Risk of diabetes mellitus in systemic lupus erythematosus: systematic review and meta-analysis.

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.

Burden of Other Musculoskeletal Disorders in Latin America and the Caribbean: Findings of Global Burden of Disease Study 2019.

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.

SLICC-Frailty Index and Its Association with Low Bone Mineral Density and Vertebral Fractures in Women with Systemic Lupus Erythematosus.

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.

Metabolomic Profile of Insulin Resistance Women with Systemic Lupus Erythematosus.

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.

Low disease activity state associated with fewer incident vertebral fractures in Mestizo women with systemic lupus erythematosus.

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.

Trends in mortality in patients with systemic autoimmune rheumatic diseases (SARD) during the COVID-19 pandemic in Mexico.

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.

Twenty-year trends in all-cause mortality of patients with systemic lupus erythematosus in Mexico: Results from a nationwide health registry.

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.

Higher body mass index and disease duration are associated with increased risk of left ventricular diastolic dysfunction in women with systemic lupus erythematosus.

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.

Trends in all-cause hospitalizations for systemic lupus erythematosus in Mexico, 2000-2019.

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, a leading cause of death in young Mexican females: a nationwide population-based study, 2000-2020.

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.

A Retrospective Analysis of Longitudinal Changes in Bone Mineral Density in Women with Systemic Lupus Erythematosus.

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.

Medication adherence is influenced by resilience in patients with systemic lupus erythematosus.

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.

Changing trends in rheumatoid arthritis mortality in Mexico, from 1998 to 2017.

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.

Insulin resistance metabolomic profile in non-diabetic women with systemic lupus erythematosus.

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%.

INTRODUCCIÓN: En lupus eritematoso sistémico (LES) es más frecuente la prevalencia de resistencia a la insulina (RI) y síndrome metabólico (SMet) que en controles. OBJETIVO: Evaluar la RI en mujeres no diabéticas con LES mediante biomarcadores usando técnicas metabolómicas de alta resolución. MÉTODO: Estudio transversal en pacientes con LES. Se empleó un abordaje metabolómico usando cromatografía de líquidos de ultra-alta resolución con espectrometría de masa de alta resolución. El SMet fue evaluado de acuerdo con los criterios NCEP-ATP III. RESULTADOS: Se incluyeron 70 pacientes con LES. Tuvieron RI y SMet 45 (64.2%) y 27 (38.5%), respectivamente. Pacientes con RI tenían un mayor índice de masa corporal e hipertensión con mayor frecuencia que aquellas sin RI. El daño crónico y la actividad de la enfermedad no se relacionaron con RI. Un puntaje de Quantose RI ≥ 63 fue más elevado en pacientes con SMet (81.5 vs 53.5%; p = 0.02). El puntaje Quantose RI también se correlacionó con el número de criterios para SMet (r: 0.35; p = 0.003). CONCLUSIONES: En mujeres con LES no diabéticas, la prevalencia de RI basada en el puntaje de Quantose RI fue del 64.2%.

Histamine induces intracellular Ca2+ oscillations and nitric oxide release in endothelial cells from brain microvascular circulation.

The neuromodulator histamine is able to vasorelax in human cerebral, meningeal and temporal arteries via endothelial histamine 1 receptors (H1 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.

Systemic lupus erythematosus, endothelial progenitor cells and intracellular Ca2+ signaling: A novel approach for an old disease.

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 (Ca2+) 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 Ca2+ 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 Ca2+ signaling to improve ECFCs' reparative phenotype and suggest this strategy as a new approach to treat SLE patients.

Comparing cytology, colposcopy and human papillomavirus cervical intraepithelial lesion screening methods in women with systemic lupus erythematosus.

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.

Clinical relevance of monitoring serum adalimumab levels in axial spondyloarthritis.

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.

Type 2 Diabetes Alters Intracellular Ca2+ Handling in Native Endothelium of Excised Rat Aorta.

An increase in intracellular Ca2+ concentration ([Ca2+]i) plays a key role in controlling endothelial functions; however, it is still unclear whether endothelial Ca2+ handling is altered by type 2 diabetes mellitus, which results in severe endothelial dysfunction. Herein, we analyzed for the first time the Ca2+ 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 Ca2+-sensitive fluorophore, Fura-2/AM, we found that the endothelial Ca2+ 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 "Ca2+ add-back" protocol revealed no difference in the inositol-1,4,5-trisphosphate-releasable endoplasmic reticulum (ER) Ca2+ pool, while store-operated Ca2+ entry was surprisingly down-regulated in OZDF aortae. Pharmacological manipulation disclosed that sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity was down-regulated by reactive oxygen species in native aortic endothelium of OZDF rats, thereby exaggerating the Ca2+ 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 Ca2+ toolkit.