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Objective: This study aimed to investigate the current status and performance of machine learning (ML) approaches in providing reproducible treatment response predictions., Methods: This systematic review was conducted in accordance with the PRISMA statement and the CHARMS checklist. We searched PubMed, Cochrane Library, Web of Science, Scopus, and EBSCO databases for cohort studies that derived and/or validated ML models focused on predicting rheumatoid arthritis (RA) treatment response. We extracted data and critically appraised studies based on the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) and Prediction Model Risk of Bias Assessment Tool (PROBAST) guidelines., Results: From 210 unduplicated records identified by the literature search, we retained 29 eligible studies. Of these studies, 10 developed a predictive model and reported a mean adherence to the TRIPOD guidelines of 45.6 % (95 % CI: 38.3-52.8 %). The remaining 19 studies not only developed a predictive model but also validated it externally, with a mean adherence of 42.9 % (95 % CI: 39.1-46.6 %). Most of the articles had an unclear risk of bias (41.4 %), followed by a high risk of bias, which was present in 37.9 %., Conclusions: In recent years, ML methods have been increasingly used to predict treatment response in RA. Our critical appraisal revealed unclear and high risk of bias in most of the identified models, suggesting that researchers can do more to address the risk of bias and increase transparency, including the use of calibration measures and reporting methods for handling missing data., Funding: None., Competing Interests: Declaration of competing interest The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the risk of DM and evaluate the impact of SLE therapies on the risk of developing DM in patients with SLE., Methods: Electronic database searches of PubMed, Embase, Cochrane Library and Web of Science were performed from inception to February 2023. Cohort and cross-sectional studies that analysed the risk of DM in patients with SLE were included. The associations between diabetes and antirheumatic agents, such as antimalarials and glucocorticoids, were analysed in cohort studies. Data were pooled using fixed- or random-effects meta-analysis to estimate pooled odd ratios (OR), relative risks (RR) and 95% confidence intervals (CIs). This study was registered with PROSPERO (CRD42023402774)., Results: A total of 37 studies (23 cross-sectional and 14 cohort studies) involving 266 537 patients with SLE were included. The pooled analyses from cross-sectional studies and cohort studies did not show an increased risk of DM in SLE patients (OR = 1.05, 95% CI 0.87-1.27; P = 0.63 and RR = 1.32, 95% CI 0.93-1.87; P = 0.12, respectively). However, several cohort studies consistently demonstrated a reduced risk of diabetes with antimalarials, while glucocorticoid use has been associated with an increased risk of developing diabetes. Age, sex, hypertension and immunosuppressants have not been identified as risk factors for DM in SLE patients., Conclusion: Although there was no increased risk of DM in patients with SLE compared with controls, HCQ users or adherents had a decreased risk, whereas glucocorticoid users had an increased risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Antiphospholipid antibody syndrome (usually named antiphospholipid syndrome, APS) is an autoimmune disorder seen mainly in young people. Clinically, APS is described by pregnancy complications and/or a hypercoagulable state, including the venous or arterial vasculature, and strongly related to antiphospholipid antibodies. Although several cardiac manifestations have been involved with APS, and accelerated atherosclerosis is present in this condition, little is known about cardiovascular (CV) risk and the relation between APS. Several studies have used imaging markers to associate them with the main clinical features of patients with APS and the probability of having subclinical atherosclerosis. However, it has not yet been established which markers are most related to the risk of developing CV diseases (CVD) in these patients. In this narrative review, we focus on non-invasive imaging markers that can predict CVD, including carotid intima-media thickness and carotid plaques assessed by carotid ultrasonography or coronary artery calcium score, which usually by computed tomography. We also examine the evidence about vascular function markers used in APS, such as arterial flow-mediated brachial dilation and artery stiffness measured by the velocity of the pulse wave. We present the current status of non-invasive imaging markers, which suggest the existence of subclinical atherosclerosis in patients with APS. However, new prospective research is required to identify the predictive value of these findings and their modification by current treatments for APS., Competing Interests: Declaration of Competing Interest All authors have nothing to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To describe the results from the Global Burden Disease (GBD) study 2019 on the burden of other musculoskeletal (MSK) disorders in Latin America and the Caribbean (LAC)., Methods: In this cross-sectional study, we analyzed data from all LAC region in the GBD study from 1990 to 2019. Other MSK (other than rheumatoid arthritis, osteoarthritis, gout, low back pain, and neck pain) burden was measured as prevalence, mortality, years lived with disability (YLD), and disability-adjusted life (DALY), by year, sex, and country. We show the counts, rates, and 95% uncertainty intervals (95% UI). Joinpoint regression analysis was used to estimate the average annual percentage change (AAPC) from 1990 to 2019. A correlational analysis between the burden parameters and sociodemographic index (SDI) was performed., Results: In 2019, there were 52.0 million (95% UI, 44.8-60.1 million) individuals with other MSK disorders in LAC. The age-standardized mortality rate in 2019 was 1.2 (95% UI, 0.8-1.6) per 100,000 inhabitants. The AAPC was estimated as 0.1% (95% confidence interval [CI], 0.1-0.2) and 0.2% (95% CI, 0.1-0.3) for prevalence and mortality rates, respectively. The age-standardized DALY rate was 685.4 (95% UI, 483.6-483.6) per 100,000 inhabitants, representing an AAPC of 0.2% (95% CI, 0.1-0.3). The burden was larger in women and the elderly. The SDI was positively correlated with the prevalence of YLD in 2019., Conclusions: LAC region has experienced a significant burden of other MSK disorders over the last three decades. To challenge this growing burden, population-based strategies designed to reduce the burden of other MSK and strengthen health systems to contribute effective and cost-efficient care are necessary., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study aimed to describe the disease burden and trends of musculoskeletal (MSK) disorders in Mexico from 1990 to 2019., Method: A cross-sectional study using systematic analysis from the Global Burden of Disease Study 2019 (GBD study 2019) was performed to analyze data on MSK disorders and estimate crude and age-standardized rates per 100,000 population concerning disease prevalence, incidence, mortality, disability-adjusted life-years (DALY), and years lived with disability (YLD). The average annual percentage change (AAPC) was calculated using the joinpoint regression., Results: In 2019, there were 4.8 million (95% UI 4.3, 5.4) new cases and 3,312 (95% UI 2201, 4,790) deaths attributable to MSK disorders. In 2019, MSK disorders ranked first, increasing from 1990 (second rank) for the YLD in Mexico. Subnational variations were identified, with the state of Oaxaca having the highest age-standardized incidence rate (ASIR) per 100,000 population in 2019. Joinpoint analysis revealed a significant increase in prevalence in Mexico from 1990 to 2019 (AAPC: 0.14%; 95%CI 0.09-0.19), incidence (AAPC: 0.05%; 95%CI 0.03-0.07), DALY (AAPC: 0.13%; 95%CI 0.04-0.22), and YLD (AAPC: 0.13%; 95%CI 0.02-0.24). Among the risk factors, occupational ergonomic factors and high body mass index (BMI) had the largest influence on MSK disorders., Conclusions: In Mexico, we observed an increase the national burden of MSK disorders from 1990 to 2019. Specific determinants, such as occupational ergonomic factors and high BMI, contribute to the MSK disorder burden. The burden of MSK disorders requires an improved and prompt assessment to plan valuable diagnostic and management approaches. Key Points • In Mexico, the burden of musculoskeletal (MSK) disorders increased from 1990 to 2019. • Specific risk factors, such as occupational ergonomic factors and high body mass index, contribute to the MSK disorder burden., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

The Systemic Lupus International Clinics (SLICC)-Frailty Index (FI) is associated with adverse outcomes in systemic lupus erythematosus (SLE). However, to our knowledge, its association with bone mineral density (BMD) and vertebral fractures (VF), has not been investigated using a standardized methods. Our aim was to evaluate the relationship between frailty assessed by SLICC-FI, and BMD and VF in Mestizo women with SLE. Adult women were included in this cross-sectional study. Information concerning the risk factors for VF and BMD in the lumbar spine and total hip was acquired. SLICC-FI was assessed at baseline. A semi-quantitative method was utilized to evaluate the prevalence of VF on lateral thoracolumbar radiographs. Univariate and multivariate regression analyses were performed adjusting for age, body mass index (BMI), SLE duration, cumulative glucocorticoid dose, bisphosphonate use, and BMD measurements. We included 202 women with SLE (mean age [SD] = 43.3 [13.6] years). The mean (SD) SLICC-FI value was 0.14 (0.09). Eleven (5.4%) patients were categorized as robust, 62 (30.7%) as relatively less fit, 84 (41.6%) as least fit, and 45 (22.3%) as frail. Both univariate and multivariate models showed associations between frailty (defined as SLICC-FI > 0.21) and prevalent VF in the entire population (OR 5.76, 95% CI 2.53-13.12; P < 0.001) and in the premenopausal group (OR 4.29, 95% CI; P = 0.047). We also found an association between the SLICC-FI and low BMD. In conclusion, frailty assessed by SLICC-FI might be associated with VF and low BMD in mestizo females with SLE., (© 2023. The Author(s).)

Background: Low disease activity state (LDAS) has been linked to a significant reduction in flares and damage accrual in patients with systemic lupus erythematosus (SLE); however, the effect of LDAS on the risk of vertebral fractures (VFs) in subjects with SLE is unknown, considering that low bone mineral density (BMD) and VF are frequent in SLE., Objective: to evaluate whether achieving LDAS ≥50% of the observation time prevents new VF and BMD changes in Mestizo women., Methods: We carried out a longitudinal, observational, and retrospective study. Mestizo women with SLE were included for a median of an 8-year follow-up. LDAS was described as Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≤4, prednisone ≤7.5 mg/day, and stable immunosuppressive therapies. BMD measurements and lateral thoracic and lumbar radiographs for a semiquantitative analysis for VF were assessed at baseline and during the follow-up. Uni- and multivariable interval-censored survival regression models were carried out., Results: We included 110 patients: 35 (31.8%) had new VF. A total of 56 patients (50.1%) achieved LDAS ≥50% of the time during the follow-up and achieved a significantly lesser risk of incident VF (HR = 0.16; 95% CI, 0.06-0.49). After adjusting by age, BMI, menopause, prevalent VF, baseline BMD, cumulative glucocorticoid use, and anti-osteoporotic therapy, LDAS-50 was significantly related to a decrease in the risk of a new VF (HR = 0.39; 95% CI, 0.16-0.98). There was no association between LDAS and BMD measurement changes. When only patients on LDAS but not in remission ( n = 43) were evaluated for the risk of incident VF, both uni- and multivariate analyses were significant (HR = 0.12; 95 CI, 0.04-47; p = 0.001, and HR = 0.26; 95% CI, 0.7-0.88; p = 0.03)., Conclusions: LDAS ≥50% of the time was significantly associated with a diminished risk of new VF in Mestizo women with SLE, even in patients not in remission. However, LDAS did not help modify BMD changes over time., Competing Interests: Declaration of conflicting of interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The study aimed to analyze the influence of the COVID-19 pandemic on mortality rates in patients with systemic autoimmune rheumatic diseases (SARD) in Mexico. We selected SARD-related deaths using National Open Data and Information from the Ministry of Health, Mexico, and ICD-10 codes. We assessed the observed compared to the predicted mortality values for 2020 and 2021, employing trends from 2010 to 2019 with joinpoint and prediction modelling analyses. Among 12,742 deaths due to SARD between 2010 and 2021, the age-standardized mortality rate (ASMR) increased significantly between 2010 and 2019 (pre-pandemic) (annual percentage change [APC] 1.1%; 95% CI 0.2-2.1), followed by a non-significant decrease during the pandemic period (APC 13.9%; 95% CI 13.9-5.3). In addition, the observed ASMR of 1.19 for 2020 for SARD and of 1.14 for 2021 were lower than the predicted values of 1.25 (95% CI 1.22-1.28) for 2020 and 1.25 (95% CI 1.20-1.30) for 2021. Similar findings were identified for specific SARD, mainly systemic lupus erythematosus (SLE), or by sex or age group. Interestingly, the observed mortality rates for SLE in the Southern region of 1.00 in 2020 and 1.01 in 2021 were both significantly greater than the predicted values of 0.71 (95% CI 0.65-0.77) in 2020 and 0.71 (95% CI 0.63-0.79). In Mexico, the observed SARD mortality rates were not higher than the expected values during the pandemic, except for SLE in the Southern region. No differences by sex or age group were identified., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The aims of this study were in systemic lupus erythematosus (SLE) patients: 1) to compare the metabolomic profile of insulin resistance (IR) with controls and 2) to correlate the metabolomic profile with other IR surrogates and SLE disease variables and vitamin levels. In this cross-sectional study, serum samples were collected from women with SLE (n=64) and gender- and age-matched controls (n=71), which were not diabetic. Serum metabolomic profiling was performed using UPLC-MS-MS (Quantse score). HOMA and QUICKI were carried out. Serum 25(OH)D concentrations were measured by chemiluminescent immunoassay. In women with SLE, the metabolomic Quantose score significantly correlated with HOMA-IR, HOMA2-IR, and QUICKI. Although concentrations of IR metabolites were not different between SLE patients and controls, fasting plasma insulin levels were higher and insulin sensitivity lower in SLE women. Interestingly, the Quantose IR score was significantly correlated with complement C3 levels (r=0.7; p=0.001). 25 (OH)D did not correlate with any metabolite or the Quantose IR index. Quantose IR may be a useful tool for IR assessment. There was a possible correlation between the metabolomic profile and complement C3 levels. The implementation of this metabolic strategy may help develop biochemical insight into metabolic disorders in SLE., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Type 2 Diabetes Mellitus (T2DM) is a rapidly rising disease with cardiovascular complications constituting the most common cause of death among diabetic patients. Chronic hyperglycemia can induce vascular dysfunction through damage of the components of the vascular wall, such as vascular smooth muscle cells (VSMCs), which regulate vascular tone and contribute to vascular repair and remodeling. These functions are dependent on intracellular Ca 2+ changes. The mechanisms by which T2DM affects Ca 2+ handling in VSMCs still remain poorly understood. Therefore, the objective of this study was to determine whether and how T2DM affects Ca 2+ homeostasis in VSMCs. We evaluated intracellular Ca 2+ signaling in VSMCs from Zucker Diabetic Fatty rats using Ca 2+ imaging with Fura-2/AM. Our results indicate that T2DM decreases Ca 2+ release from the sarcoplasmic reticulum (SR) and increases the activity of store-operated channels (SOCs). Moreover, we were able to identify an enhancement of the activity of the main Ca 2+ extrusion mechanisms (SERCA, PMCA and NCX) during the early stage of the decay of the ATP-induced Ca 2+ transient. In addition, we found an increase in Ca 2+ entry through the reverse mode of NCX and a decrease in SERCA and PMCA activity during the late stage of the signal decay. These effects were appreciated as a shortening of ATP-induced Ca 2+ transient during the early stage of the decay, as well as an increase in the amplitude of the following plateau. Enhanced cytosolic Ca 2+ activity in VSMCs could contribute to vascular dysfunction associated with T2DM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Moreno-Salgado, Coyotl-Santiago, Moreno-Vazquez, Lopez-Teyssier, Garcia-Carrasco, Moccia and Berra-Romani.)

Objective: We carried out a systematic review (SR) of adherence in diagnostic and prognostic applications of ML in SLE using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) Statement., Methods: A SR employing five databases was conducted from its inception until December 2021. We identified articles that evaluated the utilization of ML for prognostic and/or diagnostic purposes. This SR was reported based on the PRISMA guidelines. The TRIPOD statement assessed adherence to reporting standards. Assessment for risk of bias was done using PROBAST tool., Results: We included 45 studies: 29 (64.4%) diagnostic and 16 (35.5%) prognostic prediction- model studies. Overall, articles adhered by between 17% and 67% (median 43%, IQR 37-49%) to TRIPOD items. Only few articles reported the model's predictive performance (2.3%, 95% CI 0.06-12.0), testing of interaction terms (2.3%, 95% CI 0.06-12.0), flow of participants (50%, 95% CI; 34.6-65.4), blinding of predictors (2.3%, 95% CI 0.06-12.0), handling of missing data (36.4%, 95% CI 22.4-52.2), and appropriate title (20.5%, 95% CI 9.8-35.3). Some items were almost completely reported: the source of data (88.6%, 95% CI 75.4-96.2), eligibility criteria (86.4%, 95% CI 76.2-96.5), and interpretation of findings (88.6%, 95% CI 75.4-96.2). In addition, most of model studies had high risk of bias., Conclusions: The reporting adherence of ML-based model developed for SLE, is currently inadequate. Several items deemed crucial for transparent reporting were not fully reported in studies on ML-based prediction models., Review Registration: PROSPERO ID# CRD42021284881. (Amended to limit the scope)., Competing Interests: Declaration of Competing Interest All authors have nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by damage to multiple systems and a higher risk of cardiovascular disease. In addition, several studies have found that insulin resistance (IR) is more prevalent in SLE patients than controls, increasing the risk of prediabetes, type 2 diabetes mellitus (T2DM) and morbidity. The objective of this review article was to summarize the most relevant evidence about the relationship among IR, T2DM and SLE, including the effects of proinflammatory states, acute-phase proteins, pro-inflammatory cytokines, and pharmacological SLE treatment. A better understanding of the mechanisms involved in these comorbidities will allow better treatment strategies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The purpose of this review is to present the main aspects of the genetic component of autoimmune rheumatic diseases, including the characteristics of the multifactorial or polygenic inheritance model, and its monogenic forms, as well as the main associated genes in both cases. The epigenetic changes involved, and the influence of the environment and sex that confer greater risk to women suffering from any of these diseases. Finally, to make known the advances that the study of omic sciences has allowed, opening the way to a new molecular classification of these diseases, aimed at personalized medicine. A review of the literature of the last 5 years, of English-language publications, in the PubMed database was performed and 28 review articles, and 19 original articles were included. Knowledge of the genetic factors involved in the aetiology of autoimmune rheumatic diseases, thanks to the availability of molecular studies, allows a better understanding of their pathophysiology and the possibility of diagnosis and treatment based on molecular markers in the future., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Background: Patients with systemic lupus erythematosus (SLE) have an increased cardiovascular (CV) risk. Insulin resistance (IR), which is higher in patients with SLE, adversely impacts left ventricular (LV) remodeling and function. The aims were to determine LV dysfunction and evaluate the influence of potential risk factors on subclinical LV dysfunction in women with SLE, including IR., Methods: This cross-sectional study included adult women with SLE without diabetes mellitus (DM), hypertension or severe obesity. Diastolic dysfunction (DD) was verified according to current guidelines. Insulin resistance was estimated using the Quantose score., Results: We included 77 women. The frequency of IR was 65%. All participants had a normal ejection fraction (EF), and 11 (15.7%) had abnormal LV global longitudinal strain (GLS). Twenty-three (32.8%) had DD. The GLS% and global circumferential strain (GCS)% did not differ in patients with and without IR (-20.8 ± 3.1 vs -20.5 ± 2.1; p = 0.61 and -27.9 ± 4.4 vs -27.4 ± 3.7; p = 0.57, respectively). The prevalence of DD was 38.1% in patients with IR versus 25% in those without ( p = 0.30). E/e' and E/A ratios did not differ between groups (6.6 ± 1.9 vs 6.6 ± 1.5; p = 0.98 and 1.3 ± 0.3 vs 1.3 ± 0.2; p = 0.27). Higher BMI (OR: 1.2, 95% CI 1.1-1.5) and disease duration (OR: 1.2, 95% CI 1.1-1.4) were associated with DD., Conclusions: Patients with overweight/obesity may be at higher risk of LV dysfunction. Although IR was high in our patients with SLE was not associated with systolic dysfunction or DD. Body mass index and disease duration were associated with an increased risk of DD.

Background: Hospitalizations due to systemic lupus erythematosus (SLE) incur substantial resource use. Hospitalization trends provide a key benchmark of the disease burden. However, there is little long-term data in Mexico. Therefore, we evaluated Mexican hospitalization trends for SLE during 2000-2019., Methods: Hospitalization trends of SLE were studied using data from 2000 to 2019 releases of the National Dynamic Cubes of the General Direction of Health Information, which provides data on hospitalization discharges in Mexico. Patients aged ≥15 years hospitalized during the study period with a principal discharge diagnosis of SLE (ICD-10 code M32) were included., Results: From 2000 to 2019, there were 17,081 hospitalizations for SLE, of which 87.6% were in females and 87% in subjects aged 15-44 years. From 2000 to 2019, the age-standardized hospitalization rate for patients with SLE increased from 0.38 per 100,000 persons to 0.65 per 100,000 persons with an average annual percentage change (APC) of 2.9% (95% CI 6.2-63.2). Although there was a significant uptrend from 2000 through 2011, there was a significant decline from 2011 to 2019 (APC: -4.8%, 95% CI -7.0% to -2.5%). Similar trends were identified in subjects aged 15-44 years and in both sexes. The length of stay and inpatient mortality decreased between 2000-2009 and 2010-2019., Conclusions: Although there was a substantial increase in SLE hospitalizations in 2000-2019, in 2011-2019, a decreased trend was reported in younger patients and in females and males. The length of stay was also reduced.

Systemic lupus erythematosus (SLE) is one of the leading causes of death in younger adults, but advances in diagnosis and management during recent years may have reduced mortality. We examined whether SLE is a leading cause of death in Mexico among females. Data for death counts for the female population were obtained from the General Board of Health Information (DGIS) Open Access datasets, which evaluate death certificates, from 2000 to 2020. SLE was defined using the Tenth Revision of the International Classification of Disease codes: M32.1, M32.8, and M32.9. From 2000 to 2020, there were 12,114 deaths of females with SLE recorded as an underlying cause of death in Mexico. SLE ranked among the top 20 leading causes of death in females aged 10-54 years. SLE ranked fifteenth for deaths in people aged 15-24 years, sixteenth in those aged 25-34 years and 35-44 years, and eighteenth in those aged 45-54 years. After three frequent external injury causes of death were excluded from the analysis, focusing on the organic causes of death, SLE ranked twelfth in those aged 15-24 years and thirteenth in those aged 25-34 years and 35-44 years. In Mexico, SLE is among the leading causes of death in young females, emphasizing its significance as a public health issue., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Histamine is an inflammatory mediator that can be released from mast cells to induce airway remodeling and cause persistent airflow limitation in asthma. In addition to stimulating airway smooth muscle cell constriction and hyperplasia, histamine promotes pulmonary remodeling by inducing fibroblast proliferation, contraction, and migration. It has long been known that histamine receptor 1 (H1R) mediates the effects of histamine on human pulmonary fibroblasts through an increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ), but the underlying signaling mechanisms are still unknown. Herein, we exploited single-cell Ca 2+ imaging to assess the signal transduction pathways whereby histamine generates intracellular Ca 2+ signals in the human fetal lung fibroblast cell line, WI-38. WI-38 fibroblasts were loaded with the Ca 2+ -sensitive fluorophore, FURA-2/AM, and challenged with histamine in the absence and presence of specific pharmacological inhibitors to dissect the Ca 2+ release/entry pathways responsible for the onset of the Ca 2+ response. Histamine elicited complex intracellular Ca 2+ signatures in WI-38 fibroblasts throughout a concentration range spanning between 1 µM and 1 mM. In accord, the Ca 2+ response to histamine adopted four main temporal patterns, which were, respectively, termed peak, peak-oscillations, peak-plateau-oscillations, and peak-plateau. Histamine-evoked intracellular Ca 2+ signals were abolished by pyrilamine, which selectively blocks H1R, and significantly reduced by ranitidine, which selectively inhibits H2R. Conversely, the pharmacological blockade of H3R and H4R did not affect the complex increase in [Ca 2+ ] i evoked by histamine in WI-38 fibroblasts. In agreement with these findings, histamine-induced intracellular Ca 2+ signals were initiated by intracellular Ca 2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate (InsP 3 ) receptors (InsP 3 R) and sustained by store-operated Ca 2+ channels (SOCs). Conversely, L-type voltage-operated Ca 2+ channels did not support histamine-induced extracellular Ca 2+ entry. A preliminary transcriptomic analysis confirmed that WI-38 human lung fibroblasts express all the three InsP 3 R isoforms as well as STIM2 and Orai3, which represent the molecular components of SOCs. The pharmacological blockade of InsP 3 and SOC, therefore, could represent an alternative strategy to prevent the pernicious effects of histamine on lung fibroblasts in asthmatic patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Berra-Romani, Vargaz-Guadarrama, Sánchez-Gómez, Coyotl-Santiago, Hernández-Arambide, Avelino-Cruz, García-Carrasco, Savio, Pellavio, Laforenza, Lagunas-Martínez and Moccia.)

Objective: The role of vascular damage in cognitive dysfunction (CD) in SLE is not entirely understood. Nailfold capillaroscopy (NFC) is a noninvasive method that may aid the description of further vascular contributions to CD in SLE. Therefore, the aim of our study was to examine and compare finger nailfold capillary morphology in subjects with SLE with and without CD., Methods: We conducted a cross-sectional study in patients with SLE. Demographic, clinical, and laboratory characteristics were collected. We evaluated nailfold capillary findings including avascular zones, hemorrhage, dilated and tortuous capillaries, disarrangement, crossing, subpapillary venular plexus, branched loops, and shortened loops by NFC. The Montreal Cognitive Assessment (MoCA) scale was used to screen cognitive function. CD was defined as a score < 26/30., Results: Sixty-five females (97.0%) and 2 males (3%) with SLE were analyzed. Means of age and disease duration were 44.3 ± 12.0 years and 15.5 ± 7.6 years, respectively. Thirty-five (54.7%) patients had CD. The rate of patients with ≥ 1 NFC abnormality was 50% in both patients with and without CD (P = 0.14). Eight (22.8%) patients with CD compared to 1 without (3.5%) displayed dilated capillaries (P = 0.036). Other NFC abnormalities differed between patients with and without CD, but the possible relationships between dilated capillaries and CD disappeared after adjusting by age, diabetes, and hypertension., Conclusions: NFC findings were not associated with mild CD in patients with SLE. Our exploratory data do not support systemic microvasculopathy measured by NFC related to CD in patients with SLE., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: To investigate national temporal trends over time in mortality rates in patients with systemic sclerosis (SSc) in Mexico between 1998 and 2017., Methods: Deaths between 1998 and 2017 were extracted from General Board of Health Information (DGIS) Open Access datasets. 2We identified all persons aged ≥15 years with a diagnosis of SSc (ICD-10 code M34). We calculated the age-standardized mortality rate (ASMR) for SSc and non-SSc (information provided by the National Institute of Statistics, Geography, and Informatics). A Joinpoint regression model was used to determine mortality trends by sex and geographic regions. Annual percentage change (APC) and average APC (AAPC) were calculated using Joinpoint analysis., Results: From 1998 to 2017, the overall ASMR of SSc increased (AAPC = 2.5%), whereas the ASMR for non-SSc remained stable. By subpopulations, females, and males with SSc had a significant uptrend in the ASMR (APC = 4.6 and 4.4%, respectively), between 1998 and 2008 for the former and between 1998 and 2010 for the later. Females had a non-significant ASMR uptrend between 2008 and 2017 and males a non-significant ASMR decline between 2010 and 2017. Women had a higher SSc-ASMR to non-SSc-ASMR ratio than males. The relative cumulative change between 1998 and 2017 differed between females (78.1%) and males (50.8%), and residents of the Southern region had the largest cumulative change (147.8%)., Conclusions: SSc mortality rate increased in Mexico between 1998 to 2017, with SSc mortality higher than non-SSc mortality. However, the SSc mortality rate steeply increased in the first ten years but has plateaued in the last 10 years of the study period. Variations by sex and geographic regions were also identified., Competing Interests: Conflict of Interest The authors declare no potential financial or personal conflict of interest. Compliance with ethical standards. Ethical approval. This research study was approved by the East Biomedical Research Center Ethics Committee (R-2020-2106-027)., (Copyright © 2022. Published by Elsevier Inc.)

Background: Coronary artery disease (CAD) assessed by coronary computed tomography (CT) in patients with systemic lupus erythematosus (SLE) has been investigated in several studies, but with conflicting results. The aim of this systematic review and meta-analysis of the literature was synthesize the evidence on this topic., Methods: The relevant literature was identified and evaluated from inception until January 2021 in PubMed, Embase, Web of Science and Cochrane library. Studies reporting coronary artery calcification (CAC), and its prevalence and extent using the coronary calcium score (CCS) were included. Data extracted from eligible studies were used to calculate effect estimates (ESs) and 95% confidence intervals (95%CI) and weighted mean differences (WMD) with 95%CI., Results: Twenty-four studies were eligible for inclusion. For the CAC prevalence, 11 studies were included (918 SLE patients and 3952 controls) and the pooled prevalence for the random effect was 29.8% (95%CI 25.7-32.9%) for SLE patients and 11.8% (95%CI 16.2-20.4%) in controls (RR 2.22, 95%CI 1.42 to 3.48; p= 0.0005) and no significant increase in the WMD for CCS (MD= 0.32, 95%CI -5.55 to 6.20, p= 0.91) compared with controls in seven studies. Greater organ damage and glucocorticoid use has been associated with a higher CCS. According to two studies, the coronary CT angiography calcified and non-calcified plaque burden were increased in SLE patients compared with controls., Conclusions: In SLE, asymptomatic CAD by CAC is more prevalent and there is more multivessel disease compared with controls without lupus. However, the extent of CAC was not increased in SLE patients., Systematic Review Registration: PROSPERO CRD42021228710., (Copyright © 2022. Published by Elsevier B.V.)

The present study sought to describe the use of generic drugs and single-tablet regimen (STR) de-simplification for the treatment of human immunodeficiency virus (HIV) infection among 41 hospitals from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). In June 2018, we collected information on when generic antiretroviral drugs (ARVs) were introduced in the different hospitals, how the decisions to use them were made, and how the information was provided to the patients. Most of the nine available generic ARVs in Spain by June 2018 had been introduced in at least 85% of the participating hospitals, except for zidovudine (AZT)/lamivudine (3TC) and AZT. The time difference between the effective marketing date of each generic ARV and its first dispensing date in the hospitals was much shorter for the more recently approved generic ARV since the year 2017. However, only up to 20% of the hospitals de-simplified efavirenz (EFV)/tenofovir disoproxil (TDF)/emtricitabine (FTC), dolutegravir (DTG)/abacavir (ABC)/3TC, and rilpivirine (RPV)/TDF/FTC (to generic EFV+TDF/FTC, DTG+generic ABC/3TC, and RPV+generic TDF/FTC, respectively), whereas the generic STR EFV/TDF/FTC was introduced in 87.8% of the centers. The median times between the date of effective marketing of generic TDF/FTC and the date of de-simplification of EFV/TDF/FTC and RPV/TDF/FTC were 723 [interquartile range (IQR): 369-1,119] and 234 (IQR: 142-264) days, respectively; this time was 155 (IQR: 28-287) days for de-simplification of DTG/ABC/3TC. In conclusion, despite the widespread use of generic ARVs, STRs de-simplification was only undertaken in <20% of the hospitals. There was wide variability in the timing of the introduction of each generic ARV after they were available in the market.

Objective: Regional variations in systemic lupus erythematosus (SLE) mortality may be due to different spectra of local environmental factors. The aim of this study was to assess mortality trends in adults with SLE using a nationwide health registry., Methods: Data came from the Dynamic Cubes of the General Direction of Health Information for 1998-2017 for mortality. In patients aged ≥15 years, SLE as the principal cause of death was defined according to ICD-10 code M32 and was classified by sex and age. Joinpoint trend analyses of annual age-standardized mortality rates (ASMR) for SLE patients and non-SLE people were made., Results: We identified 11 449 SLE deaths and 9,989,874 non-SLE deaths. The SLE ASMR increased more than the non-SLE ASMR, with a 98.2% cumulative increase in the ratio of SLE to non-SLE deaths. Whereas the non-SLE ASMR remained relatively stable throughout the study period (overall and by sex), the SLE ASMR significantly increased between 1998 and 2009, non-significantly decreased between 2009 and 2013 and non-significantly increased thereafter. Both women and men had a large cumulative increase in the SLE ASMR/non-SLE ASMR ratio (73.9 and 191.3%, respectively). The Southeast region had the largest cumulative increases in the ratio of SLE to non-SLE ASMR (108.8%). Of the 11,449 deaths, 445 (3.8%) were in geographical areas where ≥40% of the population is indigenous., Conclusion: SLE mortality rates have increased since 1998 and remain high compared with non-SLE mortality: significant sex and regional disparities persist.

The aim was to analyze the distribution and trends of deaths reported for rheumatoid arthritis (RA) in Mexico in 1998-2017. We carried out a cross-sectional study. Data were obtained from Dynamic Cubes, General Direction of Health Information, on deaths related to RA in Mexico. Seropositive RA was diagnosed using the International Classification of Diseases version 10. Variables were categorized by diagnosis, age, and gender. Time trends of age-standardized mortality rates (ASMRs) were analyzed for RA, and the annual percent change (APC) was estimated using Joinpoint trend analysis. We found 714 deaths mentioned as RA and 9,749,956 non-RA deaths between 1998 and 2017. Overall RA mortality decreased from 0.14 in 2004 to 0.04 per 100 000 in 2017 (APC: - 10.3%; 95% CI - 16.5%, - 3.3%), while the non-RA ASMR remained stable. In females, there was an initial increase of 27.3% per year through 1998-2004 and a reduction of - 11.7% per year subsequently, while in males, the APC remained stable between 1998 and 2017. The trend for RA mortality resulted in a cumulative change in the ratio of RA ASMR to non-RA ASMR of - 20.6% in females and + 3.2% in males. Although mortality attributable to RA increased from 1998 to 2004 in Mexico, it began to improve after 2004, particularly in females. Prospective, population-based data could help to identify risk factors that could be altered to improve outcomes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Helicobacter pylori (H. pylori) is a gram-negative bacterium that adapts to the gastric mucosa and provokes symptoms associated with gastritis. Chronic H. pylori infection in patients with a genetic predisposition can trigger autoimmune diseases due to the immune interaction of cellular and humoral responses. Infections are a triggering factor for systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren syndrome (SS), although the association between H. pylori and these diseases is unclear. Therefore, we reviewed this interaction and its clinical importance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

The novel SARS-CoV-2 human coronavirus in Wuhan, China, has triggered a worldwide respiratory disease outbreak (COVID-19). Acute respiratory distress syndrome, multiorgan dysfunction and thrombotic events are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a "cytokine storm", also known as cytokine release syndrome, may play a major role in the pathology of COVID-19. In addition to anti-viral therapy and supportive treatment in critically ill patients, unique medications for this condition are also under investigation. Here we reviewed therapeutic options, including the antibody therapy that might be an immediate strategy for SARS-CoV-2 therapy., (© 2020 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Most prospective studies of bone mineral density (BMD) in systemic lupus erythematosus (SLE) patients have been of relatively short duration, with a maximum of 6 years. To describe long-term changes in BMD in women with SLE and identify risk factors associated with BMD loss. We retrospectively evaluated 132 adult Mexican-Mestizo women with SLE who underwent dual X-ray absorptiometry (DXA). Demographic and clinical data were collected and BMD at the lumbar spine (L1-L4) and total hip were collected at baseline and during the follow up. At baseline, the mean age of participants was 43.4 ± 12.5 years, 50.8% had osteopenia and 11% osteoporosis. The median follow-up was 13 (IQR 10.2-14.0) years. During follow up, 79% of patients used glucocorticoid (GCT). The mean percentage of changes in BMD during follow up were: - 14.03 ± 11.25% (- 1.49%/year) at the lumbar spine, and - 15.77 ± 11.57% (- 1.78%/year) at the total hip, with significant changes (p < 0.001 for both comparisons). Multivariate analysis showed older age, GCT use at baseline, and transition to the menopause during the follow-up were significantly associated with greater reductions in BMD. This retrospective longitudinal study found significant BMD loss at the lumbar spine and hip. Older age, menopausal transition and GCT use were independently associated with BMD decline in women with SLE., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The novel SARS-CoV-2 human coronavirus in Wuhan, China, has triggered a worldwide respiratory disease outbreak (COVID-19). Acute respiratory distress syndrome (ARDS), multiorgan dysfunction and thrombotic events are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a "cytokine storm", also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. In addition to anti-viral therapy and supportive treatment in critically ill patients, unique medications for this condition are also under investigation. Here we reviewed therapeutic options, including the antibody therapy that might be an immediate strategy for SARS-CoV-2 therapy., (Copyright © 2020 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Background and Aims: Autoimmune diseases (AID) share various clinical signs and symptoms and pathophysiological mechanisms including the increased risk of cardiovascular disease. The coronary artery calcium score (CACS) is potentially useful in improving the cardiovascular risk assessment. The aim of this study was to evaluate CACS in six AIDs analyzed as a group compared with controls through a systematic literature review (SLR) and meta-analysis., Methods: A literature search (Medline/OVID, Lilacs, Embase, and Cochrane/OVID) up to January 6, 2021 was made (PROSPERO CRD42020197182). Observational studies (patients with six AIDs: rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], Sjögren's syndrome, systemic sclerosis, dermatopolymyositis, and antiphospholipid syndrome) compared with controls were included. CACS, reported in Agatston units, was the primary outcome in both groups. Mean differences and a random-effects model (DerSimonian and Laird) were calculated., Results: Nineteen articles were meta-analyzed (4568 subjects: 2142 AID and 2426 controls). Mean age was 48.1 and 44.2 years, respectively and 75.6% and 84.9% were women, respectively. Of cases, 52.9% had RA, 44.4% SLE and 2.7% had systemic sclerosis. The pooled analysis showed a higher CACS in patients with AIDs (7.42; 95% CI 1.79 to 13.05; chi 2 -p = 0.01) compared with controls. Meta-regression models showed that age in cases and controls reduced the difference in CACS between groups (p < 0.05), HDL had an inverse relationship (p = 0.04), and CRP levels had a directly proportional relationship with CACS in cases (p = 0.036)., Conclusions: The quantitative results of this meta-analysis suggest that CACS is higher in patients with AID, possibly due to chronic exposure to pro-inflammatory molecules. These results have clinical implications since the finding of highly elevated CACS in patients with AID will enable physicians and researchers to develop a risk stratification model that includes CACS as one of the screening tools for detecting coronary atherosclerosis in these patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Cardiovascular (CV) morbidity is a well-established problem in systemic lupus erythematosus (SLE). Antimalarial (AM) therapy has been seen as a potential atheroprotective agent. The aim was to assess the impact of AM therapy on traditional and novel atherosclerosis (AT) biomarkers in patients with SLE., Methods: A search of MEDLINE, EMbase, and Cochrane library for studies evaluating the impact of AM on AT biomarkers in SLE was conducted. Data extraction included serum, functional and structural traditional and novel biomarkers. A narrative synthesis of the findings and a meta-analysis with random effects was conducted estimating mean differences (MD), OR, HR and 95% CIs., Results: The search strategy produced 148 articles, of which 64 were extracted for analysis. The MD in VLDL-cholesterol (-10.29, 95% CI -15.35, 5.24), triglycerides (-15.68, 95% CI -27.51, -3.86), and diastolic BP (-3.42, 95% CI -5.62, -1.23) differed significantly in patients on AM therapy compared with those without AM therapy. Patients on AM had a lower prevalence and incidence of diabetes mellitus than patients not on AM (HR: 0.39, 95% CI 0.17, 0.88). HCQ use was associated with lower blood pressure (BP) variability. Structural markers like carotid intima-media thickness (IMT), carotid plaque (CP) and coronary artery calcification (CAC) were not influenced by AM. For functional markers like endothelial and arterial stiffness the benefit was unclear. The GRADE approach showed a very low-to-low quality of evidence (QoE) per outcome., Conclusions: There is some evidence on the associations between AM therapy and some AT markers. However, the data on which this conclusion was based was of low to very low evidence., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Sistemic Sclerosis (SSc) is a heterogeneous autoimmune disease with a high rate of progression and therapeutic failure, and treatment is a challenge, new therapeutic proposals being needed, being mesenchymal stem cells (MSCs) considered as alternative therapy for SSc for its immunomodulatory capacity. We evaluated the efficacy and safety of human MSC (hMSC) in patients with SSc through a systematic literature review (SLR)., Methods: SLR (PRISMA guideline) on MEDLINE/OVID, LILACS, EMBASE, and Cochrane/OVID bases (until July 2020, without limits). All types of clinical studies were considered: patients ≥18 years old with SSc and treatment with hMSC., Exclusion Criteria: animal models, autologous/allogenic hematopoietic stem cell transplants, narrative reviews, letters to the editor. MeSH and "Key word" terms were used. The level of evidence and the quality rating were rated [Joanna Briggs Institute (JBI) lists]. Registration in PROSPERO repository (ID CRD42020185245) The Synthesis Without Meta-analysis (SWiM) guideline was followed., Results: We initially identified 508 articles, of which 11 were finally included (8 case series and 3 case reports). The 11 articles included 101 patients (85 female, age range 18-75 years). The level of evidence was mostly 4 (JBI); the quality of evidence was met (≥50% of JBI items). SWiM showed that vascular skin involvement (digital ulcers, necrosis, and gangrene) and associated pain were the predominant outcomes, while improvements were found in almost all cases. One patient died in the first month, and the frequency of complications was low. Expanded hMSCs were used in 24 patients and other cell sources in the remaining patients., Conclusion: There is too little reported data to reach definite conclusions about the use of hMSC in SSc. Further studies with better epidemiological designs are needed to evaluate the benefit of hMSCs in SSc patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Evidence on the relationship between resilience and medication adherence in systemic lupus erythematosus (SLE) patients is lacking. We aimed to examine the impact of resilience on medication adherence in SLE patients., Method: In a cross-sectional analysis SLE outpatients were assessed for resilience (Connor-Davison Resilience Scale, CD-RISC), depressive symptoms (CES-D) and medication adherence (Compliance Questionnaire for Rheumatology [CQR]). The disease activity index (mexSLEDAI) and damage (SLICC Damage Index) were administered. Factors independently associated with adherence were identified using multivariate logistic regression., Results: Of the 157 patients, 152 (96.8%) were female with a median age of 45.9 (IQR: 39.0-55.5) years and disease duration of 14 (IQR: 10.0-19.0) years. Medication adherence (CQR ≥80%) and depressive symptoms were found in 74.5% and 43.9% of patients, respectively. Adherent patients had a lower CES-D score and a higher CD-RISC score. In the multivariate analysis adjusting for demographic and clinical confounders, resilience and older age protected against non-adherence (OR 0.96, [95% CI 0.94-0.99] and OR 0.96 [95% CI 0.93-0.98], respectively)., Conclusion: In SLE patients, resilience and older age, which possibly associated with better medication adherence, may protect against non-adherence.

Objective: Most patients with mild COVID-19 had to stay at home trying to implement an optimal quarantine. The aim of this study was to describe the COVID-19 cases during the first wave of the pandemic in Spain, how they managed the disease at home, focusing on differences by age, as well as differences in knowledge, attitudes and preventive practices, compared with the uninfected population., Design: An online survey was used to conduct a cross-sectional study of individuals who were 14 years or older living in Spain during the COVID-19 lockdown. The main variable was a COVID-19 case. Logistic regression models for COVID-19 cases were obtained using a backward stepwise procedure to assess the association between social variables, disease knowledge, attitudes, prevention practices and emotional impact., Results: 3398 people completed the survey. Participants' mean age was 49.6 (SD=14.3). COVID-19 was significantly more prevalent among married people (5.3%) and those currently doing an on-site work (8.7%). Most of the COVID-19 cases stayed at home (84.0%) during the episode. There were significant age-based differences with regard to self-isolation conditions at home during the disease. COVID-19 cases showed better attitudes, practices and knowledge about disease symptoms and transmission than the uninfected population. COVID-19 cases also felt more depressed (adjusted OR: 3.46, 95% CI 1.45 to 8.26) and had better preventive behaviour than the uninfected population, such as always wearing a mask outside the home (adjusted OR 1.58, 95% CI 1.06 to 2.30)., Conclusion: COVID-19 cases found it difficult to comply with recommended home self-isolation conditions, with differences by age group. COVID-19 had an important impact on care dependency in non-hospitalised patients, who were mostly dependent on their families for care. It is necessary to reinforce social and health services and to be ready to meet the care needs of populations during the different waves or in future epidemics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Patients with systemic lupus erythematosus (SLE) have a higher prevalence of insulin resistance (IR) and metabolic syndrome (MetS) than controls., Objective: To evaluate IR in non-diabetic women with SLE by means of biomarkers using high-throughput metabolomic techniques., Method: Cross-sectional study in patients with SLE. A metabolomic approach was employed using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. MetS was evaluated according to NCEP-ATP III criteria., Results: Seventy patients with SLE were included, out of whom 45 (64.2%) and 27 (38.5%) had IR and MetS, respectively. Patients with IR had a higher body mass index and hypertension more often than those without IR. Chronic damage and disease activity were not related to IR. A Quantose-IR score ≥ 63 was more common in patients with MetS (81.5 vs. 53.5%; p = 0.02). Quantose-IR score was also correlated with the number of criteria for MetS (r: 0.35; p = 0.003)., Conclusions: In non-diabetic women with SLE, the prevalence of IR based on Quantose-IR score was 64.2%., (Copyright: © 2021 Permanyer.)

Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease featured by an increased cardiovascular risk that may lead to premature patient's death. It has been demonstrated that SLE patients suffer from early onset endothelial dysfunction which is due to the impairment of endogenous vascular repair mechanisms. Vascular integrity and homeostasis are maintained by endothelial progenitor cells (EPCs), which are mobilized in response to endothelial injury to replace damaged endothelial cells. Two main EPCs subpopulations exist in peripheral blood: endothelial colony forming cells (ECFCs), which represent truly endothelial precursors and can physically engraft within neovessels, and myeloid angiogenic cells (MACs), which sustain angiogenesis in a paracrine manner. Emerging evidence indicates that ECFCs/MACs are down-regulated and display compromised angiogenic activity in SLE, thereby contributing to the pathogenesis of this disease. Intracellular calcium (Ca 2+ ) signaling plays a crucial role in maintaining vascular integrity by stimulating migration, proliferation and tube formation in both ECFCs and MACs. Herein, we illustrate the evidences that support the role played by EPCs dysfunction in SLE. Subsequently, we discuss about the hypothesis that the Ca 2+ handling machinery is compromised in SLE-derived ECFCs and MACs, thereby resulting in their reduced pro-angiogenic activity. Finally, we speculate about the proposal to exploit intracellular Ca 2+ signaling to improve ECFCs' reparative phenotype and suggest this strategy as a new approach to treat SLE patients., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To compare the performance of cytology, colposcopy and human papillomavirus in detecting cervical intraepithelial lesions in women with systemic lupus erythematosus., Methods: Papanicolaou smears (normal, low-grade squamous intraepithelial lesion, high grade squamous intraepithelial lesion), colposcopy findings, human papillomavirus and co-testing (Papanicolaou smear + human papillomavirus) were compared with cervical biopsy findings in women with systemic lupus erythematosus. Sensitivity, specificity, false-positive and false-negative rates, positive and negative predictive values and likelihood ratios of cytologic smears, colposcopy findings, human papillomavirus and co-testing were determined., Results: Cytology and colposcopy were performed in 170 systemic lupus erythematosus women (mean age and disease duration of 43.7±12.1 years and 9.7±5.3 years, respectively) and biopsies were performed in 55 patients (38.2% normal, 60.0% low-grade squamous intraepithelial lesion and 1.8% high grade squamous intraepithelial lesion). The sensitivity, specificity, positive predictive value and negative predictive value of cytology were 14.7% (95% confidence interval 5.5-31.8%), 95.2% (95% confidence interval 74.1-99.7%), 83.3% (95% confidence interval 36.4-99.1%) and 40.8% (95% confidence interval 27.3-55.7%), respectively. The sensitivity, specificity and positive predictive value of colposcopy findings were 100.0% (95% confidence interval 87.3-100.0%), 0.0% (95% confidence interval 0.0-19.2%) and 61.8% (95% confidence interval 47.7-74.2%), respectively. The sensitivity and specificity of co-testing were 8.0% (95% confidence interval 1.3-27.5%) and 100.0% (95% confidence interval 71.6-100.0%). The positive predictive value and negative predictive values were 100.0% (95% confidence interval 19.7-100.0%) and 36.1% (95% confidence interval 33.5-38.8%), respectively., Conclusions: In systemic lupus erythematosus patients, colposcopy impressions were more sensitive than cytology and co-testing. However, cytology and co-testing were the most specific tests. The results should be interpreted with caution due to the small sample size.

Background and Aims: Non-invasive surrogates of cardiovascular (CV) disease such as endothelial dysfunction (ED) and peripheral arterial stiffness (AS) have been evaluated in systemic lupus erythematosus (SLE) patients. The aim of this study was to systematically review and meta-analyze reports of cardiovascular disease (CVD) in SLE patients, as measured by ED and AS., Methods: Studies analyzing the relationship of SLE with ED (flow-mediated dilatation [FMD], nitroglycerin-mediated dilatation [NMD] and peripheral arterial tonometry [PAT]) and AS (augmentation index [AIx], pulse wave velocity [PWV]) were systematically searched for in PubMed, Cochrane library, EMBASE, VHL, SciELO and Web of Science databases. Inclusion criteria included peer-review and English language. Mean differences (MD) and 95% confidence intervals (CIs) were estimated using the random effect model. The study was registered with PROSPERO, number CRD42019121068., Results: The meta-analysis included 49 studies. FMD data from 18 studies including 943 SLE subjects (mean age = 38.71 [95%CI 36.21, 41.21] years) and 644 unaffected controls (mean age = 38.63 [95%CI 36.11, 41.15] years) were included. When compared with unaffected controls, FMD in SLE subjects was decreased by 4.3% (95%CI: -6.13%, -2.47%): p < 0.001). However, NMD did not significantly differ between SLE patients and controls (MD = - 2.68%; 95% CI -6.00, 0.62; p = 0.11). A significantly increased AS between SLE patients and controls according to overall PWV (MD = 1.12 m/s; 95% CI 0.72-1.52; p < 0.001) was observed, but not for the brachial-ankle PWV. AIx was also increased in SLE patients compared with healthy controls (MD = 4.55%; 95% CI 1.48-7.63; p = 0.003)., Conclusions: Overall, SLE patients showed impaired FMD, an independent predictor of CV events. There was a higher degree of AS in SLE patients compared with controls. ED and AS in SLE should be considered when planning preventive strategies and therapies., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to determine the frequency of Helicobacter pylori in SLE patients and to compare clinical characteristics and gastroduodenal lesions in patients with and without H. pylori infection., Methods: Adult SLE patients were selected and subjected to endoscopy. Gastroduodenal lesions were examined by endoscopy and biopsy (antrum and corpus). Biopsies were evaluated by hematoxylin and eosin and Giemsa staining. Immunochromatographic membrane-based assay using amplification was used to test for H. pylori antigen (coproantigen) in stool samples in all participants. Clinical characteristics and gastroduodenal lesions were compared between patients with and without H. pylori infection., Results: A total of 118 SLE patients were included (mean age 44.7 ± 11.7 years, mean disease duration 11.6 ± 6.0 years), of whom 101 (85.6%) were receiving non-steroidal anti-inflammatory drugs (NSAIDs). The coproantigen test was positive in 32 (27.1%) patients. H. pylori was present in twenty six patients (22.0%) in the gastric biopsy. The frequency of gastric erosions and gastric ulcers were 55.1% and 0.8%, respectively. Gastric erosions were less frequent in SLE patients with H. pylori infection than those without H. pylori (43.5.7% vs. 62.5%; p = 0.04). The age, disease duration, disease activity, chronic damage, gastroprotective drugs, and immunosuppressive therapy did not differ between the two groups., Conclusions: We found a high frequency of H. pylori infection in SLE patients. The severity of SLE and reception of gastroprotective therapy do not seem to be related to H. pylori infection. Immunosuppressive therapy may not be protective against H. pylori infection in SLE patients.Key Points• In patients with systemic lupus erythematosus (SLE), the frequency of Helicobacter pylori infection was 39% and gastric erosions were frequent.• Disease activity, chronic damage, gastroprotective drugs, and immunosuppressive therapy may not affect the prevalence of H. pylori infection in SLE patients.

The neuromodulator histamine is able to vasorelax in human cerebral, meningeal and temporal arteries via endothelial histamine 1 receptors (H 1 Rs) which result in the downstream production of nitric oxide (NO), the most powerful vasodilator transmitter in the brain. Although endothelial Ca 2+ signals drive histamine-induced NO release throughout the peripheral circulation, the mechanism by which histamine evokes NO production in human cerebrovascular endothelial cells is still unknown. Herein, we exploited the human cerebral microvascular endothelial cell line, hCMEC/D3, to assess the role of intracellular Ca 2+ signaling in histamine-induced NO release. To achieve this goal, hCMEC/D3 cells were loaded with the Ca 2+ - and NO-sensitive dyes, Fura-2/AM and DAF-FM/AM, respectively. Histamine elicited repetitive oscillations in intracellular Ca 2+ concentration in hCMEC/D3 cells throughout a concentration range spanning from 1 pM up to 300 μM. The oscillatory Ca 2+ response was suppressed by the inhibition of H 1 Rs with pyrilamine, whereas H 1 R was abundantly expressed at the protein level. We further found that histamine-induced intracellular Ca 2+ oscillations were initiated by endogenous Ca 2+ mobilization through inositol-1,4,5-trisphosphate- and nicotinic acid dinucleotide phosphate-sensitive channels and maintained over time by store-operated Ca 2+ entry. In addition, histamine evoked robust NO release that was prevented by interfering with the accompanying intracellular Ca 2+ oscillations, thereby confirming that the endothelial NO synthase is recruited by Ca 2+ spikes also in hCMEC/D3 cells. These data provide the first evidence that histamine evokes NO production from human cerebrovascular endothelial cells through intracellular Ca 2+ oscillations, thereby shedding novel light on the mechanisms by which this neuromodulator controls cerebral blood flow., (© 2019 Wiley Periodicals, Inc.)

Introducción: Las concentraciones séricas subóptimas de vitamina D se presentan en múltiples enfermedades crónicas, como las enfermedades autoinmunitarias. Los objetivos del estudio fueron: 1) comparar las concentraciones séricas de 25-hidroxivitamina D (25OHD3) en pacientes con lupus eritematoso sistémico (LES) con y sin nefritis lúpica (NL), y 2) evaluar la asociación de las concentraciones séricas de 25OHD3 con la actividad de la enfermedad., Material Y Métodos: Estudio comparativo, transversal, que incluyó 48 mujeres con LES, con y sin NL. Se excluyeron aquellas con enfermedad renal crónica en estadio IV, cáncer, hiperparatiroidismo, embarazo o lactancia. La actividad fue evaluada con el instrumento SLEDAI-2K. La concentración sérica de 25OHD3 se determinó mediante inmunoanálisis quimioluminiscente., Resultados: La media de edad de las pacientes con y sin NL fue de 36.3 ± 8.6 años y 42.7 ± 7.6 años, respectivamente. Se observó una elevada prevalencia de valores subóptimos de 25OHD3 en todas las pacientes (93%). Las concentraciones séricas de 25OHD3 fueron diferentes entre pacientes con y sin NL: 21.5 ± 6.8 ng/ml frente a 19.2 ± 7.1 ng/ml (p = 0.362). No se encontró correlación entre la concentración sérica de 25OHD3 y la actividad de la enfermedad (r = -045, p = 0.761)., Conclusiones: En pacientes con LES, las concentraciones séricas de 25OHD3 fueran diferentes entre pacientes con y sin NL; sin embargo, esta diferencia no fue significativa. Además, no se encontró correlación entre las concentraciones séricas de 25OHD3 y la actividad de la enfermedad evaluada por SLEDAI-2K., Background: Sub-optimal serum vitamin D levels occur in multiple chronic diseases such as autoimmune diseases. The objectives of this study were: 1) compare the serum concentration of 25-hidroxivitamin D (25OHD3) in patients with systemic lupus erythematosus (SLE) with and without lupus nephritis (LN), and 2) evaluate the association of serum concentration of 25OHD3 with the activity of the disease., Material and Methods: A comparative, cross-sectional study was conducted, including 48 women with SLE, with and without clinical diagnosis of LN, according to the score of renal activity evaluated by SLEDAI-2K. Patients with stage IV chronic kidney disease, cancer, hyperparathyroidism, pregnancy and lactation were excluded. The activity was evaluated by the SLEDAI-2K instrument. The serum concentration of 25OHD3 was assessed by chemiluminescent immunoassay., Results: The mean age of patients with and without LN was 36.3 ± 8.6 and 42.7 ± 7.6 years, respectively. High prevalence of suboptimal 25OHD3 levels was observed (93%). 25OHD3 concentrations were different between patients with and without LN, 21.5 ± 6.8 ng/mL vs. 19.2 ± 7.1 ng/mL (p = 0.362). No correlation was found between serum 25OHD3 concentration (r = −045, p = 0.761)., Conclusions: There were no differences found in serum concentrations of 25OHD3 in patients with or without NL. Moreover, no correlation was found between serum 25OHD3 levels and the activity of the disease evaluated by SLEDAI-2K., (Copyright: © 2020 Revista Medica del Instituto Mexicano del Seguro Social.)

An increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) plays a key role in controlling endothelial functions; however, it is still unclear whether endothelial Ca 2+ handling is altered by type 2 diabetes mellitus, which results in severe endothelial dysfunction. Herein, we analyzed for the first time the Ca 2+ response to the physiological autacoid ATP in native aortic endothelium of obese Zucker diabetic fatty (OZDF) rats and their lean controls, which are termed LZDF rats. By loading the endothelial monolayer with the Ca 2+ -sensitive fluorophore, Fura-2/AM, we found that the endothelial Ca 2+ response to 20 µM and 300 µM ATP exhibited a higher plateau, a larger area under the curve and prolonged duration in OZDF rats. The "Ca 2+ add-back" protocol revealed no difference in the inositol-1,4,5-trisphosphate-releasable endoplasmic reticulum (ER) Ca 2+ pool, while store-operated Ca 2+ entry was surprisingly down-regulated in OZDF aortae. Pharmacological manipulation disclosed that sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA) activity was down-regulated by reactive oxygen species in native aortic endothelium of OZDF rats, thereby exaggerating the Ca 2+ response to high agonist concentrations. These findings shed new light on the mechanisms by which type 2 diabetes mellitus may cause endothelial dysfunction by remodeling the intracellular Ca 2+ toolkit.

Objective: A protective function of vitamin D in metabolic syndrome (MetS) has been described. The objective of the present study was to examine the relationship between serum 25-hydroxyvitamin D (25(OH)D) concentrations and MetS in non-diabetic systemic lupus erythematosus (SLE) women., Methods: Cross-sectional analyses of the relationship between concentrations of 25(OH)D, MetS, and its components were made in 160 non-diabetic SLE women. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. Serum 25(OH)D was measured by chemiluminescent immunoassay. Serum 25(OH)D concentrations were categorized into quartiles (<16.6, 16.6-21.1, 21.2-26.3, ≥26.4 ng/mL)., Results: A total of 79 (49.3%) SLE women had MetS. Without adjusting for body mass index (BMI) or smoking, the odds of having MetS decreased according to increasing quartiles of 25(OH)D concentrations (P for trend = .03). The odds ratio (OR) of having MetS was 0.4 (95% confidence interval: 0.2-0.9, P = .04) for the highest vs the lowest quartile of 25(OH)D concentrations when adjusted by age. The crude OR of having elevated hypertriglyceridemia decreased according to increasing quartiles of 25(OH)D concentrations (P for trend = .036). However, further adjustments for BMI and smoking removed the inverse association between 25(OH)D concentrations and MetS and its individual components., Conclusion: In non-diabetic SLE women with mild activity, 25(OH)D concentrations are not associated with MetS and its components., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with multisystemic involvement. Gastrointestinal (GI) manifestations are frequent but functional gastrointestinal disorders (FGIDs) have scarcely been studied in SLE. To determine the prevalence of FGIDs and their potential risk factors in SLE female patients vs controls., Methods: Systemic lupus erythematosus patients meeting the American College of Rheumatology (ACR) criteria and controls completed the Rome III questionnaire for FGIDs and a structured interview to assess sociodemographic, clinical, and treatment variables after excluding organic GI diseases. Logistic regression was used to determine risk factors (ie, alcohol drinking, medications) for FGIDs., Key Results: Responders included 113 SLE patients and 122 age-matched controls. The presence of at least one FGIDs was higher in SLE (73.4%) vs controls (54.1%), P = .003. The most frequent FGIDs in SLE patients were nausea and vomiting disorders (NVD), belching disorders, globus, anorectal pain, functional heartburn (FH), and functional bloating (FB). After adjustment for confounding variables, SLE was associated with NVD (OR: 7.1, 95% CI: 2.7-19.1) globus (3.5, 1.3-9.3), anorectal pain (3.4, 1.4-8.4), and FH (2.5, 1.5-4.4). The simultaneous presence of >1 FGID was more common in SLE patients than controls (69.8% vs 31.8%). Glucocorticoids (5.2, 1.3-19.9) and non-steroidal anti-inflammatory drugs (NSAIDs; 3.0, 1.1-8.0) were associated with any FGID in SLE patients while alcohol drinking with gallbladder/sphincter of Oddi disorders 7.4 (1.1-47.3)., Conclusions and Inferences: Functional gastrointestinal disorders are more frequent in SLE patients compared with controls. Medication that may alter gastrointestinal homeostasis, such as glucocorticoids and NSAIDs, are potential risk factors for FGIDs in SLE., (© 2019 John Wiley & Sons Ltd.)

Systemic lupus erythematosus (SLE) is associated with a high burden of cardiovascular disease (CVD), which is in part imputed to classical vascular risk factors such as hypertension. Hypertension is frequent among patients with SLE and studies show it is more prevalent in SLE patients than in people without SLE. Despite the high frequency of hypertension in SLE patients, the pathophysiological mechanisms underlying the development of hypertension remain poorly understood. 24-h ambulatory blood pressure monitoring has emerged as a valuable tool in determining blood pressure (BP) in SLE patients in whom hypertension has been associated with damage accrual, stroke and cognitive dysfunction. Although prevalent, current guidelines neglect the specific management of hypertension in SLE patients in their recommendations. This review discusses the mechanisms that may lead to hypertension and the literature evaluating hypertension screening and management in SLE patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To compare resilience in women with SLE and healthy women and determine whether sociodemographic factors and depressive symptoms were associated with resilience in patients with SLE., Methods: This was a cross-sectional study. Participants were 123 women with SLE according to the ACR criteria and 132 age-matched healthy women (median = 45 (IQR = 34-54) years). Scales administered were: SLEDAI-2 K for disease activity, Graffar method, SLICC damage index, Center for Epidemiologic Studies Depression Scale, and the Spanish version of the Resilience Scale of Wagnild and Young. The statistical analysis was made using the Student t, Mann Whitney, Chi-square, and Spearman's Rho tests and multivariate analysis with a generalized linear model (GLM). Statistical significance was set as p < .05., Results: There were no differences in resilience scores between women with SLE and healthy women (median = 80, IQR = 75-87 vs. median = 80, IQR = 74-86.75, p = .38), although patients with SLE had higher self-efficacy scores (median = 47 IQR = 43-50 vs. median = 45, IQR = 42-48, p = .002) and depressive symptoms (median = 10, IQR = 5-18 vs. median = 8, IQR = 5-18, p = .01). The overall resilience score correlated with depressive symptoms (r = -0.537, p < .01). The GLM showed no association between sociodemographic factors and resilience in patients with SLE., Conclusions: Resilience did not differ between women with SLE and healthy women. In patients with SLE, depressive symptoms may influence resilience and its domains, but sociodemographic factors do not., Public Health Significance Statement: The results suggest that resilience was similar between females with systemic lupus erythematosus (SLE) and age-matched healthy women. Depressive symptoms correlated negatively with resilience in patients with SLE. Sociodemographic factors were not associated with resilience in patients with SLE., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Our aim was to assess the relationship between serum adalimumab levels, anti-drug antibodies (ADA) and disease activity in patients with axial spondylarthritis (SpA). We have carried out a single-centre cross-sectional study. adalimumab and ADA levels were analysed with ELISA and correlated with SpA activity using BASDAI and ASDAS scores. Adalimumab cut-off value was calculated to discriminate inactive disease/low disease activity (BASDAI < 4; ASDAS < 2.1) from moderate/high disease activity (BASDAI ≥ 4; ASDAS ≥ 2.1), using a receiver operating characteristic (ROC) curve. Up to January 2016, 51 consecutive patients were included. The median (range) age was 46.6 (18-68) and 47.1% were women. ADA prevalence was 27.5%, with none detected in the 21.6% receiving concomitant disease-modifying antirheumatic drugs (DMARDs) (p = 0.021). Adalimumab level was normal (> 3 mg/l) in 36 patients (70.6%), all without ADA. Fifteen patients (29.4%) had subtherapeutic adalimumab levels (< 3 mg/l), with ADA in 14 (93%). Median adalimumab (mg/l) was significantly higher in patients with inactive disease/low disease activity: BASDAI < 4 vs ≥ 4: 9.5 vs 2.6 (p < 0.01); ASDAS-CRP < 2.1 vs ≥ 2.1: 9.3 vs 0.3 (p < 0.001); ASDAS-ESR < 2.1 vs ≥ 2.1: 9.9 vs 3.0 (p < 0.001), and this finding was consistent with the result of the multivariate model. Patients with inactive disease/low disease activity presented significantly lower ADA levels. The adalimumab level cut-offs and area under the curve (AUC) obtained in the ROC curves were: ASDAS-CRP (< 2.1) 4.6 mg/l (AUC 81.2%; 95% CI 67.5-94.9; p < 0.001); ASDAS-ESR (< 2.1) 7.7 mg/l (AUC 82.4%; 95% CI 69.3-95.5; p < 0.001); BASDAI (< 4) 6.4 mg/l (AUC 73.5%; 95% CI 58.6-88.3; p < 0.01). In conclusion, presence of ADA in axial SpA patients treated with adalimumab was associated with lower serum drug levels. ADA levels were lower and adalimumab levels were higher in patients with inactive disease/low disease activity based on BASDAI and ASDAS indices. Concomitant treatment with MTX reduces de likelihood of finding ADA. Serum adalimumab levels above 4.6 mg/l are recommended to avoid compromising efficacy.