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.

Characterizing hand and wrist ultrasound pattern in primary Sjögren's syndrome: a case-control study.

INTRODUCTION/OBJECTIVES: To evaluate the clinical relevance of high-resolution hand and wrist ultrasound (US) findings and their possible associations with anti-citrullinated peptide antibodies in primary Sjögren's syndrome (pSS). METHODS: Ninety-seven consecutive pSS patients (American-European Consensus Group, 2002) without meeting the American College of Rheumatology (ACR) criteria (1987) for rheumatoid arthritis (RA); 20 RA patients (ACR/European League Against Rheumatism (EULAR) criteria, 2010); and 80 healthy individuals with comparable age, gender, and ethnicity were enrolled in a case-control study. Disease activity was assessed by EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). US was performed by one expert blinded to anti-CCP, anti-MCV, and IgM rheumatoid factor tested by ELISA. RESULTS: Frequencies of grade 3 synovitis (9.3 vs. 0%, p = 0.004), tenosynovitis (36.1 vs. 3.8%, p < 0.001), and erosions (27.8 vs. 7.5%, p = 0.001) on US were higher in pSS patients than in healthy controls. ESSDAI presented a moderate correlation with the synovitis number (p = 0.001) and tenosynovitis (p < 0.001). Most pSS patients with erosions on US (81.5%) had negative anti-CCP. Nevertheless, anti-CCP ≥ 3× cut-off value was associated with the presence of erosions in pSS (p = 0.026). Erosions in pSS were mainly small size contrasting with moderate/large size in RA (p < 0.001), and positive power Doppler synovitis predominated in RA (p < 0.001). CONCLUSIONS: US identified significant frequencies of grade 3 synovitis, tenosynovitis, and erosions in pSS. Synovitis and tenosynovitis numbers were correlated with ESSDAI. Association between erosions on US and anti-CCP (high titers) in pSS possibly identifies a subgroup with severe arthritis. These findings suggest that US is a useful method for assessing joint involvement in pSS.Key Points• US identified significant frequencies of grade 3 synovitis, tenosynovitis, and erosions in pSS patients in comparison with age- and race-healthy individuals.• Numbers of synovitis and tenosynovitis on US were correlated with ESSDAI values.• Most pSS patients with erosions on US were negative for anti-CCP, but anti-CCP ≥ 3× cut-off value was associated with the presence of erosions in this disease.• Erosions in pSS were mainly small size contrasting with moderate/large size in RA, and positive power Doppler synovitis predominated in RA.

Antiphospholipid syndrome damage index (DIAPS): distinct long-term kinetic in primary antiphospholipid syndrome and antiphospholipid syndrome related to systemic lupus erythematosus.

BACKGROUND: Antiphospholipid syndrome (APS) is an acquired thrombophilia that affects young productive individuals, with permanent damage and negative impact on quality of life. Recently, a damage index specific for APS (DIAPS) was developed. There are, however, no data regarding the comparison of its performance and long-term damage in primary antiphospholipid syndrome (PAPS) and APS related to systemic lupus erythematosus (SLE; APS + SLE). The primary purpose of this study was therefore to compare the long-term damage in patients with these conditions. METHODS: This is a retrospective analysis of a single tertiary center cohort followed for approximately 10 years using a standardized prospective electronic chart database. Fifty consecutive PAPS patients age matched with 50 APS+SLE patients were consecutively selected for the study, and DIAPS was calculated once a year during follow-up. Long-term damage and damage kinetics in both groups were compared. RESULTS: PAPS and APS + SLE had comparable age (47.10 ± 12.4 vs. 44.04 ± 10.80 years; p = 0.19) and time of follow-up (9.40 ± 3.60 vs. 10.94 ± 4.50 years; p = 0.06). At diagnosis, PAPS had higher DIAPS than APS + SLE (1.72 ± 1.17 vs. 0.82 ± 0.96; p < 0.001). At the end of the 10-year follow-up, both groups presented comparable mean damage scores (2.04 ± 1.50 vs. 2.24 ± 1.61; p = 0.52). The damage increment throughout the observation period for PAPS was solely 35%, whereas for APS + SLE it was gradual, persistent and reached 139% at the end of follow-up, with a total damage increment for PAPS lower than APS + SLE (0.43 ± 0.30 vs. 1.22 ± 1.24; p < 0.001). Of note, the frequency of individuals who acquired damage was lower in PAPS than in APS + SLE (32% vs. 71%; p < 0.001). PAPS also had a longer delay in diagnosis than APS + SLE (4.00 ± 4.20 vs. 2.54 ± 3.05 years; p = 0.04). This delay was positively correlated with a higher damage score at diagnosis (r = 0.36, p < 0.001) in all groups. CONCLUSION: We identified a distinct pattern of damage in PAPS and APS related to SLE. Damage in PAPS is an early event, while APS+SLE is associated with higher long-term damage, with a striking increment of damage along the follow-up. A diagnosis delay is correlated with higher damage scores. Damage surveillance therefore requires different approaches for these two conditions.

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.

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.

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.

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.

Characteristics of 1555 childhood-onset lupus in three groups based on distinct time intervals to disease diagnosis: a Brazilian multicenter study.

Objective The objective of this study was to compare demographic data, clinical/laboratorial features and disease activity at diagnosis in three different groups with distinct time intervals between onset of signs/symptoms and disease diagnosis. Methods A multicenter study was performed in 1555 childhood-onset systemic lupus erythematosus (American College of Rheumatology criteria) patients from 27 pediatric rheumatology services. Patients were divided into three childhood-onset systemic lupus erythematosus groups: A: short time interval to diagnosis (<1 month); B: intermediate time interval (≥1 and <3 months); and C: long time interval (≥3 months). An investigator meeting was held to define the protocol. Demographic data, SLICC classification criteria and SLEDAI-2 K were evaluated. Results The number of patients in each group was: A = 60 (4%); B = 522 (33.5%); and C = 973 (62.5%). The median age at diagnosis (11.1 (4.2-17) vs. 12 (1.9-17.7) vs. 12.5 (3-18) years, P = 0.025) was significantly lower in group A compared with groups B and C. The median number of diagnostic criteria according to SLICC (7 (4-12) vs. 6 (4-13) vs. 6 (4-12), P < 0.0001) and SLEDAI-2 K (18 (6-57) vs. 16 (2-63) vs. 13 (1-49), P < 0.0001) were significantly higher in group A than the other two groups. The frequency of oral ulcers in the palate (25% vs. 15% vs. 11%, P = 0.003), pleuritis (25% vs. 24% vs. 14%, P < 0.0001), nephritis (52% vs. 47% vs. 40%, P = 0.009), neuropsychiatric manifestations (22% vs. 13% vs. 10%, P = 0.008), thrombocytopenia (32% vs. 18% vs. 19%, P = 0.037), leucopenia/lymphopenia (65% vs. 46% vs. 40%, P < 0.0001) and anti-dsDNA antibodies (79% vs. 66% vs. 61%, P = 0.01) were significantly higher in group A compared with the other groups. In contrast, group C had a less severe disease characterized by higher frequencies of synovitis (61% vs. 66% vs. 71%, P = 0.032) and lower frequencies of serositis (37% vs. 33% vs. 25%, P = 0.002), proteinuria >500 mg/day (48% vs. 45% vs. 36%, P = 0.002) and low complement levels (81% vs. 81% vs. 71%, P < 0.0001) compared with groups A or B. Conclusions Our large Brazilian multicenter study demonstrated that for most childhood-onset systemic lupus erythematosus patients, diagnosis is delayed probably due to mild disease onset. Conversely, the minority has a very short time interval to diagnosis and a presentation with a more severe and active multisystemic condition.

Increased visceral adipose tissue and altered adiposity distribution in premenopausal lupus patients: correlation with cardiovascular risk factors.

Objective Visceral adipose tissue (VAT) correlates with cardiovascular risk factors and has never been assessed in systemic lupus erythematosus (SLE). Our aim was to evaluate VAT in premenopausal SLE patients. Methods Sixty-three premenopausal SLE patients and 186 age-matched healthy women were included. Demographic, anthropometric, disease and treatment parameters were evaluated. VAT was measured by dual X-ray absorptiometry (DXA) with APEX 4.0 software. Results SLE patients had a disease duration of 5.25 ± 3.80 years, SLEDAI activity score of 4.35 ± 5.13, SLICC/ACR-DI of 0.70 ± 0.80, current prednisone dose of 11.60 ± 12.10 mg/day and cumulative glucocorticoid dose of 22.34 ± 12.94 g. Overweight/obese SLE patients and controls had similar VAT parameters ( p > 0.05). Among individuals with BMI <25 kg/m2, SLE patients and controls had similar weight, fat mass and fat percentage ( p > 0.05) but patients had higher values of VAT parameters (VAT mass: 260.60 ± 117.23 vs. 194.77 ± 71.42 g, p = 0.001; VAT area: 54.05 ± 24.30 vs. 40.40 ± 14.82 cm2, p = 0.001; VAT volume: 281.75 ± 126.81 vs. 210.61 ± 77.29 cm3, p = 0.001) and trunk/limb fat mass ratio (0.78 ± 0.21 vs. 0.67 ± 0.12, p = 0.002) compared to controls. In SLE, VAT area correlated with weight ( r = 0.66, p < 0.001), non-HDL cholesterol ( r = 0.53, p < 0.001), LDL cholesterol ( r = 0.48, p < 0.001) and triglycerides ( r = 0.33, p = 0.008), but not with disease duration, SLEDAI, SLICC/ACR-DI or current glucocorticoid use ( p > 0.05). Conclusion This study provides original evidence that SLE is associated with increased VAT and altered adiposity distribution. The correlation with traditional risk factors for cardiovascular disease, independent of current glucocorticoid dose and disease activity, suggests the role of visceral fat as an additional tool for risk assessment in these young patients.

Ribosomal P antibody: 30 years on the road.

The identity of the protein antigens targeted by anti-cytoplasmic antibodies in lupus was discovered 30 years ago. These antigens are three acidic ribosomal phosphoproteins, P0, P1, and P2. Precise identification of the shared epitope on these three proteins enabled sensitive and specific immunoassays to be developed. Anti-P antibodies are highly specific for systemic lupus erythematosus (SLE) and occur in 15%-35% of patients, depending on ethnicity as well as the age of onset. Increased frequencies of detection of anti-P have been reported in childhood SLE as well as in neuropsychiatric, renal, and hepatic disease. While longitudinal studies by the Systemic Lupus International Collaborating Clinics (SLICC) consortium supported the association of anti-P with neuropsychiatric lupus, the predictive value of antibody determination remains controversial. This is likely explained by the heterogeneity of neuropsychiatric lupus as well as by the different methodologies used for assay. A number of experimental studies have suggested a direct pathogenic role for anti-P antibodies in brain disease. Findings include cross reactivity between anti-P and a neuronal surface antigen, which was detected in areas of the brain involved in memory, cognition, and emotion. Direct injection of anti-P antibodies into the brains of rodents was also associated with abnormal electrical activity and behavioral disturbances. Taken together, research over the last 30 years has established anti-P antibodies as a useful diagnostic marker of SLE and at least a subset of patients with neuropsychiatric disease. Further research is required to fine tune the association of anti-P with clinical manifestations and establish beyond high probability a pathophysiologic role for the antibodies.

Electrophysiological dysfunction induced by anti-ribosomal P protein antibodies injection into the lateral ventricle of the rat brain.

Objective Anti-ribosomal P antibodies (anti-P) are strongly associated with neuropsychiatric lupus. This study was designed to determine whether these antibodies are capable of causing electro-oscillogram (EOSG) and behavior alterations in rats. Methods IgG fraction anti-P positive and affinity-purified anti-P antibodies were injected intraventricularly in rats. Sequential cortical and subcortical EOSGs were analyzed during 30 days. IgG anti-Ro/SS-A and normal IgG were used as controls. Results All 13 animals injected with IgG anti-P demonstrated a high prevalence of polyspikes, diffusely distributed in hippocampal fields and cerebral cortex. These abnormalities persisted approximately a month. Remarkably, an identical electrical disturbance was observed with the inoculation of affinity-purified anti-P antibodies. The EOSG alterations were associated with behavioral disorders with varying degrees of severity in every animal injected with anti-P. In contrast, no changes in EOSG or behavioral disturbances were observed in the control group. Conclusion Our study indicates that anti-P antibodies can directly induce electrophysiological dysfunction in central nervous system particularly in hippocampus and cortex associated with behavior disturbances.

Anti-ribosomal P antibody: a multicenter study in childhood-onset systemic lupus erythematosus patients.

Objectives Anti-ribosomal P protein (anti-P) autoantibodies are highly specific for systemic lupus erythematosus (SLE). However, the evaluation of this autoantibody in childhood-onset SLE (cSLE) populations has been limited to a few small series, hampering the interpretation of the clinical and laboratorial associations. Therefore, the objective of this multicenter cohort study was to evaluate demographic, clinical/laboratorial features, and disease damage score in cSLE patients with and without the presence of anti-P antibody. Methods This was a retrospective multicenter study performed in 10 pediatric rheumatology services of São Paulo state, Brazil. Anti-P antibodies were measured by ELISA in 228 cSLE patients. Results Anti-P antibodies were observed in 61/228 (27%) cSLE patients. Frequencies of cumulative lymphadenopathy (29% vs. 15%, p = 0.014), acute confusional state (13% vs. 5%, p = 0.041), mood disorder (18% vs. 8%, p = 0.041), autoimmune hemolytic anemia (34% vs. 15%, p = 0.001), as well as presence of anti-Sm (67% vs. 40%, p = 0.001), anti-RNP (39% vs. 21%, p = 0.012) and anti-Ro/SSA antibodies (43% vs. 25%, p = 0.016) were significantly higher in cSLE patients with anti-P antibodies compared to those without these autoantibodies. A multiple regression model revealed that anti-P antibodies were associated with autoimmune hemolytic anemia (odds ratio (OR) = 2.758, 95% confidence interval (CI): 1.304-5.833, p = 0.008) and anti-Sm antibody (OR = 2.719, 95% CI: 1.365-5.418, p = 0.004). The SLICC/ACR damage index was comparable in patients with and without anti-P antibodies ( p = 0.780). Conclusions The novel association of anti-P antibodies and autoimmune hemolytic anemia was evidenced in cSLE patients and further studies are necessary to determine if anti-P titers may vary with this hematological manifestation.

Outcomes of 847 childhood-onset systemic lupus erythematosus patients in three age groups.

Objective The objective of this study was to assess outcomes of childhood systemic lupus erythematosus (cSLE) in three different age groups evaluated at last visit: group A early-onset disease (<6 years), group B school age (≥6 and <12 years) and group C adolescent (≥12 and <18 years). Methods An observational cohort study was performed in ten pediatric rheumatology centers, including 847 cSLE patients. Results Group A had 39 (4%), B 395 (47%) and C 413 (49%). Median disease duration was significantly higher in group A compared to groups B and C (8.3 (0.1-23.4) vs 6.2 (0-17) vs 3.3 (0-14.6) years, p < 0.0001). The median Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) (0 (0-9) vs 0 (0-6) vs 0 (0-7), p = 0.065) was comparable in the three groups. Further analysis of organ/system damage revealed that frequencies of neuropsychiatric (21% vs 10% vs 7%, p = 0.007), skin (10% vs 1% vs 3%, p = 0.002) and peripheral vascular involvements (5% vs 3% vs 0.3%, p = 0.008) were more often observed in group A compared to groups B and C. Frequencies of severe cumulative lupus manifestations such as nephritis, thrombocytopenia, and autoimmune hemolytic anemia were similar in all groups ( p > 0.05). Mortality rate was significantly higher in group A compared to groups B and C (15% vs 10% vs 6%, p = 0.028). Out of 69 deaths, 33/69 (48%) occurred within the first two years after diagnosis. Infections accounted for 54/69 (78%) of the deaths and 38/54 (70%) had concomitant disease activity. Conclusions This large multicenter study provided evidence that early-onset cSLE group had distinct outcomes. This group was characterized by higher mortality rate and neuropsychiatric/vascular/skin organ damage in spite of comparable frequencies of severe cumulative lupus manifestations. We also identified that overall death in cSLE patients was an early event mainly attributed to infection associated with disease activity.

Autoimmune hemolytic anemia in systemic lupus erythematosus at diagnosis: differences between pediatric and adult patients.

Objective To determine the overall prevalence of autoimmune hemolytic anemia (AIHA), and to compare clinical and laboratory features in a large population of children and adult lupus patients at diagnosis. Methods This retrospective study evaluated the medical charts of 336 childhood-onset systemic lupus erythematosus (cSLE) and 1830 adult SLE (aSLE) patients followed in the same tertiary hospital. Demographic data, clinical features and disease activity were recorded. AIHA was defined according to the presence of anemia (hemoglobin <10 g/dL) and evidence of hemolysis (reticulocytosis and positive direct antiglobulin test (DAT)/Coombs test) at SLE diagnosis. Evans syndrome (ES) was defined by the combination of immune thrombocytopenia (platelet count <100,000/mm3) and AIHA. Results The frequency of AIHA at diagnosis was significantly higher in cSLE patients compared to aSLE (49/336 (14%) vs 49/1830 (3%), p = 0.0001), with similar frequency of ES (3/336 (0.9%) vs 10/1830 (0.5%), p = 0.438). The median of hemoglobin levels was reduced in cSLE vs aSLE patients (8.3 (2.2-10) vs 9.5 (6.6-10) g/dL, p = 0.002) with a higher frequency of multiple hemorrhagic manifestations (41% vs 7%, p = 0.041) and erythrocyte transfusion due to bleeding (24% vs 5%, p = 0.025). cSLE patients also had more often constitutional involvement (84% vs 31%, p < 0.001), fever (65% vs 26%, p < 0.001), weight loss > 2 kg (39% vs 6%, p < 0.001), reticuloendothelial manifestations (48% vs 8%, p < 0.001), hepatomegaly (25% vs 2%, p < 0.001) and splenomegaly (21% vs 2%, p = 0.004). Other major organ involvements were common but with similar frequencies in cSLE and aSLE ( p > 0.05). Median systemic lupus erythematosus disease activity index 2000 (SLEDAI-2 K) was comparable in cSLE and aSLE (p = 0.161). Conclusions We identified that AIHA was not a common condition in cSLE and aSLE, with distinct features characterized by a higher prevalence/severity in children and concomitant constitutional symptoms in the majority of them.

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.

Herpes zoster infection in childhood-onset systemic lupus erythematosus patients: a large multicenter study.

OBJECTIVE: The aim of this multicenter study in a large childhood-onset systemic lupus erythematosus (cSLE) population was to assess the herpes zoster infection (HZI) prevalence, demographic data, clinical manifestations, laboratory findings, treatment, and outcome. METHODS: A retrospective multicenter cohort study (Brazilian cSLE group) was performed in ten Pediatric Rheumatology services in São Paulo State, Brazil, and included 852 cSLE patients. HZI was defined according to the presence of acute vesicular-bullous lesions on erythematous/edematous base, in a dermatomal distribution. Post-herpetic neuralgia was defined as persistent pain after one month of resolution of lesions in the same dermatome. Patients were divided in two groups for the assessment of current lupus manifestations, laboratory findings, and treatment: patients with HZI (evaluated at the first HZI) and patients without HZI (evaluated at the last visit). RESULTS: The frequency of HZI in cSLE patients was 120/852 (14%). Hospitalization occurred in 73 (61%) and overlap bacterial infection in 16 (13%). Intravenous or oral aciclovir was administered in 113/120 (94%) cSLE patients at HZI diagnosis. None of them had ophthalmic complication or death. Post-herpetic neuralgia occurred in 6/120 (5%). After Holm-Bonferroni correction for multiple comparisons, disease duration (1.58 vs 4.41 years, p < 0.0001) was significantly lower in HZI cSLE patients compared to those without HZI. Nephritis (37% vs 18%, p < 0.0001), lymphopenia (32% vs 17%, p < 0.0001) prednisone (97% vs 77%, p < 0.0001), cyclophosphamide (20% vs 5%, p < 0.0001) and SLE Disease Activity Index 2000 (6.0 (0-35) vs 2 (0-45), p < 0.0001) were significantly higher in the former group. The logistic regression model showed that four independent variables were associated with HZI: disease duration < 1 year (OR 2.893 (CI 1.821-4.597), p < 0.0001), lymphopenia <1500/mm(3) (OR 1.931 (CI 1.183-3.153), p = 0.009), prednisone (OR 6.723 (CI 2.072-21.815), p = 0.002), and cyclophosphamide use (OR 4.060 (CI 2.174-7.583), p < 0.0001). CONCLUSION: HZI is an early viral infection in cSLE with a typical dermatomal distribution. Lymphopenia and immunosuppressive treatment seem to be major factors underlying this complication in spite of a benign course.

Bone impairment assessed by HR-pQCT in juvenile-onset systemic lupus erythematosus.

UNLABELLED: High-resolution peripheral quantitative computed tomography (HR-pQCT) analysis of female juvenile-onset systemic lupus erythematosus (JoSLE) patients revealed trabecular/cortical bone damage and reduced bone strength primarily at the distal radius compared to healthy controls. We demonstrated for the first time that JoSLE patients with vertebral fracture (VF) present trabecular impairment at the distal radius. INTRODUCTION: This study investigated the volumetric bone mineral density (vBMD), microarchitecture, and biomechanical features at the distal radius and tibia using HR-pQCT and laboratory bone markers in JoSLE patients compared to controls to determine whether this method discriminates JoSLE patients with or without VF. METHODS: We compared 56 female JoSLE patients to age- and Tanner-matched healthy controls. HR-pQCT was performed at the distal radius and tibia. Serum levels of the amino-terminal pro-peptide of type I collagen, the C-terminal telopeptide of type I collagen, intact parathormone, sclerostin, and 25-hydroxyvitamin D (25OHD) were evaluated. VFs were analyzed using VFA-dual-energy X-ray absorptiometry (DXA) (Genant's method). RESULTS: Reduced density and strength parameters and microarchitecture alterations of cortical and trabecular bones were observed in JoSLE patients compared to controls, primarily at the distal radius (p < 0.05). Patients with VF exhibited a significant decrease in trabecular bone parameters solely at the distal radius (Total.BMD, p = 0.034; Trabecular.BMD [Tb.BMD], p = 0.034; bone volume (BV)/trabecular volume (TV), p = 0.034; apparent modulus, p = 0.039) and higher scores for disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI), p = 0.002). Bone metabolism markers were similar in all groups. Logistic regression analysis of parameters that were significant in univariate analysis revealed that Tb.BMD (OR 0.98, 95 % CI 0.95-0.99, p = 0.039) and SLICC/ACR-DI (OR 7.37, 95 % CI 1.75-30.97, p = 0.006) were independent risk factors for VF. CONCLUSION: In conclusion, this study is the first demonstration of bone microstructure and strength deficits in JoSLE patients, particularly at the distal radius. Our results demonstrated that VF was associated with trabecular radius alteration and emphasized the potential detrimental effect of disease damage on this condition.

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.