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Suzana BV Mello,1 Elaine R Tavares,2 Adriana Bulgarelli,2 Eloisa Bonfá,1 Raul C Maranhão2,31Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; 2Lipid Metabolism Laboratory, the Heart Institute (INCOR) of the Medical School Hospital, São Paulo, Brazil; 3Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, BrazilObjective: Commercial methotrexate formulations (MTX) have poor anti-inflammatory action for intra-articular treatment of rheumatoid arthritis. Our aim was to investigate whether an association between methotrexate and lipidic nanoemulsions (LDE) could improve MTX intra-articular action.Methods: For its association to LDE, MTX was previously esterified with dodecyl bromide. LDE-MTX was prepared by high pressure homogenization. Antigen-induced arthritis (AIA) was achieved in rabbits sensitized with methylated bovine serum albumin, and the rabbits were subsequently intra-articularly injected with the antigen. Twenty-four hours after AIA induction, groups of four to nine rabbits were intra-articularly injected with increasing doses (0.0625–0.5 µmol/kg) of LDE-MTX, and were compared to treatment with 0.5 µmol/kg commercial MTX, LDE alone, and saline (controls). Synovial fluid was collected 48 hours after AIA induction for analysis of protein leakage and cell content. Synovial membranes were collected for histopathology. Uptake of LDE labeled with 3H-cholesteryl ether by the synovial tissue was also determined.Results: Uptake of radioactive LDE by arthritic joints was 2.5-fold greater than by normal joints. Treatment with intra-articular LDE-MTX elicited a clear dose response pattern by reducing the synovial leukocyte infiltrate (P = 0.004) and protein leakage (P = 0.032) when compared with arthritic non-treated joints. In contrast, the intra-articular injection of commercial MTX and LDE did not reduce leukocyte infiltrate or protein leakage. Toxicity to treatment was not observed in any of the animals.Conclusion: The association between LDE and MTX presented a marked anti-inflammatory effect that was absent after intra-articular commercial MTX treatment. Therefore, the new formulation is a candidate for future clinical studies.Keywords: nanoparticles, cholesterol, methotrexate, arthritis, antigen-induced arthritis

Aims: To evaluate the presence of temporomandibular disorders (TMD) in systemic sclerosis (SSc) patients and its possible association with the severity of skin involvement. Methods: The presence of TMD was evaluated in 35 SSc women and 30 age- and sex-matched healthy controls by means of the anamnestic (Ai) and clinical (Di) Helkimo indices; the jaw mobility was further analyzed (MI). Skin involvement was scored by the Modified Rodnan Skin Score (MRSS). Results: Signs and symptoms of TMD were more frequent in SSc patients than in controls, the frequency distribution of the different clinical dysfunction indices differing significantly (P < .001) between patients (Di0 8.6%, DiI 48.6%, DiII 22.8%, and DiIII 20%) and controls (Di0 50%, DiI 33.3%, and DiII 16.7%). Cyclophosphamide for severe and rapidly progressive cutaneous fibrosis was prescribed in six out of seven patients with severe signs (DiIII), in contrast this treatment was indicated for only two out of 25 patients with mild to moderate signs (DiI and DiII, P < .001). Impaired jaw mobility was more frequent in SSc patients than controls (P < .001). It was severe in 77.1% (MIII) and mild in 22.9% (MII) of the cases, in contrast to controls (MI0 33.4%, MII 53.3%, and MIII 13.3%; P < .001). Approximately half of SSc patients with severe (MIII) but none of those with mild impairment were on cyclophosphamide treatment for severe cutaneous fibrosis (P = .02). Conclusion: Severe signs of TMD according to the anamnestic and clinical Helkimo indices were very frequent in SSc patients. J Orofac Pain 2010;24:197-202. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this paper is to determine the factors predictive of flares in systemic lupus erythematosus (SLE) patients. Methods: A case-control study nested within the Grupo Latino Americano De Estudio de Lupus (GLADEL) cohort was conducted. Flare was defined as an increase ≥4 points in the SLEDAI. Cases were defined as patients with at least one flare. Controls were selected by matching cases by length of follow-up. Demographic and clinical manifestations were systematically recorded by a common protocol. Glucocorticoid use was recorded as average daily dose of prednisone and antimalarial use as percentage of time on antimalarial and categorized as never (0%), rarely (>0-25%), occasionally (>25%-50%), commonly (>50%-75%) and frequently (>75%). Immunosuppressive drugs were recorded as used or not used. Results: A total of 465 cases and controls were included. Mean age at diagnosis among cases and controls was 27.5 vs 29.9 years, p=0.003; gender and ethnic distributions were comparable among both groups and so was the baseline SLEDAI. Independent factors protective of flares identified by multivariable analysis were older age at diagnosis (OR=0.929 per every five years, 95% CI 0.869-0.975; p=0.004) and antimalarial use (frequently vs never, OR=0.722, 95% CI 0.522-0.998; p=0.049) whereas azathioprine use (OR=1.820, 95% CI 1.309-2.531; p<0.001) and SLEDAI post-baseline were predictive of them (OR=1.034, 95% CI 1.005-1.064; p=0.022). Conclusions: In this large, longitudinal Latin American cohort, older age at diagnosis and more frequent antimalarial use were protective whereas azathioprine use and higher disease activity were predictive of flares. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]