Factors predictive of serious infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, multi-national, Latin American lupus cohort.

AIM: The aim of this study was to identify factors predictive of serious infections over time in patients with systemic lupus erythematosus (SLE). METHODS: A multi-ethnic, multi-national Latin American SLE cohort was studied. Serious infection was defined as one that required hospitalization, occurred during a hospitalization or led to death. Potential predictors included were sociodemographic factors, clinical manifestations (per organ involved, lymphopenia and leukopenia, independently) and previous infections at baseline. Disease activity (SLEDAI), damage (SLICC/ACR Damage Index), non-serious infections, glucocorticoids, antimalarials (users and non-users), and immunosuppressive drugs use; the last six variables were examined as time-dependent covariates. Cox regression models were used to evaluate the predictors of serious infections using a backward elimination procedure. Univariable and multivariable analyses were performed. RESULTS: Of the 1243 patients included, 1116 (89.8%) were female. The median (interquartile range) age at diagnosis and follow-up time were 27 (20-37) years and 47.8 (17.9-68.6) months, respectively. The incidence rate of serious infections was 3.8 cases per 100 person-years. Antimalarial use (hazard ratio: 0.69; 95% confidence interval (CI): 0.48-0.99; p = 0.0440) was protective, while doses of prednisone >15 and ≤60 mg/day (hazard ratio: 4.18; 95 %CI: 1.69-10.31; p = 0.0019) and >60 mg/day (hazard ratio: 4.71; 95% CI: 1.35-16.49; p = 0.0153), use of methylprednisolone pulses (hazard ratio: 1.53; 95% CI: 1.10-2.13; p = 0.0124), increase in disease activity (hazard ratio: 1.03; 95% CI: 1.01-1.04; p = 0.0016) and damage accrual (hazard ratio: 1.22; 95% CI: 1.11-1.34; p < 0.0001) were predictive factors of serious infections. CONCLUSIONS: Over time, prednisone doses higher than 15 mg/day, use of methylprednisolone pulses, increase in disease activity and damage accrual were predictive of infections, whereas antimalarial use was protective against them in SLE patients.

Complete urological evaluation including sperm DNA fragmentation in male systemic lupus erythematosus patients.

OBJECTIVE: To evaluate sperm DNA fragmentation analysis in non-azoospermic male systemic lupus erythematosus (SLE) patients. METHODS: Twenty-eight consecutive male SLE patients (American College of Rheumatology criteria) and 34 healthy controls were evaluated for demographic/exposures data, urological evaluation, hormone profile and sperm analysis (including sperm DNA fragmentation). Clinical features, disease activity/damage scores and treatment were also evaluated. RESULTS: The median age (33 (20-52) vs. 36.5 (25-54) years, P = 0.329) and frequency of varicocele (25% vs. 32%, P = 0.183) were similar in SLE patients and healthy controls. Sperm DNA fragmentation showed significantly higher levels of cells class III (44 (9-88) vs. 16.5 (0-80)%, P = 0.001) and cell class IV (10.5 (3-86) vs. 7 (0-36)%, P = 0.039) in SLE. The sperm DNA fragmentation index was also significantly higher in SLE patients (62 (31-97) vs. 25.5 (0-100)%, P < 0.001). Conventional sperm parameters (including sperm count, motility and morphology) were similar in both groups. In SLE patients no correlations were observed between sperm DNA fragmentation index and age, disease duration, Systemic Lupus Erythematosus Disease Activity Index 2000 and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index scores, and cumulative dose of prednisone, hydroxychloroquine, intravenous cyclophosphamide, methotrexate, azathioprine and mycophenolate mofetil ( P > 0.05). Further analysis of SLE patients treated with and without intravenous cyclophosphamide showed that total sperm motility was significantly lower in the former group (64% (15-83) vs. 72% (57-86), P = 0.024). The sperm DNA fragmentation index was alike in both groups (52.5 (31-95) vs. 67.5 (34-97)%, P = 0.185). CONCLUSIONS: To our knowledge, this is the first demonstration that male non-azoospermic SLE patients have increased sperm DNA fragmentation without evident gonadal dysfunction. Intravenous cyclophosphamide does not seem to be a major determinant for this abnormality. Future prospective study is necessary to determine the impact of this alteration in these patients' fertility.

Effectiveness of renoprotective approaches for persistent proteinuria in lupus nephritis: more than just immunosuppression.

OBJECTIVE: The objective of this study is to evaluate the efficacy of a tightly controlled renoprotective protocol in systemic lupus erythematosus (SLE) patients with persistent proteinuria. METHODS: Thirteen SLE patients with nephritis and persistent proteinuria (>1 g/24 hours) were included. The protocol consisted of regular clinical evaluations every two weeks to assess blood pressure (BP, target <130/80 mmHg), adherence to therapy, diet and smoking. No change in immunosuppressive drugs was allowed but reduction of glucocorticoid dose was permitted if indicated. Clinical, laboratory and treatment evaluations were performed at baseline and at the end of the study (after three months). RESULTS: SLE patients had a mean age of 37.85 ± 7.68 years and disease duration of 9.85 ± 7.29 years. At baseline, patients had a mean duration of maintenance therapy of 10.38 ± 7.56 months, 12 with mycophenolate mofetil (92.3%) and one with azathioprine (7.7%). At least one dose optimization of antihypertensive regimen was required in all patients during the study. Seven patients (53.8%) had BP>130/80mmHg at baseline. At the end, 11 patients (84.6%) achieved stable BP target; 92.3% were using an angiotensin-converting enzyme inhibitor, 53.9% an angiotensin receptor blocker, and 46.2% were using combined therapy. All patients had a significant reduction in proteinuria levels (2.26 ± 1.09 vs 0.88 ± 0.54 g/24 hours, p < 0.001) and 61.5% achieved proteinuria <1 g/24 hours. A significant decrease in mean prednisone dose was observed (10.96 ± 6.73 vs 5.38 ± 3.36 mg/day, p = 0.013) as well as mean Systemic Lupus Erythematosus Disease Activity Index score (4.38 ± 0.72 vs 3.08 ± 1.86, p = 0.043). No significant changes were identified in serum creatinine, albumin, potassium, complement 3 and complement 4 levels ( p > 0.05). CONCLUSION: This study provides evidence that a tightly controlled renoprotective protocol is effective in reducing persistent proteinuria in lupus nephritis. The concomitant reduction of prednisone without any change in immunosuppression reinforces the importance of strategies beyond the treatment of nephritis activity.

Nivolumab-induced new-onset seronegative rheumatoid arthritis in a patient with advanced metastatic melanoma: A case report and literature review.

Immune-related adverse events have been reported in patients treated with anti-programmed death-1 receptor drugs such as nivolumab. We present a case of a new-onset seronegative rheumatoid arthritis in a patient with metastatic melanoma treated with nivolumab.

Unexpectedly high genetic diversity and divergence among populations of the apomictic Neotropical tree Miconia albicans.

Since tropical trees often have long generation times and relatively small reproductive populations, breeding systems and genetic variation are important for population viability and have consequences for conservation. Miconia albicans is an obligate, diplosporous, apomictic species widespread in the Brazilian Cerrado, the savanna areas in central Brazil and elsewhere in the Neotropics. The genetic variability would be, theoretically, low within these male-sterile and possibly clonal populations, although some variation would be expected due to recombination during restitutional meiosis. We used ISSR markers to assess genetic diversity of M. albicans and to compare with other tropical trees, including invasive species of Melastomataceae. A total of 120 individuals from six populations were analysed using ten ISSR primers, which produced 153 fully reproducible fragments. The populations of M. albicans presented mean Shannon's information index (I) of 0.244 and expected heterozygosity (He ) of 0.168. Only two pairs of apparently clonal trees were identified, and genetic diversity was relatively high. A hierarchical amova for all ISSR datasets showed that 74% of the variance was found among populations, while only 26% of the variance was found within populations of this species. Multivariate and Bayesian analyses indicated marked separation between the studied populations. The genetic diversity generated by restitutional meiosis, polyploidy and possibly other genome changes may explain the morpho-physiological plasticity and the ability of these plants to differentiate and occupy such a wide territory and different environmental conditions. Producing enormous amounts of bird-dispersed fruits, M. albicans possess weedy potential that may rival other Melastomataceae alien invaders.

Lymphocytopenia is associated with anti-Beta-2 glycoprotein-1 in patients with 220 systemic lupus erythematosus.

BACKGROUND: Anti B2-Glicoprotein 1 (B2-GPI) is an antiphospholipid antibody that may be present in primary or secondary antiphospholipid syndrome (APS). Systemic Lupus erythematosus (SLE) is the main disease associated with secondary APS. OBJECTIVE: To study the prevalence of anti B2-GPI in SLE patients. METHODS: Anti B2-GPI (IgM/IgG) was studied by ELISA in 88 patients with SLE of both genders; 18.6% of which with secondary APS. Charts were reviewed for clinical and serological profile. RESULTS: Anti B2-GPI was present in 18.6% of the whole sample and in 29.4% of those with secondary APS. At univariated analysis, the presence of anti B2-GPI was more common in patients with serositis (p=0.04), lymphocytopenia (p=0.003) and anti cardiolipin (aCl) IgM antibodies (p=0.04). In a logistic regression study, only the associations with lymphocytopenia (OR=8.2; 95%CI=2.1-39.3) and aCl IgM (p=0.04; OR=3.4; 95%CI=1.05-11.1) remained significant. CONCLUSION: There is a 18.6% prevalence of positive anti B2-GPI in SLE population that is associated with the presence of aCl IgM and lymphocytopenia.

Effects of acute aerobic exercise on leukocyte inflammatory gene expression in systemic lupus erythematosus.

UNLABELLED: Systemic lupus erythematosus (SLE) is an autoimmune disease with a persistent systemic inflammation. Exercise induced inflammatory response in SLE remains to be fully elucidated. The aim of this study was to assess the effects of acuteexercise on leukocyte gene expression in active (SLEACTIVE) and inactive SLE (SLEINACTIVE) patients and healthy controls(HC). METHODS: All subjects (n = 4 per group) performed a 30-min single bout of acute aerobic exercise (~70% of VO2peak) on a treadmill, and blood samples were collected for RNA extraction from circulating leukocyte at baseline, at the end of exercise, and after three hours of recovery. The expression of a panel of immune-related genes was evaluated by a quantitative PCR array assay. Moreover, network-based analyses were performed to interpret transcriptional changes occurring after the exercise challenge. RESULTS: In all groups, a single bout of acute exercise led to the down-regulation of the gene expression of innate and adaptive immunity at the end of exercise (e.g., TLR3, IFNG, GATA3, FOXP3, STAT4) with a subsequent up-regulation occurring upon recovery. Exercise regulated the expression of inflammatory genes in the blood leukocytes of the SLE patients and HC, although the SLE groups exhibited fewer modulated genes and less densely connected networks (number of nodes: 29, 40 and 58; number of edges: 29, 60 and 195; network density: 0.07, 0.08 and 0.12, for SLEACTIVE, SLEINACTIVE and HC, respectively). CONCLUSION: The leukocytes from the SLE patients, irrespective of disease activity, showed a down-regulated inflammatory geneexpression immediately after acute aerobic exercise, followed by an up-regulation at recovery. Furthermore, less organized gene networks were observed in the SLE patients, suggesting that they may be deficient in triggering a normal exercised-induced immune transcriptional response.

Primary antiphospholipid syndrome: absence of premature atherosclerosis in patients without traditional coronary artery disease risk factors.

OBJECTIVE: To investigate if patients with Primary Antiphospholipid Syndrome (PAPS) with venous and/or arterial thrombosis without traditional coronary artery disease (CAD) risk factors develop early atherosclerotic vascular damage. METHODS: 27 female patients with PAPS (Sidney criteria) and 27 age, body mass index (BMI), and sex matched controls were consecutively selected. Exclusion criteria were: black race, age ≥55 years, traditional cardiovascular risk factors, other thrombophilias or connective tissue diseases, corticosteroids use and pregnancy. All subjects underwent Pulse Wave Velocity (PWV) and Echo-Tracking (ET), both in carotidal bed, to analyse vascular functional properties. RESULTS: Age (p = 0.92) and BMI (p = 0.91) were comparable in both groups. PAPS patients and controls had similar PWV (9.07 ± 1.08 m/s vs 9.42 ± 1.47 m/s, p = 0.34) as well as echo tracking parameters such as intima-media thickness (683 ± 171 µm vs 636 ± 140 µm, p = 0.52), carotideal diameter (p = 0.26), distensibility (p = 0.92), compliance coefficients (p = 0.36) and elastic modulus (p = 0.78). Patients with exclusively venous thrombosis showed lower PWV than patients with arterial thrombosis (8.55 ± 0.70 m/s vs 9.56 ± 0.94 m/s, p = 0.01), but no difference regarding intima-media thickness (683 ± 171 µm vs 636 ± 140 µm, p = 0.52) was observed. CONCLUSION: Patients with PAPS do not seem to be at higher risk of developing premature atherosclerosis. Patients who suffered exclusively venous thrombosis seem to be at lower risk than those with exclusively arterial events. Other studies need to confirm our findings.

Inflammatory cytokine kinetics to single bouts of acute moderate and intense aerobic exercise in women with active and inactive systemic lupus erythematosus.

The aim of this study was to evaluate changes in the cytokines INF-γ, IL-10, IL-6, TNF-α and soluble TNF receptors (sTNFR1 and sTNFR2) in response to single bouts of acute moderate and intense exercise in systemic lupus erythematosus women with active (SLE(ACTIVE)) and inactive (SLE(INACTIVE)) disease. Twelve SLE(INACTIVE) women (age: 35.3 ± 5.7 yrs; BMI: 25.6±3.4 kg/m2), eleven SLE(ACTIVE) women (age: 30.4 ± 4.5 yrs; BMI: 26.1±4.8 kg/m2), and 10 age- and BMI-matched healthy control women (HC) performed 30 minutes of acute moderate (~50% of VO(2)peak) and intense (~70% of VO(2)peak) exercise bout. Cytokines and soluble TNF receptors were assessed at baseline, immediately after, every 30 minutes up to three hours, and 24 hours after both acute exercise bouts. In response to acute moderate exercise, cytokines and soluble TNF receptors levels remained unchanged in all groups (P>0.05), except for a reduction in IL-6 levels in the SLE(ACTIVE) group at the 60th and 180th minutes of recovery (P<0.05), and a reduction in sTNFR1 levels in the HC group at the 90th, 120th, 150th, 180th minutes of recovery (P<0.05). The SLE(INACTIVE) group showed higher levels of TNF-α, sTNFR1, and sTNFR2 at all time points when compared with the HC group (P<0.05). Also, the SLE(ACTIVE) group showed higher levels of IL-6 at the 60th minute of recovery (P<0.05) when compared with the HC group. After intense exercise, sTNFR1 levels were reduced at the 150th (P=0.041) and 180th (P=0.034) minutes of recovery in the SLE(INACTIVE) group, whereas the other cytokines and sTNFR2 levels remained unchanged (P>0.05). In the HC group, IL-10, TNF-α, sTNFR1, and sTNFR2 levels did not change, whilst INF-γ levels decreased (P=0.05) and IL-6 levels increased immediately after the exercise (P=0.028), returning to baseline levels 24 hours later (P > 0.05). When compared with the HC group, the SLE(INACTIVE) group showed higher levels of TNF-α and sTNFR2 in all time points, and higher levels of sTNFR1 at the end of exercise and at the 30th minute of recovery (P<0.05). The SLE(ACTIVE) group also showed higher levels of TNF-α at all time points when compared with the HC group (P<0.05), (except after 90 min, 120 min and 24 hours of recovery) (P>0.05). Importantly, the levels of all cytokine and soluble TNF receptors returned to baseline 24 hours after the end of acute exercise, irrespective of its intensity, in all three groups (P>0.05). This study demonstrated that both the single bouts of acute moderate and intense exercise induced mild and transient changes in cytokine levels in both SLE(INACTIVE) and SLE(ACTIVE) women, providing novel evidence that acute aerobic exercise does not trigger inflammation in patients with this disease.

Increased corticotropin-releasing hormone (CRH) expression in cutaneous lupus lesions.

OBJECTIVE: Corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) axis activation leads to the production of hormones, such as adrenocorticotrophic hormone (ACTH) and the α-melanocyte stimulating hormone (α-MSH). Data regarding the role of these hormones in systemic lupus erythematosus (SLE) are scarce. In the present study we aim to evaluate the participation of this axis in the cutaneous involvement of SLE. METHODS: Seventeen SLE patients were clinically evaluated, and biopsies from affected and unaffected skin of these patients were compared with 17 healthy control individuals. Immunohistochemical analyses for CRH, ACTH, α-MSH, and MC-1R were performed, and the serum levels of α-MSH, IL-1, IL-1ra, IL-6, IL-10, IL-12p70, IL-17, TNF-α, and IFN-γ were measured. RESULTS: The affected skin of the SLE patients exhibited higher CRH expression in the deep dermis compared to the skin of the controls (p = 0.024), whereas the tissue expression of ACTH, cortisol, α-MSH and its receptor MC-1R were comparable in SLE patients and controls. Higher serum levels of IFN-γ (p = 0.041), TNF-α (p = 0.001) and IL-6 (p = 0.049) were observed in SLE patients compared with controls, while α-MSH levels were similar in both groups. CONCLUSION: The novel finding of elevated CRH expression solely in the affected skin deep dermis supports the notion of a cutaneous local dysfunction of the CRH-POMC axis in the pathogenesis of cutaneous SLE lesions.

Ovarian reserve in adult patients with childhood-onset lupus: a possible deleterious effect of methotrexate?

OBJECTIVES: To assess ovarian reserve markers and anti-corpus luteum antibodies (anti-CoL) in adult patients with childhood-onset systemic lupus erythematosus (c-SLE). METHOD: Fifty-seven adult c-SLE female patients and 21 healthy controls were evaluated for anti-CoL. Ovarian reserve was assessed by: follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol, anti-Müllerian hormone (AMH), and antral follicle count (AFC). Demographic data, menstrual abnormalities, disease activity, damage, and treatment were also analysed. RESULTS: The median current age was similar in adult c-SLE patients and controls (27.7 vs. 27.7 years, p = 0.414). The medians of AMH (1.1 vs. 1.5 ng/mL, p = 0.037) and AFC (6 vs. 16, p < 0.001) were significantly reduced in SLE patients compared to controls without significant menstrual abnormalities. Anti-CoL were solely observed in c-SLE patients (16% vs. 0%, p = 0.103) and were not associated with demographic data, ovarian reserve parameters, disease activity/damage, and treatment. Further evaluation of c-SLE patients treated with cyclophosphamide revealed a higher median of FSH levels compared to c-SLE patients not treated with cyclophosphamide and controls (8.8 vs. 5.7 vs. 5.6 IU/L, p = 0.032) and lower median AMH (0.4 vs. 1.5 vs. 1.5 ng/mL, p = 0.004) and AFC (4.0 vs. 6.5 vs. 16 IU/L, p = 0.001) levels. Nineteen patients treated exclusively with methotrexate demonstrated a negative correlation between the cumulative dose and AMH levels (p = 0.027, r = -0.507). CONCLUSIONS: The present study demonstrated for the first time that a high cumulative methotrexate dose is a possible cause of subclinical ovarian dysfunction in adult c-SLE patients. Further studies are required to confirm this deleterious effect in other rheumatic diseases, particularly juvenile idiopathic arthritis and idiopathic inflammatory myopathy.

Podocyte injury in pure membranous and proliferative lupus nephritis: distinct underlying mechanisms of proteinuria?

Proteinuria is a major feature of lupus nephritis (LN) and reflects podocyte injury. Analysis of podocyte biomarkers was performed attempting to identify if podocyte phenotype is distinct in pure membranous and proliferative LN. Expression of synaptopodin, Wilms tumor protein 1 (WT1), glomerular epithelial protein 1 (GLEPP1) and nephrin was evaluated in 52 LN biopsies by immunohistochemistry. Preserved synaptopodin expression was observed in only 10 (19.2%) of all biopsies while 42 (80.8%) had reduced expression. Both groups had comparable proteinuria at the time of biopsy (p = 0.22); however, in the mean follow-up of four years there was a tendency toward lower mean levels of proteinuria in patients with preserved synaptopodin staining (0.26±0.23 vs. 0.84±0.90 g/24 h, p = 0.05) compared with those with diminished expression. Thirty-nine (75%) biopsies were classified as proliferative and 13 (25%) as pure membranous. Comparison of podocyte biomarkers demonstrated a predominance of preserved staining of synaptopodin (69.2%), WT1 (69.2%), GLEPP1 (53.9%) and nephrin (60%) in the pure membranous group whereas only <10% of the proliferative showed preserved expression. Our data suggest that in proliferative forms there seems to occur structural podocyte damage, whereas in the pure membranous the predominant preserved pattern suggests a dysfunctional podocyte lesion that may account for the better long-term prognosis of proteinuria outcome.

Impaired aerobic exercise capacity and cardiac autonomic control in primary antiphospholipid syndrome.

Primary antiphospholipid syndrome (PAPS) is associated with increased risk of cardiovascular disease and mortality. Aerobic capacity and cardiac autonomic control are also associated with these risks. The aim of our study was to assess aerobic capacity and cardiac autonomic control in PAPS patients. Thirteen women with PAPS and 13 healthy controls matched for age, gender, and body mass index were enrolled for the study. Both groups were sedentary and were not under chronotropic, antidepressants and hypolipemiant drugs. All subjects performed a treadmill-graded maximal exercise. Aerobic capacity was assessed by peak oxygen uptake (VO2peak), time at anaerobic ventilatory threshold (VAT) and respiratory compensation point (RCP) and time-to-exhaustion, whereas cardiac autonomic control was assessed by chronotropic reserve (CR) and heart rate recovery at the first and second minutes after graded exercise (HRR1min and HRR2min, respectively). All aerobic capacity indexes were reduced more in PAPS patients than in healthy subjects: VO2peak (30.2 ± 4.7 vs 34.6 ± 4.3 ml.kg(-1).min(-1), p = 0.021), time at VAT (3.0 ± 1.5 vs 5.0 ± 2.0 min, p = 0.016), time at RCP (6.5 ± 2.0 vs 8.0 ± 2.0 min, p = 0.050), time-to-exhaustion (8.5 ± 2.0 vs 11.0 ± 2.5 min, p = 0.010). HRR1min (22 ± 9 vs 30 ± 7 bpm, p = 0.032) and HRR2min (33 ± 9 vs 46 ± 8 bpm, p = 0.002) were delayed in PAPS patients compared to healthy controls but CR was not significantly different (p = 0.272). In conclusion, an impaired aerobic capacity and cardiac autonomic control was identified in PAPS.

Clinical and immunological features of 888 Brazilian systemic lupus patients from a monocentric cohort: comparison with other populations.

Epidemiological studies with systemic lupus erythematosus (SLE) patients have been reported worldwide but, until now, a large evaluation had not been performed in Brazil. Therefore, we determined the clinical and immunological features of 888 SLE patients followed at our service from 2008 to 2012. The mean age at SLE onset and the mean disease duration were 29.9 ± 9.5 years old and 14.5 ± 8.4 years, respectively. A predominance of female gender (91.9%) and Caucasian ethnicity (69.9%) were observed. Cumulative mucocutaneous manifestations (90.7%) were most commonly identified (malar rash (83.2%), photosensitivity (76.9%)) followed by articular (87.4%), hematological (44.0%) and renal (36.9%) involvements. Antinuclear antibody was detected in all patients, followed by anti-dsDNA (35.1%), anti-Sm (21.8%) and anti-ribosomal P protein antibodies (19.8%). Additional comparison of clinical and laboratory features between genders revealed that malar rash was observed more in female SLE patients (84.5% vs. 69.4%, p = 0.001). Male lupus patients presented a higher frequency of anti-dsDNA (45.8% vs. 34.2%, p = 0.047) and a trend of more nephritis (47.2% vs. 36.0%, p = 0.059). In conclusion, we identified a high prevalence of mucocutaneous manifestations in this Brazilian SLE cohort compared to other countries, mainly malar rash that was most commonly observed in female patients. Anti-dsDNA and other specific SLE autoantibodies were also identified in a higher frequency, predominantly in the male gender.

Increased arterial stiffness assessed by pulse wave velocity in Behçet's disease and its association with the lipid profile.

OBJECTIVE: To evaluate the structural and functional properties of vessels in Behçet's Disease (BD) using carotid-femoral pulse wave velocity (PWV) and an echo-tracking system. METHODS: BD patients without traditional cardiovascular risk factors were selected. All BD patients performed PWV and carotid ultrasound. BD patients were divided into groups based on the presence of systemic (vascular and/or ocular and/or central nervous system involvement) and vascular involvement. Healthy controls age- and sex-matched with the same exclusion criteria were selected. RESULTS: A total of 23 BD patients (mean age 35.0 ± 7.6 years) had significantly higher PWV levels compared with controls (8.48 ± 1.14 vs. 7.53 ± 1.40 m/s, P = 0.017). Intima-media thickness (594.87 ± 138.61 vs. 561.08 ± 134.26 µm, P = 0.371), diastolic diameter (6383.78 ± 960.49 vs. 6447.65 ± 1159.73 µm, P = 0.840), distension (401.95 ± 117.72 vs. 337.91 ± 175.36 µm, P = 0.225) and relative distension (6.26 ± 2.83 vs. 5.42 ± 2.46 µm, P = 0.293) were similar in both groups. The systemic disease group had significantly higher levels of PWV (8.79 ± 1.21 vs. 7.88 ± 0.72 m/s, P = 0.036) compared to those with exclusive mucocutaneous manifestations. BD patients with vascular involvement had similar PWV and echo-tracking parameters compared to those without vascular involvement (P > 0.05), but had higher total and LDL cholesterol levels (P = 0.019 and P = 0.012, respectively). The multivariate linear regression analysis identified triglycerides as the most important factor in increasing PWV levels (P = 0.001) in BD. CONCLUSIONS: PWV is more useful than carotid ultrasound in detecting structural and functional vascular damage in BD and emphasizes the role of the disease itself in promoting these alterations. Our findings also reinforce the need for rigorous control of all risk factors in BD, particularly lipoproteins.

Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect.

UNLABELLED: The influence of antimalarials on lipids in systemic lupus erythematosus (SLE) has been identified in several studies but not in many prospective cohorts. The aim of this study was to longitudinally determine the effect of antimalarials on the lipoprotein profile in SLE. PATIENTS AND METHODS: Fasting total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein cholesterol (LDL) plasma levels were determined at entry and after 3 months of hydroxychloroquine (HCQ) treatment in a longitudinal evaluation of 24 patients with SLE. RESULTS: a significant decrease in TC (198 ± 33.7 vs. 183 ± 30.3 mg/dl, p = 0.023) and LDL levels (117 ± 31.3 vs. 101 ± 26.2 mg/dl, p = 0.023) were detected after the 3 months of HCQ therapy. The reduction of 7.6% in TC (p = 0.055) and 13.7% in LDL levels (p = 0.036) determined a significant decrease in the frequency of dyslipidemia (26% vs. 12.5%, p = 0.013) after HCQ therapy. CONCLUSION: This longitudinal study demonstrated the beneficial effect of antimalarials on lipids in SLE since this therapy induced a reduction of atherogenic lipoproteins.

Alveolar hemorrhage: distinct features of juvenile and adult onset systemic lupus erythematosus.

We compared outcomes of alveolar hemorrhage (AH) in juvenile (JSLE) and adult onset SLE (ASLE). From 263 JSLE and 1522 ASLE, the AH occurred in 13 (4.9%) and 15 (1.0%) patients, respectively (p < .001). Both groups had comparable disease duration (2.6 ± 3.0 vs. 5.6 ± 7.0 years, p = .151) and median SLEDAI scores [17.5 (2 to 32) vs. 17.5 (3 to 28), p = 1.000]. At AH onset, a higher frequency of JSLE were already on a high prednisone dose ( > 0.5 mg/kg/day) compared to ASLE (54% vs. 15%, p = .042). The mean drop of hemoglobin was significantly lower in JSLE (2.9 ± 0.9 vs. 5.5 ± 2.9 g/dL, p = .006). Although treatments with methylprednisolone, plasmapheresis, intravenous immunoglobulin and cyclophosphamide were similar in both groups (p > .050), regarding outcomes, there was a trend in high frequency of mechanical ventilation use (85% vs. 47%, p = .055) and also significant mortality (69% vs. 13%, p = .006) in JSLE compared to ASLE. The sepsis frequency was comparable in both groups (50% vs. 27%, p = .433). We have identified that AH in JSLE has a worse outcome most likely related to respiratory failure. The AH onset in JSLE already treated with high-dose steroids raises the concern of inadequate response to this treatment and reinforces the recommendation of early aggressive alternative therapies in this group of patients.

PPARγ expression is increased in systemic lupus erythematosus patients and represses CD40/CD40L signaling pathway.

Systemic lupus erythematosus (SLE) is a heterogeneous disease involving several immune cell types and pro-inflammatory signals, including the one triggered by binding of CD40L to the receptor CD40. Peroxisome-proliferator activated receptor gamma (PPARγ) is a transcription factor with anti-inflammatory properties. Here we investigated whether CD40 and PPARγ could exert opposite effects in the immune response and the possible implications for SLE. Increased PPARγ mRNA levels were detected by real-time PCR in patients with active SLE, compared to patients with inactive SLE PPARγ/GAPDH mRNA = 2.21 ± 0.49 vs. 0.57 ± 0.14, respectively (p < 0.05) or patients with infectious diseases and healthy subjects (p < 0.05). This finding was independent of the corticosteroid therapy. We further explored these observations in human THP1 and in SLE patient-derived macrophages, where activation of CD40 by CD40L promoted augmented PPARγ gene transcription compared to non-stimulated cells (PPARγ/GAPDH mRNA = 1.14 ± 0.38 vs. 0.14 ± 0.01, respectively; p < 0.05). This phenomenon occurred specifically upon CD40 activation, since lipopolysaccharide treatment did not induce a similar response. In addition, increased activity of PPARγ was also detected after CD40 activation, since higher PPARγ-dependent transcription of CD36 transcription was observed. Furthermore, CD40L-stimulated transcription of CD80 gene was elevated in cells treated with PPARγ-specific small interfering RNA (small interfering RNA, siRNA) compared to cells treated with CD40L alone (CD80/GAPDH mRNA = 0.11 ± 0.04 vs. 0.05 ± 0.02, respectively; p < 0.05), suggesting a regulatory role for PPARγ on the CD40/CD40L pathway. Altogether, our findings outline a novel mechanism through which PPARγ regulates the inflammatory signal initiated by activation of CD40, with important implications for the understanding of immunological mechanisms underlying SLE and the development of new treatment strategies.

Penile anthropometry in systemic lupus erythematosus patients.

The aim of this study was to evaluate penile anthropometry in systemic lupus erythematosus (SLE) patients compared with healthy controls and the possible relevant pubertal, clinical, hormonal and treatment factors that could influence penile dimensions. Twenty-five consecutive SLE patients were assessed by urological examination, sexual function, testicular ultrasound, hormones, sperm analysis, genetic analysis, clinical features and treatment. The control group included 25 age-matched healthy males. SLE patients had a lower median penis length and circumference [8 (7.5-10) vs. 10 (8-13) cm, p = 0.0001; 8 (7-10) vs. 10 (7-11) cm, p = 0.001; respectively], lower median testicular volume by right and left Prader [15 (10-25) vs. 20 (12-25) ml, p = 0.003; 15 (10-25) vs. 20 (12-25) ml, p = 0.006; respectively], higher median of follicle-stimulating hormone [5.8 (2.1-25) vs. 3.3 (1.9-9) IU/l, p = 0.002] and lower morning total testosterone levels (28% vs. 0%, p = 0.009) compared with controls. In spite of that, erectile dysfunction was not observed in patients or controls. Analyses of lupus patients revealed that the median penis circumference was lower in patients with disease onset before first ejaculation compared with those with disease onset after first ejaculation [7.8 (7-10) vs. 9.0 (7.5-10) cm, p = 0.026]. No differences were observed in the median penile anthropometry regarding sexual dysfunction (p = 0.610), lower morning total testosterone levels (p = 0.662), oligo/azoospermia (p = 0.705), SLE Disease Activity Index ≥ 4 (p = 0.562), Systemic Lupus International Collaborating Clinics/ACR Damage Index ≥ 1 (p = 0.478), prednisone cumulative dose (p = 0.789) and intravenous cyclophosphamide therapy (p = 0.754). Klinefelters syndrome (46XY/47XXY) was diagnosed in one (4%) SLE patient with decreased penile size whereas Y-chromosomal microdeletions was absent in all of them. In conclusion, we have identified reduced penile dimensions in SLE patients with no deleterious effect in erectile function. Disease onset before first ejaculation seems to affect penis development in pre-pubertal lupus.