Hormone therapy effect on menopausal systemic lupus erythematosus patients: a systematic review.

Systemic lupus erythematosus (SLE) primarily affects women, who may need hormone therapy (HT) in menopause. There is, however, some concern as to its efficacy and safety. This systematic review aimed to determine the effect of HT on the activity of SLE and its safety. The study was a qualitative systematic review. Research was conducted with data retrieved from Embase, MEDLINE and Cochrane databases using MESH terms up to April 2021, with no bar on date or language. Sixteen studies were selected for analysis. Most of them showed HT to be effective in the treatment of menopausal symptoms with no impact in SLE activity, but one randomized clinical trial showed an increase in the number of thrombotic events. The present systematic review demonstrated the efficacy of HT for treating the menopausal symptoms of SLE patients. The risk of flare and thrombosis seems to be very low.

Left ventricular pseudoaneurysm associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is associated with several cardiac manifestations but, to our knowledge, there have been no previously published reports on left ventricular (LV) pseudoaneurysm in this disease. We describe a case of a 30-year-old woman with SLE who presented with a disease flare (acute and subacute cutaneous lupus, pericarditis, fever, leukopenia) associated with heart failure syndrome. The patient was diagnosed with a large LV pseudoaneurysm and a bovine pericardium patch closure was performed. Coronary arteries were angiographically normal, and cardiac magnetic resonance imaging did not exhibit detectable myocardial fibrosis or infarction. Trauma, previous cardiac surgery, Chagas disease, and antiphospholipid syndrome were excluded. Histopathology of the pericardium revealed lymphocytic arteriolitis raising the possibility of an autoimmune-mediated mechanism for this complication. The unequivocal concomitant diagnosis of lupus flare, the exclusion of other causes of pseudoaneurysm and the histopathological finding of arteriolitis in this patient reinforces the hypothesis of lupus-mediated lesion.

Late-onset biopsy-proven lupus nephritis without other associated autoimmune diseases: severity and long-term outcome.

BACKGROUND/PURPOSE: Lupus nephritis (LN) usually develops within the first years of systemic lupus erythematosus (SLE) onset and rarely after that. There are scarce studies comparing early- versus late-onset nephritis (before versus after five years of SLE diagnosis). The aim of this study was to compare the severity and long-term outcome (after 7 years) in these two, late-onset and early-onset, nephritis groups. METHODS: This study included 93 patients from rheumatology tertiary centers from Brazil and Italy, all of them with biopsy-proven LN with > 7 years follow-up. Patients were divided in two groups: early-onset nephritis ( n = 75) and late-onset nephritis ( n = 18). Clinical and laboratorial data were obtained using a standardized electronic chart database protocol carried out at 1-6 months interval and established in 2000. Patients >50 years or with concomitant autoimmune diseases were excluded. Variables evaluated at the LN presentation were Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), creatinine, albumin, anti-DNA positivity and nephritis class. Variables evaluated at the long-term outcome (after 7 years) were Systemic Lupus International Collaborating Clinics Damage Index (SDI), creatinine, dialysis and mortality. RESULTS: The average time of LN presentation was 10.94 ± 3.73 years for the late-onset and 1.20 ± 1.60 years for the early-onset group. Their similar nephritis duration (12.44 ± 3.2 versus 13.28 ± 4.03 years, p = 0.41) and comparable mean ages (49.17 ± 9.9 versus 44.11 ± 10.8 years old, p = 0.06) allow a more accurate comparison. Regarding severity, late-onset was similar to early-onset group: SLEDAI (8 (range: 6-22) versus 12 (range: 2-24), p = 0.47), creatinine (1.36 ± 0.94 versus 1.36 ± 1.13 mg/dl, p = 0.99); albumin (2.84 ± 0.65 versus 2.59 ± 0.84 mg/dl, p = 0.30); proteinuria (3.77 ± 2.18 versus 5.01 ± 4.51 g/vol, p = 0.26); proliferative nephritis (44% ( n = 8) versus 60% ( n = 45), p = 0.23). There was also no difference in the long-term outcomes between groups: SDI (1 (range: 0-5) versus 0.5 (range: 0-5), p = 0.27); creatinine (2.04 ± 2.38 versus 1.69 ± 2.26 mg/dl, p = 0.56); dialysis (22% ( n = 4) versus 13% ( n = 10), p = 0.46) and mortality (0% ( n = 0) versus 12% ( n = 9), p = 0.19). CONCLUSION: This study provides novel evidence of comparable long-term outcomes between late-onset and early-onset nephritis, which is most likely explained by the observation that at presentation, the clinical, laboratorial and histological features of late-onset and early-onset nephritis are similar. This suggests that there should be no distinct treatment targets and therapeutic interventions for the late- and early-onset groups.

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.

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.

RANKL and OPG gene polymorphisms: associations with vertebral fractures and bone mineral density in premenopausal systemic lupus erythematosus.

UNLABELLED: Premenopausal women with systemic lupus erythematosus (SLE) have a higher prevalence of low bone mineral density and vertebral fractures. Multiple genetic loci for osteoporotic fracture were identified in recent genome-wide association studies. This study provides a novel data demonstrating that receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) polymorphisms likely plays an important role in the bone remodeling process in SLE premenopausal women. INTRODUCTION: The purpose of this study was to evaluate single-nucleotide polymorphisms (SNPs) of the RANKL, RANK, and OPG genes in premenopausal SLE patients and their association with sRANKL and OPG serum levels, vertebral fractures, and bone mineral density (BMD). METHODS: A total of 211 premenopausal SLE patients (American College of Rheumatology (ACR) criteria) and 154 healthy controls were enrolled. SNPs of RANKL 290A>G (rs2277438), OPG 1181G>C (rs2073618), 245T>G (rs3134069), 163A>G (rs3102735), and RANK A>G (rs3018362) were obtained by real-time PCR. sRANKL/OPG serum levels were determined by ELISA. BMD and vertebral fractures were evaluated by dual-energy X-ray absorptiometry (DXA). RESULTS: SLE patients and controls had similar frequencies of the RANKL 290 G allele (p = 0.94), OPG 1181 C allele (p = 0.85), OPG 245 G allele (p = 0.85), OPG 163 G allele (p = 0.78), and RANK G allele (p = 0.87). Further analysis of the SLE patients revealed that the frequency of the RANKL 290 G allele was lower in patients with fractures than that in patients without fractures (28.1 vs 46.9%, p = 0.01). In addition, the frequency of the OPG 245 G allele was higher in patients with low BMD than that in patients with normal BMD (31.4 vs 18.1%, p = 0.04). No association of OPG 1181 G>C, OPG 163 A>G, and RANK A>G SNPs with BMD/fractures was found. Additionally, no association was observed between RANKL/OPG/RANK SNPs and sRANKL/OPG serum levels. CONCLUSIONS: Our study provides novel data demonstrating that RANKL/OPG genetic variations appear to play a role in bone remodeling, particularly in its major complication, fracture, in premenopausal patients with SLE.

Lower P1NP serum levels: a predictive marker of bone loss after 1 year follow-up in premenopausal systemic lupus erythematosus patients.

SUMMARY: Predictors of bone mineral density (BMD) loss are additional tools in the management of osteoporosis in premenopausal women with systemic lupus erythematosus (SLE). This study provides original evidence that N-terminal propeptide of type 1 collagen (P1NP), the most specific bone formation marker, is a predictor of BMD loss in this group of women. INTRODUCTION: SLE is associated with a high risk of low bone mass/fractures but this risk is still controversial in premenopausal women. Our aim was to determine the 1 year incidence of BMD loss in premenopausal SLE women and the value of bone turnover markers as predictors of this complication. METHODS: This study enrolled a convenience sample of 63 premenopausal SLE patients. BMD was evaluated by dual X-ray absorptiometry at lumbar spine and hip at baseline and after 12 months. BMD changes above the least significant change were considered significant. Serum levels of P1NP and CTX (electrochemiluminescence), OPG, and RANKL (ELISA) were determined at baseline. RESULTS: Mean age was 31.1±6.8 years, and disease duration was 5.25±3.8 years. 36.5 % of patients presented BMD loss and 17.5 % BMD gain at lumbar spine and/or hip. Patients were divided in three groups: BMD loss (BL), no BMD change (NC), and BMD gain (BG). Patients with BL and NC received similar cumulative/mean/maximum glucocorticoid doses during the study, but patients with BG received lower doses (p<0.05). Baseline P1NP levels were different in the groups (BL: 36.95±23.37 vs. NC: 54.63±30.82 vs. BG: 84.09±43.85 ng/mL; p=0.031 BL vs. NC, p<0.001 BL vs. BG, and p=0.039 NC vs. BG). There was no difference in CTX, OPG, or RANKL levels. After multivariate analysis, P1NP remained as an independent risk factor for BMD loss (p<0.03). CONCLUSIONS: This study provides original evidence that lower levels of P1NP, the most specific bone formation marker, are predictive of BMD loss over 12 months in premenopausal SLE patients.

LTBI screening in rheumatoid arthritis patients prior to anti-TNF treatment in an endemic area.

SETTING: Recommendations for screening for latent tuberculous infection (LTBI) in patients eligible for anti-tumour necrosis factor (TNF) agents remain unclear in endemic regions. OBJECTIVE: To evaluate the long-term efficacy of LTBI screening and treatment in patients with rheumatoid arthritis (RA) receiving TNF blockers. DESIGN: A total of 202 RA patients were screened for LTBI before receiving anti-TNF treatment using the tuberculin skin test (TST), chest X-ray (CXR) and history of exposure to tuberculosis (TB). All subjects were regularly followed at 1- to 3-month intervals. RESULTS: Eighty-five patients (42%) were treated with a single anti-TNF agent, while 117 patients (58%) changed anti-TNF agents once or twice. LTBI screening was positive in 66 patients, 44 were TST-positive, 23 had a history of TB exposure and 14 had an abnormal CXR. Exposure alone accounted for LTBI diagnosis in 14 patients with a negative TST. LTBI patients were treated with isoniazid (300 mg/day) for 6 months, and none developed TB. During follow-up, TST was repeated in 51 patients. Conversion was observed in 5; 3 were diagnosed with LTBI and 2 with active TB respectively 14 and 36 months after receiving anti-TNF treatment, suggesting new TB exposure. CONCLUSION: LTBI screening and treatment before anti-TNF treatment is effective in endemic areas and reinforces the importance of establishing contact history for diagnosing LTBI in RA patients.

Ovarian reserve in women with primary antiphospholipid syndrome.

OBJECTIVE: The objective of this paper is to evaluate ovarian reserve in primary antiphospholipid syndrome (PAPS) women and the association between ovarian reserve tests and clinical and laboratorial parameters, and anti-corpus luteum antibody (anti-CoL). METHODS: We screened 85 female patients between 18 to 40 years old with APS. Of these, 67 patients were excluded because of association with other autoimmune diseases (n = 42), contraindication or unwillingness to stop hormonal contraceptive (n = 21), current pregnancy or breastfeeding (n = 3) and previous ovarian surgery (n = 1). Therefore, a cross-sectional study was conducted in 18 PAPS patients and 24 healthy women. They were evaluated at early follicular phase with measurement of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) and sonographic antral follicle count (AFC). Serum measurement of anti-CoL was determined by immunoblot analysis. All analyses were performed after at least six months from the last intake of hormonal contraceptive and resumption of menstruation. RESULTS: The mean age was comparable in PAPS and controls (33.0 ± 5.0 vs. 30.4 ± 7.0 years; p = 0.19). Regarding ovarian reserve tests, the frequencies of low AFC (≤10) (56% vs. 22%, p = 0.04) and very low AFC (≤5) (37% vs. 9%, p = 0.04) were significantly higher in PAPS patients than controls. Trends of higher frequencies of reduced (<1.0 ng/ml), low (<0.5 ng/ml) and negligible (<0.2 ng/ml) AMH levels were found in PAPS patients (p = 0.08, p = 0.07 and p = 0.07, respectively). FSH, LH and estradiol were similar in patients and controls. There was no association between low ovarian reserve and specific types of antiphospholipid antibodies. Anti-CoL was solely observed in PAPS patients (11% vs. 0%; p = 0.177) and was not related to ovarian reserve tests. CONCLUSION: Women suffering from PAPS possessed reduced ovarian reserve, with prevalence greater than 50%.

Diagnosis and classification of autoimmune orchitis.

Autoimmune orchitis is characterized by testis inflammation and the presence of specific antisperm antibodies (ASA). It is classified in two categories. Primary autoimmune orchitis is defined by infertility and asymptomatic orchitis associated with ASA (100%) directed to the basement membrane or seminiferous tubules in infertile men, without any systemic disease and usually asymptomatic. Secondary autoimmune orchitis is characterized by symptomatic orchitis and/or testicular vasculiti`s associated with a systemic autoimmune disease, particularly vasculitis. These patients typically demonstrate testicular pain, erythema and/or swelling. ASA in secondary autoimmune orchitis have been reported in up to 50% of patients, especially in systemic lupus erythematosus patients. The pathogenesis of primary as well as secondary autoimmune orchitis is still unknown. Although the etiology is likely to be multifactorial, testicular inflammation, infection or trauma may induce T cell response with pro-inflammatory cytokine production with a consequent blood-testis-barrier permeability alteration, ASA production and apoptosis of spermatocytes and spermatids. ASA is known to cause immobilization and/or agglutination of spermatozoa, which may block sperm-egg interaction resulting in infertility. Assisted reproduction has been used as an efficient option in primary cases and immunosuppressive therapy for secondary autoimmune orchitis, although there is no double-blind, randomized trial to confirm the efficacy of any treatment regimens for these conditions.

Prevalence of sarcopenia and associated risk factors by two diagnostic criteria in community-dwelling older men: the São Paulo Ageing & Health Study (SPAH).

UNLABELLED: Sarcopenia is an aging syndrome that can be characterized by many criteria adjusted or not by fat mass. This study suggested that the optimal criteria should be selected according to body mass index (BMI) in older men and identified age, BMI, race, smoking, physical activity, hip bone mineral density (BMD) as risk factors for this syndrome. INTRODUCTION: This study aims to analyze the prevalence of sarcopenia and associated risk factors using appendicular skeletal mass (ASM)/height(2) and ASM adjusted for total fat mass criteria in older men from community. METHODS: Three hundred ninety-nine men were included and answered a questionnaire about lifestyle and medical history. Individuals were classified by their BMI using the classification adjusted by age. Body composition and bone mineral density were measured by dual X-ray absorptiometry. Sarcopenia was classified according to both criteria. Logistic regression models were used to analyze risk factors associated with sarcopenia. RESULTS: The mean BMI was 26.46 kg/m(2): 12.5 % underweight, 43.6 % normal, and 43.9 % overweight/obese. Fifty-four (13.5 %) were considered sarcopenic by ASM/height(2) and 79 (19.8 %) by ASM adjusted for fat (p = 0.001). Fifty-one (12.8 %) individuals had discordant sarcopenia classification: 13 were classified only by ASM/height(2) and 38 only by ASM adjusted for fat. Of the 13 subjects classified as sarcopenic only by ASM/height(2), 84.6 % (11/13) were underweight and solely one (7.7 %) was considered overweight/obese. In contrast, of those 38 older men classified as sarcopenic only by ASM adjusted for fat, none were underweight and 53 % (20/38) were overweight/obese. Subjects classified as sarcopenic according to both criteria had the same risk factors in the final model analyses (age, BMI, race, smoking, physical activity, hip BMD; p < 0.05). CONCLUSION: This study suggested that the optimal criteria for sarcopenia should be selected according to BMI in community-dwelling older men.

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.

Subclinical impairment of ovarian reserve in juvenile systemic lupus erythematosus after cyclophosphamide therapy.

OBJECTIVES: To perform systematic assessment of ovarian reserve markers using a combination of tests in juvenile systemic lupus erythematosus (JSLE) patients without amenorrhoea. METHODS: Twenty-seven consecutive JSLE female patients and 13 healthy controls without amenorrhoea were evaluated for 6 months. Ovarian reserve was assessed during early follicular phase by serum levels of follicle stimulating hormone (FSH), luteinising hormone (LH), estradiol, inhibin A, inhibin B and anti-Mullerian hormone (AMH). Ovarian size was measured by abdominal ultrasonography. Demographic data, disease activity, damage and treatment were also analysed. RESULTS: The median of current age was similar in JSLE patients and controls (16.5 vs. 15years, p=0.31) with a significantly higher age at menarche (13 vs. 12years, p=0.03). A trend of lower median total antral follicle count was observed in JSLE compared to controls (9 vs. 14.5, p=0.062) with similar median of other ovarian reserve parameters (p>0.05). Further evaluation of patients treated with cyclophosphamide and those without this treatment revealed a higher median FSH levels (6.4 vs. 4.6 IU/L, p=0.023). Inhibin B, AMH levels and ovarian volume were also lower but did not reach statistical significance (10.8 vs. 27.6 pg/mL, p=0.175; 0.6 vs. 1.5 ng/mL, p=0.276; 3.4 vs. 5 cm3, p=0.133; respectively). LH (2.7 vs. 2.9 IU/L, p=0.43), estradiol (50 vs. 38 pg/mL, p=0.337) and inhibin A (1.1 vs. 0 pg/mL, p=0.489) levels were comparable in both groups. CONCLUSIONS: Our study suggests that ovarian reserve after cyclophosphamide treatment may be hampered in spite of the presence of menstrual cycles emphasising the relevance of gonadal protection during the use of this alkylating agent.

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.

Menstrual and hormonal alterations in juvenile dermatomyositis.

OBJECTIVES: To evaluate age at menarche, menstrual cycles and hormone profile in juvenile dermatomyositis (JDM) patients and controls. METHODS: Twelve consecutive JDM patients were compared to 24 age-matched healthy subjects. Age at menarche and age of maternal menarche were recorded. Menstrual cycle was evaluated prospectively for 6 consecutive months and the mean cycle length and flow were calculated. The hormone profile was collected on the last menstrual cycle. Demographic data, clinical features, muscle enzymes, JDM scores and treatment were analysed. RESULTS: The median of current age of JDM patients and controls was similar (18 vs. 17 years, p=0.99). The median age at menarche of the JDM patients was higher than in the control group (13 vs. 11 years, p=0.02) whereas the median age of maternal menarche was alike in both groups (12 vs. 13 years, p=0.67). Menstrual disturbances were not observed, except for one patient who had longer length of menstrual cycle. The median of follicle stimulating hormone (FSH) was significantly higher in JDM patients compared to controls (4.5 vs. 3.0 IU/L, p=0.02) and none of them had premature ovarian failure (POF). The median of progesterone was significantly lower in JDM patients (0.3 vs. 0.7 ng/mL, p=0.01) with a higher frequency of decreased progesterone compared to controls (75% vs. 29%, p=0.01). CONCLUSIONS: Our study identifies in JDM patients delayed menarche with normal cycles and low follicular reserve. The decreased progesterone levels may suggest an underlying subclinical corpus luteum dysfunction in this disease.

Premature coronary artery calcification is associated with disease duration and bone mineral density in young female systemic lupus erythematosus patients.

Our objective was to evaluate the relevance of traditional and disease-related cardiovascular risk factors and of bone mineral density for premature coronary artery calcification in young patients with systemic lupus erythematosus. Ninety-four female patients with systemic lupus erythematosus with disease durations >5 years and <45 years were consecutively selected. Cardiovascular risks (diabetes mellitus, arterial hypertension, dyslipoproteinemia, smoking, family history, body mass index, ovarian and renal insufficiency) and systemic lupus erythematosus-related risk factors (disease duration, ACR criteria, modified SLICC/ ACR, SLEDAI and treatment) were evaluated. Bone mineral density was assessed by dual X-ray absorptiometry. Coronary artery calcification was determined by computed tomography. Coronary artery calcification was identified in 12 (12.7%) patients and was associated with a higher frequency of patients with cardiovascular risks (p = 0.001), higher number of cardiovascular risks (p = 0.002), age (p = 0.025), disease duration (p = 0.011) and SLICC (p=0.011). Individual analysis of cardiovascular risks demonstrated that menopause (p = 0.036), dyslipidemia (p = 0.003) and hypertension (p = 0.006) were significantly associated with coronary artery calcification. In addition, coronary artery calcification was associated with a lower whole body bone mineral density (p = 0.013). Multiple logistic regression analysis using cardiovascular risks, age, disease duration, SLICC and whole body bone mineral density revealed that only disease duration (p = 0.038) and whole body bone mineral density (p = 0.021) remained significant for coronary artery calcification. In conclusion, we found that disease duration and decreased bone mineral density are independent predictors for premature coronary calcification in young women with systemic lupus erythematosus, suggesting a common underlying mechanism.

Menstrual and hormonal alterations in juvenile systemic lupus erythematosus.

Menstrual cycles of 30 patients with juvenile systemic lupus erythematosus (JSLE) were compared with 30 age-matched controls. The mean age of patients with JSLE and controls was similar (17.4 +/- 3.2 vs 17.06 +/- 2.08 years, P = 0.66). The mean menarche age was higher in JSLE than controls (13.13 +/- 1.4 vs 11.56 +/- 1.5 years, P = 0.0008). On the contrary, the mean maternal menarche age was similar in both groups (P = 0.62). Menstrual abnormalities and longer length cycles were more frequently observed in JSLE than controls (63% vs 10%, P = 0.0001; 23% vs 0%, P = 0.0105, respectively). The median of follicle stimulating hormone was significantly higher in patients with JSLE compared with controls (4.6 vs 3.4 IU/L, P = 0.0207), and the median of progesterone was lower (32.5 vs 70 ng/mL, P = 0.0033). The median of luteinizing hormone was lower in patients with JSLE with menstrual abnormalities versus normal cycles (2.9 vs 5.5 IU/L, P = 0.019) and both had a high percentage of decreased progesterone levels (63% vs 73%, P = 0.70). Our findings support the notion that menstrual disturbances are frequent and may be associated with pituitary dysfunction leading to a decreased progesterone production. We also reported that in spite of premature ovarian failure being a rare event in JSLE the follicular reserve seems to be low regardless of intravenous cyclophosphamide treatment.

Osteoprotegerin/RANKL system imbalance in active polyarticular-onset juvenile idiopathic arthritis: a bone damage biomarker?

OBJECTIVE: To evaluate the importance of receptor activator of nuclear factor kappaB (RANK)/receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) modulation in active polyarticular juvenile idiopathic arthritis (pJIA) patients with and without bone erosions. METHODS: Thirty female patients (mean age 11.07+/-3.77 years, range 4-17 years) with active pJIA and 30 healthy gender- and age-matched controls were consecutively selected for this study. All involved articulations were assessed by X-ray and examined for the presence of bone erosions. The serum levels of RANKL and OPG were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with active pJIA had higher levels of serum RANKL than controls [2.90 (0.1-37.4) vs. 0.25 (0.1-5.7) pg/mL, p = 0.007] and a lower OPG/RANKL ratio [21.25 (1.8-897.6) vs. 347.5 (9-947.8), p = 0.005]. However, levels of OPG were comparable in both groups [55.24 (28.34-89.76) vs. 64.42 (30.68-111.28) pg/mL, p = 0.255]. Higher levels of serum RANKL and a lower OPG/RANKL ratio were also observed in active pJIA patients with bone erosions compared to controls [3.49 (0.1-37.4) vs. 0.25 (0.1-5.7) pg/mL, p = 0.0115 and 14.3 (1.8-897.6) vs. 347.5 (9-947.8), p = 0.016]. However, RANKL levels and OPG/RANKL ratio were similar in pJIA patients without bone erosion and controls [1.75 (0.1-10.9) vs. 0.25 (0.1-5.7) pg/mL, p = 0.055 and 29.2 (3.3-756.8) vs. 347.5 (9-947.8), p = 0.281]. CONCLUSION: These data suggest that active pJIA with bone erosions is associated with high serum levels of RANKL and a low OPG/RANKL ratio, indicating that these alterations may reflect bone damage in this disease.

High-titer antichromatin antibody is associated with proliferative class IV of lupus nephritis.

The antichromatin antibody (aCT) has been described as a useful marker for lupus nephropathy. The relevance of its nephritogenic potential may be appropriately evaluated in the context of renal histopathology. Therefore, the present study investigated the relationship of aCT with a particular histopathologic class of lupus nephritis (LN). Seventy-eight consecutive patients with systemic lupus erythematosus (ACR criteria) and active nephritis who underwent renal biopsy from 1999 to 2004 and with available frozen serum sample obtained at the time of biopsy were selected. aCT was measured by ELISA, and anti-dsDNA was measured by indirect immunofluorescence (IIF) and by ELISA. All renal biopsies were revised in a blinded manner by the same expert renal pathologist. Charts were extensively reviewed for demographic and renal features obtained at the time of biopsy. The prevalence of aCT (>or=20 U) was 59% with a mean titer of 74.3 +/- 38.7 U. Both aCT-positive and aCT-negative groups of patients had similar age, gender distribution, duration of lupus, and duration of renal disease. Anti-dsDNA was detected by IIF in 29.5% and by ELISA in 42.3% of the patients. Concomitant presence of both antibodies was observed in 63% (29/46) [anti-dsDNA by ELISA] and 45.6% (21/46) [anti-dsDNA by IIF] of the patients. Lower serum levels of C3 (73% vs. 40%, P = 0.0058) and C4 (82% vs. 46.7%, P = 0.0021) were more commonly observed in aCT >or= 20 U patients compared to the aCT-negative group. It is important to note that the use of a higher cut-off value (>or=40 U) for aCT test revealed a predominance of class IV LN (58% vs. 33%, P = 0.039) in aCT >or= 40 U compared to aCT < 40 U group. The mean levels of proteinuria, serum albumin, and creatinine were markedly altered but were comparable in both groups (P >or= 0.05). One fourth (26.3%) of the 19 patients with class IV LN and aCT >or= 40 U had no detectable anti-dsDNA (ELISA). These data suggest that high-titer aCT seems to be a valuable biomarker for proliferative class IV of LN.

Inflammatory cervicovaginal cytology is associated with disease activity in juvenile systemic lupus erythematosus.

To evaluate cervicovaginal cytology in adolescents with juvenile systemic lupus erythematosus (JSLE) and to compare them to controls. Fifty-two female adolescents with JSLE (ACR criteria) were compared to 52 age-matched healthy controls. All Pap smears were evaluated by the same cytopathologist blinded to gynecology examination (Bethesda 2001). The mean age of JSLE patients and controls were similar (16.17 +/- 1.94 versus 16.13 +/- 2.16 years, P = 0.92). The cervicovaginal cytology was found to be similar in both groups, although sexual intercourses in the last month were less frequent in JSLE than controls (23% versus 59.6%, P = 0.0003). Only one patient (2%) with JSLE versus two controls (4%) had cervical dysplasia (LGSIL) and human papilomavirus (P = 1.0). Candida spp vaginitis was observed in seven JSLE (14%) versus none in controls (P = 0.012) and was associated with immunosuppressive drugs (P = 0.01) and high dose of prednisone (P = 0.002). Of interest, inflammatory cervicovaginal cytology was observed in 21 (60%) of patients with SLEDAI > or = 4 and only four (23%) of those with SLEDAI < 4 (P = 0.001). Likewise, a higher frequency of inflammatory changes was also observed in virgin JSLE (57% versus 8%, P = 0.005). Our findings supports the notion that female genital tract may be a potential target organ in SLE since cervical inflammation is associated to disease activity independently of sexual activity.