A second immunosuppressive drug was simultaneously used in 11 patients: methotrexate ( = 11), azathioprine ( = 2), mycophenolate mofetil ( = 1) and hydroxychloroquine ( = 1). Improvement of the main outcomes was observed after 1 year of therapy when compared with baseline data: mean ± SD BCVA (0.8 ± 0.3 LogMAR vs. 0.6 ± 0.3 LogMAR; = 0.03), mean ± SD RNFL (190.5 ± 175.4 μm vs. 183.4 ± 139.5 μm; = 0.02), mean ± SD MT (270.7 ± 23.2 μm vs. 369.6 ± 137.4 μm; = 0.03). Besides, the median (IQR) prednisone-dose was also reduced from 40 (10-61.5) mg/day at baseline to. 2.5 (0-5) mg/day after one year of follow-up; = 0.001. After a mean ± SD follow-up of 35 months, 15 patients (78.9%) achieved ocular remission, and 2 (10.5%) experienced severe adverse events. Biologic therapy is effective in patients with refractory non-MS ON.
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http://dx.doi.org/10.3390/jcm9082608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464396PMC
August 2020

Association Between FGF-23 Levels and Risk of Fracture in Women With Systemic Sclerosis.

J Clin Densitom 2021 Jul-Sep;24(3):362-368. Epub 2020 Jun 2.

Systemic Autoimmune Diseases Unit, Hospital Universitario San Cecilio, Granada, Spain; School of Medicine, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria, IBS, Granada, Spain.

Introduction/background: The purpose of this study was to evaluate the association between Fracture Risk Assessment Tool (FRAX) and serum fibroblast grow factor-23 (FGF-23) levels in SSc women patients compared with healthy controls.

Methodology: This cross-sectional study was performed in San Cecilio Hospital, Granada (Spain) from November 2017 to May 2019. Sixty-two women with SSc and 62 age and sex matched healthy controls were included in this study. FGF-23 serum concentration was evaluated by indirect enzyme-linked immunosorbent assay. The FRAX scoring tool was applied using the on-line calculator (www.shef.ac.uk/FRAX).

Results: Even though there was no significant difference in FGF-23 levels between SSc women patients and healthy controls (78.2 ± 60.5 vs 80.3 ± 56.3 pg/mL, p = 0.662). FGF-23 levels were positively associated with FRAX index within the study group.

Conclusions: This study shows that FGF-23 status is associated with FRAX index in women with SSc. FGF-23 could be a promising biomarker for detecting risk fracture in SSc women patients.
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http://dx.doi.org/10.1016/j.jocd.2020.05.010DOI Listing
June 2020

Beneficial effect of Mediterranean diet on disease activity and cardiovascular risk in systemic lupus erythematosus patients: a cross-sectional study.

Rheumatology (Oxford) 2021 01;60(1):160-169

Instituto de Investigación Biosanitaria, IBS, Granada.

Objective: To analyse the influence of the Mediterranean diet (Med Diet) on SLE activity, damage accrual and cardiovascular disease risk markers.

Methods: A cross-sectional study was conducted on 280 patients with SLE [46.9 (12.85) years]. Med Diet adherence was assessed through a 14-item questionnaire on food consumption frequency and habits (total score from 0 to 14 points; higher score is greater adherence to the Med Diet). CRP, homocysteine, SLEDAI-2K (SLE disease activity), and SLICC/ACR and SDI (damage accrual) were measured. Obesity, diabetes mellitus, hypertension and blood lipids, among others, were considered cardiovascular disease risk factors.

Results: Greater adherence to the Med Diet was significantly associated with better anthropometric profiles, fewer cardiovascular disease risk factors, and lower disease activity and damage accrual scores (P ≤ 0.001 for SLEDAI and SDI). An inverse relationship between the Med Diet score and SLEDAI (P ≥ 0.001; β = -0.380), SDI (P ≤ 0.001; β = -0.740) and hsCRP (P = 0.039; β = -0.055) was observed. The odds ratio for having active SLE (SLEDAI ≥5) or the presence of damage (SDI ≥1) was lower among patients whose Med Diet score was higher (P ≤ 0.001). Finally, greater consumption of Med Diet foods (olive oil, fruits, vegetables, fish, etc.) and abstaining from red meat and meat products, sugars and pastries was associated with less SLE clinical activity and damage.

Conclusion: Greater adherence to the Med Diet seems to exert a beneficial effect on disease activity and cardiovascular risk in SLE patients. To confirm these findings, further longitudinal studies would be of interest.
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http://dx.doi.org/10.1093/rheumatology/keaa210DOI Listing
January 2021

[One world, one health: The novel coronavirus COVID-19 epidemic].

Med Clin (Barc) 2020 09 5;155(6):272. Epub 2020 Jun 5.

Unidad de Enfermedades Sistémicas, Servicio de Medicina Interna, Hospital San Cecilio, Granada, España.

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http://dx.doi.org/10.1016/j.medcli.2020.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274618PMC
September 2020

[Effectiveness of corticoid pulses in patients with cytokine storm syndrome induced by SARS-CoV-2 infection].

Med Clin (Barc) 2020 08 27;155(4):159-161. Epub 2020 May 27.

Unidad de Enfermedades Sistémicas, Servicio de Medicina Interna, Hospital Universitario Clínico San Cecilio, Granada, España.

Introduction: Cytokine storm syndrome (CSS) is a serious complication of COVID-19 patients. Treatment is tocilizumab. The use of glucocorticoids (GC) is controversial. In other very similar CSS, such as macrophage activation syndrome (MAS) and hemophagocytic syndrome (HFS), the main treatment are corticosteroids. Our objective is to evaluate the efficacy of GC in the CSS by COVID-19.

Patients: We included 92 patients with CSS associated to COVID-19 who received GC, GC, and tocilizumab and only tocilizumab. We determine CSS markers. We evaluated mortality, intubation, and a combined variable.

Results: In all cases the percentages of events were lower in the group of patients with GC was administered. The hazard ratio of the final variables with GC versus the group in which only tocilizumab was administered was lower as CGs were considered, with statistical significance for survival.

Discussion: The early use of GC pulses could control SLC, with a lower requirement to use tocilizumab and a decrease in events such as intubation and death.
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http://dx.doi.org/10.1016/j.medcli.2020.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250763PMC
August 2020

The impact of obesity on disease activity, damage accrual, inflammation markers and cardiovascular risk factors in systemic lupus erythematosus.

Panminerva Med 2020 Jun;62(2):75-82

Institute of Biomedical Research (IBS), Granada, Spain.

Background: We aimed to evaluate the relationships between obesity metrics including Body Mass Index (BMI), waist to height ratio (WtHR) and fat mass percentage, and disease activity, damage accrual, inflammation markers and traditional cardiovascular risk factors in SLE patients.

Methods: A cross-sectional study was conducted on a sample of 275 patients (90.5% females; mean age 46.37±13.85 years). Disease activity was assessed with the SLE disease activity index (SLEDAI-2K), and disease-related organ damage was assessed using the SLICC/ACR damage index (SDI). Biochemical variables of lipids profile, high-sensitivity C-reactive protein (hs-CRP), homocysteine (Hcy), anti-dsDNA titers and complement components C3 and C4 serum levels were measured. Blood pressure and ankle-brachial index (ABI) were also calculated.

Results: Significant differences were observed between normal-weight, overweight and obese patients in SLEDAI (2.60±2.48 vs. 2.71±2.65 vs. 3.84±3.02; P=0.004), SDI (0.76±1.10 vs. 1.09±1.24 vs. 1.57±1.54; P=0.002), hsCRP (2.15±2.93 vs. 3.24±3.63 vs. 5.30±5.63 mg/dL; P<0.001), complement C3 level (99.92±24.45 vs. 111.38±27.41 vs. 123.16±28.96 mg/dL; P<0.001), triglycerides serum levels (85.99±41.68 vs. 102.35±50.88 vs. 129.12±61.59 mg/dL; P<0.001) and systolic blood pressure (112.28±16.35 vs. 124.25±17.94 vs. 132.78±16.71 mmHg; P=0.001) after adjusting for age and sex.

Conclusions: Patients with SLE who are obese have worse disease activity and damage accrual, higher levels of inflammation markers hs-CRP and C3 complement, increased triglycerides serum levels and systolic blood pressure levels in comparison with overweight or normal weight SLE patients, supporting that optimizing weight in SLE patients should be a potential target to improve SLE outcomes.
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http://dx.doi.org/10.23736/S0031-0808.19.03748-0DOI Listing
June 2020
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