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Objectives To assess immunogenicity of a heterologous fourth dose of an mRNA (BNT162b2) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in autoimmune rheumatic diseases (ARD) patients with poor/non-response to inactivated vaccine (Sinovac-CoronaVac). Methods A total of 164 ARD patients who were coronavirus disease 2019 (COVID-19) poor/non-responders (negative anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies—NAb) to the third dose of Sinovac-CoronaVac received an additional heterologous dose of mRNA (BNT162b2) 3 months after last dose. IgG and NAb were evaluated before and after the fourth dose. Results Significant increases were observed after the fourth dose in IgG (66.4 vs 95.1%, P Conclusions This is the largest study to provide evidence of a remarkable humoral response after the fourth dose of heterologous mRNA SARS-CoV-2 vaccination in ARD patients with poor/non-response to the third dose of an inactivated vaccine. We further identified that treatment, particularly rituximab and prednisone, impaired antibody response to this additional dose. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, CoronavRheum #NCT04754698.

This randomized controlled study aimed to investigate whether a single bout of exercise before the homologous booster dose of a SARS-CoV-2 inactivated vaccine could enhance immunogenicity in patients with spondyloarthritis. We selected 60 consecutive patients with spondyloarthritis (SpA). Patients assigned to the intervention group performed an exercise bout comprising three exercises. Then, they remained at rest for 1 h before vaccination. The control group remained at rest before vaccination. Immunogenicity was assessed before (Pre) and 1 mo after (Post) the booster using seropositivity rates of total anti-SARS-CoV-2 S1/S2 IgG, geometric mean titers of anti-S1/S2 IgG (GMT), frequency of neutralizing antibodies (NAb) positivity, and NAb activity. At Pre, 16 patients from the exercise group and 16 patients from the control group exhibited seropositivity for IgG (59% vs. 57.1%), and 1 mo after the booster dose, seropositivity occurred in 96% versus 100% of the cases. Only 10 patients from the exercise group and 12 patients from the control group showed positive NAb serology at Pre (37% vs. 42.8%). One month following the booster, NAb positivity was 96% versus 93%. GMT was comparable between groups at Pre. At Post, GMT increased similarly in both groups. Likewise, NAb activity was similar between groups at Pre and increased similarly in both of them as a result of the booster (47.5% vs. 39.9%). In conclusion, a single bout of exercise did not enhance immunogenicity to a homologous booster dose of an inactivated SARS-CoV-2 vaccine among patients with spondyloarthritis.

To compare the perception of disease activity (DA) between adult patients with systemic autoimmune myopathies (SAMs) and their physicians, and analyse possible sources of discordance.This cross-sectional study included 75 patients with SAMs. Patients and physicians rated the global DA on a 0-10 cm visual analogue scale. A discrepancy score was calculated by subtracting physician assessment from patient assessment. Three groups were defined: (I) no discrepancy: difference within -2.0 to +2.0; (II) negative discrepancy (ND): difference-2.0 (patient underrated DA in relation to physcian); (III) positive discrepancy (PD): difference+2.0 (patient overrated DA in relation to physician). Logistic regression was used to identify predictors of discordance.Discordance in patient-physician assessment of DA was found in 21 (28%) cases. ND was observed in 3 (4%), PD in 18 (24%), and no discrepancy in 54 (72%) assessments. Due to the small number, ND cases were excluded from the analysis. PD was associated with older age, personal history of depression, past joint involvement, higher MMT-8 and lower extramuscular DA. In the regression model, for each additional year of age, the chance of PD increases, on average, by 9% (OR 1.09; 95%CI 1.01-1.17, p=0.034). Personal history of depression increases the chance of PD by 829% (OR 9.29; 95%CI 1.52-56.89, p=0.016).Almost 30% of patients had discordance in DA assessment from their physicians. The majority of them overrated their DA. These patients tend to be older and are more likely to have personal history of depression, past joint involvement, and milder disease.

Background We aimed to examine the immunogenicity pattern induced by the inactivated SARS-CoV-2 vaccine CoronaVac (Sinovac Life Sciences, Beijing, China) in SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases compared with seropositive controls, seronegative patients with autoimmune rheumatic diseases, and seronegative controls. Methods CoronavRheum is an ongoing, prospective, controlled, phase 4 study, in which patients aged 18 years or older with autoimmune rheumatic diseases, and healthy controls were recruited from a single site (Rheumatology Division of Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo) in São Paulo, Brazil Participants were vaccinated with two doses of CoronaVac (intramuscular injection, 3 μg in 0·5 mL of β-propiolactone inactivated SARS-CoV-2) on day 0 and on day 28. Blood samples were taken pre-vaccination on day 0, day 28, and also on day 69. For this subgroup analysis, participants were defined as being SARS-CoV-2 seropositive or seronegative prevaccination via anti-SARS-CoV-2 spike (S)1 or S2 IgG (cutoff of 15·0 arbitrary units [AU] per mL) or neutralising antibody titres (cutoff of ≥30%) and were matched for age and sex, via convenience sampling, in a 1:3:1:1 ratio (seropositive patients to seronegative patients to seropositive controls to seronegative controls). The primary outcomes were rates of anti-SARS-CoV-2 S1 and S2 IgG seropositivity and SARS-CoV-2 neutralising antibody positivity at day 28 and day 69 and immunogenicity dynamics assessed by geometric mean titres (GMTs) of IgG and median neutralising activity in seropositive patients with autoimmune rheumatic diseases compared with seronegative patients and seropositive and seronegative controls. We assessed safety in all participants randomly selected for this subgroup analysis. This study is registered with ClinicalTrials.gov, NCT04754698, and is ongoing for long-term immunogenicity evaluation. Findings Between Feb 4 and Feb 8, 2021, 1418 patients and 542 controls were recruited, of whom 1685 received two vaccinations (1193 patients and 492 controls). After random sampling, our immunogenicity analysis population comprised 942 participants, of whom 157 were SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases, 157 were seropositive controls, 471 were seronegative patients, and 157 were seronegative controls; the median age was 48 years (IQR 38–56) and 594 (63%) were female and 348 (37%) were male. For seropositive patients and controls, an increase in anti-SARS-CoV-2 S1 and S2 IgG titres (seropositive patients GMT 52·3 [95% CI 42·9–63·9] at day 0 vs 128·9 [105·6–157·4] at day 28; seropositive controls 53·3 [45·4–62·5] at day 0 vs 202·0 [174·8–233·4] at day 28) and neutralising antibody activity (seropositive patients 59% [IQR 39–83] at day 0 vs 82% [54–96] at day 28; seropositive controls 58% [41–79] at day 0 vs 92% [79–96] at day 28), was observed from day 0 to day 28, without further increases from day 28 to day 69 (at day 69 seropositive patients' GMT was 137·1 [116·2–161·9] and neutralising antibody activity was 79% [57–94]); and seropositive controls' GMT was 188·6 [167·4–212·6] and neutralising antibody activity was 92% [75–96]). By contrast, for seronegative patients and controls, the second dose was required for maximum response at day 69, which was lower in seronegative patients than in seronegative controls. GMTs in seronegative patients were 2·3 (95% CI 2·2–2·3) at day 0, 5·7 (5·1–6·4) at day 28, and 29·6 (26·4–33·3) at day 69, and in seronegative controls were 2·3 (2·1–2·5) at day 0, 10·6 (8·7–13·1) at day 28, and 71·7 (63·5–81·0) at day 69; neutralising antibody activity in seronegative patients was 15% (IQR 15–15) on day 0, 15% (15–15) at day 28, and 39% (15–65) at day 69, and in seronegative controls was 15% (15–15) at day 0, 24% (15–37) at day 28, and 61% (37–79) at day 69. Neither seronegative patients nor seronegative controls reached the GMT or antibody activity levels of seropositive patients at day 69. Interpretation By contrast with seronegative patients with autoimmune rheumatic diseases, seropositive patients have a robust response after a single dose of CoronaVac. Our findings raise the possibility that the reduced immunogenicity observed in seronegative patients might not be the optimum response potential to SARS-CoV-2 vaccination, and therefore emphasise the importance of at least a single booster vaccination in these patients. Funding Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and B3-Bolsa de Valores do Brasil. Translation For the Portuguese translation of the abstract see Supplementary Materials section.

The aim of this paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry for paediatric and adult patients with non-infectious uveitis (NIU).This is a physician-driven, population- and electronic-based registry implemented for both retrospective and prospective collection of real-world demographics, clinical, laboratory, instrumental and socioeconomic data of patients with uveitis and other non-infectious inflammatory ocular diseases recruited through the AIDA Network. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is thought to collect standardised information for real-life research and has been developed to change over time according to future scientific acquisitions and potentially communicate with other similar instruments. Security, data quality and data governance are cornerstones of this platform.Ninety-five centres have been involved from 19 countries and four continents from 24 March to 16 November 2021. Forty-eight out of 95 have already obtained the approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers). The AIDA Registry collects baseline and follow-up data using 3943 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger/risk factors, therapies and healthcare utilization for patients with NIU.The development of the AIDA Registry for patients with NIU will facilitate the collection of standardised data leading to real-world evidence and enabling international multicentre collaborative research through inclusion of patients and their families worldwide.

To evaluate factors associated with COVID-19 severity outcomes in patients with systemic lupus erythematosus (SLE).This was a cross-sectional analysis of baseline data of a prospective, multi-stage cohort study-"The ReumaCoV Brazil"-designed to monitor patients with immune-mediated rheumatologic disease (IMRD) during the SARS-CoV-2 pandemic. SLE adult patients with COVID-19 were compared with those without COVID-19. SLE activity was evaluated by the patient global assessment (PGA) and SLE Disease Activity Index 2000 (SLEDAI-2K).604 SLE patients were included, 317 (52.4%) with COVID-19 and 287 (47.6%) in the control group. SLE COVID-19 patients reported a lower frequency of social isolation and worked more frequently as health professionals. There was no difference in the mean SLEDAI-2K score between groups in the post-COVID-19 period (5.8 [8.6] vs. 4.5 [8.0];Hypertension and cyclophosphamide were associated with a severe outcome, and telemedicine can be a useful tool for SLE patients with COVID-19.

To assess immunogenicity of a heterologous 4th dose of a mRNA (BNT162b2) SARS-CoV-2 vaccine in autoimmune rheumatic diseases (ARD) patients with poor/non-response to inactivated vaccine (Sinovac-CoronaVac).164 ARD patients who were COVID-19 poor/non-responders (negative anti-SARS-CoV-2 S1/S2 IgG and/or neutralising antibodies-NAb) to the 3rd dose of Sinovac-CoronaVac received an additional heterologous dose of mRNA (BNT162b2) three months after last dose. IgG and NAb were evaluated before and after the 4th dose.Significant increases were observed after 4th dose in IgG (66.4% vs 95.1%, p0.001), NAb positivity (5.5% vs 83.5%, p0.001) and GMT (29.5 vs 215.8 AU/ml, p0.001), and 28 (17.1%) remained poor/non-responders. Patients with negative IgG after 4th dose were more frequently under rituximab (p= 0.001). Negative NAb was associated with older age (p= 0.015), rheumatoid arthritis (p= 0.002), systemic sclerosis (p= 0.026), leflunomide (p= 0.016), and rituximab use (p= 0.007). In multiple logistic regression analysis, prednisone dose ≥7.5 mg/day (OR = 0.34; p= 0.047), leflunomide (OR = 0.32, p= 0.036) and rituximab use (OR = 0.19, p= 0.022) were independently associated with negative NAb after the 4th vaccine dose.This is the largest study to provide evidence of a remarkable humoral response after the 4th dose of heterologous mRNA SARS-CoV-2 vaccination in ARD patients with poor/no-response to the 3rd dose of an inactivated vaccine. We further identified that treatment, particularly rituximab and prednisone, impaired antibody response to this additional dose.ClinicalTrials.gov, https://clinicaltrials.gov, CoronavRheum #NCT04754698.

Until now, researchers have not provided a well-defined muscle histological pattern for antisynthetase syndrome (ASSD). Therefore, we aimed to analyse the muscle biopsies of patients with anti-Jo-1 ASSD.This study included 26 patients with anti-Jo-1 ASSD admitted for investigation of the disease and obligatorily with muscle impairment, from 2010 to 2021, whose serial frozen muscle sections were analysed.Patients' mean age at disease diagnosis was 42.8±11.6 years, and the female gender was most predominant. Concerning muscle biopsies, cell infiltrates were present in 76.9% of the samples, and they were mainly located at the endomysium area (70%), with a predominance of macrophages (92.9%). Fiber muscle necrosis was present in 92.3% and was diffused in 54.2%. Expression of MHC-I was seen in all samples. Samples were mostly marked by the presence of CD68+ and discreet/low CD4+ and CD8+ staining, which is consistent with a higher predominance of observed necrosis and macrophage cell infiltrates. In general, 38.5% of patients had a necrotising myopathy pattern in muscle biopsies, whereas 34.6% and 26.9% had a general inflammatory myopathy pattern and nonspecific myopathy, respectively. This necrotising myopathy pattern was not associated with the demographic, clinical, or laboratory data.Our data show that almost 40% of patients with well-defined anti-Jo-1 ASSD with objective muscle impairment have a necrotising myopathy pattern in their muscle biopsies. Although this pattern is more classically related to immune-mediated necrotising myopathies, in association with clinical manifestations and the presence of anti-Jo-1 autoantibodies, this characteristic may lead to ASSD diagnosis.

This study aimed to investigate whether a single bout of exercise prior to the homologous booster dose of a SARS-CoV-2 inactivated vaccine (Sinovac-CoronaVac) could enhance immunogenicity in patients with dysfunctional immune system. This was a randomized controlled trial (1:1) within a single-arm, phase 4 vaccination trial, conducted in São Paulo, Brazil. Patients with spondyloarthritis assigned to the intervention group performed an exercise bout comprising three unilateral strength exercises involving eccentric and concentric contractions. After exercising, patients remained at rest for 1 h prior to vaccination, which was applied to the exercised arm. The control group remained at rest before vaccination. Immunogenicity was assessed before (Pre) and one month after (Post) the booster dose using seropositivity rates of total anti-SARS-CoV-2 S1/S2 IgG, geometric mean titers of anti-S1/S2 IgG (GMT), frequency of NAb positivity, and NAb activity. Before the booster dose, 16 patients from the exercise group and 16 patients from the control group exhibited seropositivity for IgG (59% vs. 57.1%), one month after the booster dose, seropositivity occurred in 96% vs. 100% of the cases (p = 0.84, group by time interaction). Only 10 patients from the exercise group and 12 patients from the control group showed positive NAb serology at Pre (37% vs. 42.8%). One month following the booster, NAb positivity was 96% vs. 93% (p = 0.41, group-by-time interaction). GMT was comparable between groups at Pre (p > 0.05). At Post, GMT increased similarly in both groups (exercise: 56.9%; control: 57.9%), with no group-by-time interaction (p = 0.82; estimated mean difference between groups at Post [EMD]: -40.4 UA/mL, 95%CI: -327, 246 UA/mL). Likewise, NAb activity was similar between groups at Pre and increased similarly in both of them as a result of the booster (47.5% vs. 39.9%), with no group-by-time interaction (p = 0.99; EMD: -6.19%, 95%CI: -17; 4.6%). In conclusion, a single bout of exercise did not enhance immunogenicity to a homologous booster dose of an inactivated SARS-CoV-2 vaccine among patients with spondyloarthritis. Studies assessing exercise as an adjuvant to first or second doses remain necessary.

We aimed to assess the safety and efficacy of transcranial direct current stimulation (tDCS) in patients with systemic autoimmune myopathies (SAMs).This prospective, randomised, sham-controlled, double-blind, study included 20 patients with SAMs allocated to receive sham or active tDCS (2mA, 20 minutes, 3 days). Electrodes were positioned with the anode over the C1 or C2, whereas the cathode was placed over the Fp2 or Fp1, respectively. The groups were evaluated in four periods with specific questionnaires and functional tests: pre-stimulation and after 30 minutes, three weeks, and eight weeks post-tDCS.Two patients from the sham group withdrew after the three sessions. The demographic data, type of myositis, disease duration, and disease status were comparable between the active and sham tDCS groups. After interventions, in the active tDCS group, the physical aspects of SF-36 in week eight, mean and better timed up-and-go test at each evaluation, peak torque of stimulated inferior limb extension improved significantly (p0.05). The emotional aspect of SF-36 decreased only in the active tDCS group (p0.001). The patients' adherence to the protocol was 100% and no serious adverse event was reported, including disease relapses.This study evidences the safety of tDCS, as well as its potential efficacy in improving muscle strength and function in SAMs patients. More studies with a larger sample and longer tDCS sessions are necessary to corroborate the results of the present study.

The determination of durability and vaccine-associated protection is essential for booster doses strategies, however data on the stability of SARS-CoV-2 immunity are scarce. Here we assess anti-SARS-CoV-2 immunogenicity decay and incident cases six months after the 2nd dose of Sinovac-CoronaVac inactivated vaccine (D210) in 828 autoimmune rheumatic diseases patients compared with 207 age/sex-balanced control individuals. The primary outcome is the presence of anti-S1/S2 SARS-CoV-2 IgG at 6 months compared to 6 weeks after 2nd vaccine dose for decay evaluation. Secondary outcomes are presence of neutralizing antibodies, percent inhibition by neutralizing, geometric mean titers and cumulative incident cases at 6 months after 2nd dose. Anti-S1/S2 IgG positivity and titers reduce to 23.8% and 38% in patients (p p p p

Objective: To evaluate inactivated CoronaVac prime vaccination, antibody decay, booster dose, and safety in ANCA-Associated Vasculitis (AAV) patients. Methods: Fifty-three AAV patients and 106 Controls (CG) received CoronaVac on days: D0 (first dose), D28(second dose), and D210 (booster dose, 32 AAV: 32 CG). The primary outcome was immunogenicity after the second vaccine dose (day 69) assessed by Seroconversion Rates (SC) of anti-SARS-CoV-2 S1/S2 IgG and Neutralizing Antibodies (NAb). Secondary outcomes were safety, immunogenicity (D28/D240), 6-months antibody decay (D210) and the booster dose response (D240). Results: At D69 SC (65.1% vs. 96.8%, p = 0.0001), GMT (21.3 UA/mL vs. 67.7 UA/mL, p < 0.001) and NAb- positivity (53.7% vs. 80.6%, p = 0.001) were moderate but lower in naïve-AAV patients than CG. Patients without SC used more often IS (93.3% vs. 53.3%, p = 0.015), mycophenolate mofetil (20% vs. 0%, p = 0.037) and prednisone (60.0% vs. 28.6%, p = 0.057) than seroconverted. NAb negativity in AAV patients was associated with prednisone treatment (57.9% vs. 18.2%, p = 0.015) and IS (84.2% vs. 55.0%, p = 0.046). Logistic regression analysis models showed that only prednisone was associated with lower seroconversion (OR = 0.2, 0,95% CI 0.05–0.86, p = 0.030) and with lower NAb positivity (OR = 0.2, 0,95% CI 0.05–0.88, p = 0.034). After six months (D69–D210) a decrease in IgG positivity occurred in 32 AAV patients (15.7%, p = 0.074) and 32 CG (18.7%, p = 0.041). For the NAb positivity, the 6-month decrease was not significant (p = 0.114) whereas a major reduction occurred for CG (p < 0.001). A booster dose (D240) resulted in an increment in IgG-positivity (21.9%, p = 0.023) and NAb-positivity (34.4%, p = 0.006) in AAV patients. No moderate/severe adverse events attributable to the vaccine were observed. Conclusion: This study provides novel data on the excellent safety and moderate immunogenicity of CoronaVac in AAV patients. A six-month mild antibody waning was observed with a good response to the booster dose, although levels remained lower than CG (CoronavRheum-NCT04754698).

To assess the body composition (BC) of patients with granulomatosis with polyangiitis (GPA) compared to healthy controls, emphasizing visceral adipose tissue (VAT) and associated BC parameters with disease activity, the damage index, and inflammatory parameters in patients with GPA.This study was conducted in 43 patients with GPA and 43 healthy controls matched by sex, age, and body mass index (BMI). BC was analyzed using dual-energy X-ray absorptiometry (DXA). The fat mass parameters evaluated were total fat mass (FM), adiposity (%), the fat mass index (FMI: fat mass/htComparing patients with GPA with healthy controls, patients had a significantly greater VAT (VAT in g: 685.81 ± 306.10 vs. 581.21 ± 235.57, p = 0.04; VAT in cmPatients with GPA have altered BC compared to healthy controls. Moreover, higher VAT was associated with disease activity and higher inflammatory markers, suggesting a relationship between GPA activity and adiposity parameters. Key points • Granulomatosis with polyangiitis patients have increased visceral adipose tissue when compared to health controls; • Granulomatosis with polyangiitis patients with higher values of visceral adipose tissue have worse disease activity and higher inflammatory markers; • This paper represents important contribution to the well-studied association between vasculitis and inflammatory markers, adding the role of adipose visceral tissue in the disease physiopathology.

Exercise seems to enhance the beneficial effect of bariatric surgery (RYGB) on insulin resistance. We hypothesized that skeletal muscle extracellular matrix (ECM) remodeling may underly these benefits. Women were randomized to either a combined aerobic and resistance exercise training program following RYGB or standard of care (RYGB). Insulin sensitivity was assessed by OGTT. Muscle biopsies were obtained at baseline, and 3 and 9 months after surgery and subjected to comprehensive phenotyping, transcriptome profiling, molecular pathway identification and validation in vitro. Exercise training improved insulin sensitivity beyond surgery alone (e.g., Matsuda index - RYGB: +123% vs. RYGB + ET: +325%; P ≤ 0.0001). ECM remodeling was reduced by surgery alone, with an additive benefit of surgery and exercise training (e.g., collagen I - RYGB: -41% vs. RYGB + ET: -76%; P ≤ 0.0001). Exercise and RYGB had an additive effect on enhancing insulin sensitivity, but surgery alone did not resolve insulin resistance and ECM remodeling. We identified candidates modulated by exercise training that may become therapeutic targets for treating insulin resistance, in particular, the transforming growth factor-beta 1/SMAD 2/3 pathway and its antagonist follistatin. Exercise-induced increases in insulin sensitivity after bariatric surgery are at least partially mediated by muscle extracellular matrix remodeling.

A high frequency of metabolic syndrome (MetS) has been recently described in different idiopathic inflammatory myopathies, but not in antisynthetase syndrome (ASS). Therefore, the aim of the present study was to determine the prevalence of MetS in ASS and also its possible association with cardiovascular the risk factors and ASS-related disease characteristics.A cross-sectional single centre study of 42 consecutive ASS patients was conducted from 2012 to 2015 and compared to 84 healthy individuals matched for gender, age, ethnicity and body mass index-matched (control group). MetS was defined according to the 2009 Join Interim Statement. Clinical and laboratory data were assessed according to a standardised protocol.ASS patients had a median age of 41.1 years with a predominance of female gender and white race. ASS patients had a higher frequency of MetS (42.9% vs. 13.1%; p0.001) as well as of insulin resistance than controls. Moreover, ASS patients had higher resistin, lower leptin and similar adiponectin levels in serum than controls. Further analysis of ASS patients with (n=18) and without (n=24) MetS revealed that older age at disease onset (48.7 vs. 35.4 years; p0.001) was identified in those with the syndrome but were similar regarding disease duration, disease status, treatment, insulin resistance and serum adipocytokine levels.The prevalence of MetS was high in ASS patients that also had serum resistin and low leptin levels. As also identified in other idiopathic inflammatory myopathies, MetS in ASS is more prevalent in older patients.

To evaluate leflunomide as an adjuvant drug in refractory dermatomyositis (DM) with primarily cutaneous activity.A retrospective, single-centre, cohort study including 18 adult patients with DM (classical or clinically amyopathic DM) and cutaneous activity from 2001 to 2016 was conducted. Patients were dependent on glucocorticoid and refractory to at least two full-dose immunosuppressants/immunomodulators or presented previous adverse events with immunobiological drugs. One immunosuppressant was maintained and leflunomide added to the treatment. Patients were followed for six consecutive months.Leflunomide proved effective and safe in 12 (66.6%) out of the 18 patients. There was total control of cutaneous activity and prednisone was tapered from 17.5 to 6.0 mg/day (p0.001). In addition, two of these patients that also had muscle involvement improved muscle strength after leflunomide treatment. Side effects or inefficacy were observed in six patients. There were no cases of serious infection or death.Leflunomide therapy appears to be effective and safe as an adjuvant drug in refractory DM with primarily cutaneous activity. Further studies are needed to confirm this data.

To investigate the effects of acute and chronic exercise in female patients with remissive Takayasu arteritis (TAK).This was a 2-part prospective study. In study 1, cytokines and soluble tumor necrosis factor (TNF) receptors were assessed at rest and every 60 minutes during a 3-hour recovery period following an acute exercise session in TAK (n = 11) and heathy control (n = 10) groups. In study 2, a subsample from the TAK group (n = 6) underwent a 12-week exercise training program. Before and after training, the acute session of aerobic exercise was performed and cytokines and soluble TNF receptors were assessed at the same time points described above. Muscle function, strength, aerobic capacity, endothelial function, quality of life, and walking impairment scores were evaluated.In study 1, the acute session of aerobic exercise led to overall similar responses on cytokine kinetics in the TAK and heathy control groups. In study 2, the exercise training program did not exacerbate inflammatory cytokines in TAK patients, while the proinflammatory cytokine TNF was diminished both at rest and following the acute session of aerobic exercise. In addition, the exercise training program increased the pro-angiogenic factors vascular endothelial growth factor (at rest) and platelet-derived growth factor AA (at rest and in response to the acute session of aerobic exercise). The exercise training program improved muscle strength and function, whereas aerobic capacity, quality of life, and endothelial function parameters remained unchanged.Exercise could be a well-tolerated, safe, and effective intervention able to induce immunomodulatory and pro-angiogenic effects and to increase strength and function in patients with TAK.

BACKGROUND / OBJECTIVES: Hyaluronic acid (HA) is rarely described in dermatomyositis (DM). Thus, we determined any clinical association of serum levels of hyaluronic acid (HA) in patients with dermatomyositis (DM).This cross-sectional single-center analysis 75 DM and 75 healthy individuals, during the period from January 2012 to July 2013. An anti-HA antibody assay was performed using specific ELISA/EIA kits, according to the manufacturer's protocol.The patients with DM and control subjects had comparable demographic distributions (p0.05). The median time duration between disease diagnosis and initial symptoms was 6.0 [3.0-12.0] months, with a median DM disease duration of 4.0 [1.0-7.0] years. The median level of serum HA was significantly increased in patients with DM compared to the control group [329.0 (80.0-958.0) vs. 133.0 (30.0-262.0) ng/mL, respectively; p0.001]. Additional analysis involving patients with DM showed that the serum level of HA did not correlate with age, duration between disease diagnosis and initial symptoms, disease duration, disease status, serum muscle enzyme levels or cumulative prednisolone dose (p0.05). Serum HA also did not correlate with gender, ethnicity, auto-antibodies or drug use (p0.05), but did correlate with cutaneous features, such as photosensitivity (p=0.001), "shawl" sign (p=0.018), "V-neck" sign (p=0.005) and cuticular hypertrophy (p=0.014).A high level of serum AH was observed in DM compared to healthy individuals. In DM, HA did not correlate to demographic, auto-antibodies and therapy parameters. However, HA correlated specifically with some cutaneous features, suggesting that this glycosaminoglycan could be involved in modulating cutaneous inflammation in this population. More studies are necessary to understand the correlation between AH and patients with DM.

Polymyositis (PM) is a rare systemic idiopathic inflammatory myopathy. Hyaluronic acid (HA) is closely linked to inflammatory cellular reactions and disease activity. Increased serum levels of HA have been reported in several inflammatory diseases, but currently, there are no studies analysing the HA in PM. Thus, clinical association of HA with PM in patients was determined in the present study.The present cross-sectional study was performed at one centre from 2012 to 2013 and included 35 consecutive adult patients with PM (Bohan and Peter criteria, 1975) and 38 adult healthy volunteers. The serum HA was assessed with anti-HA antibody, using the specific ELISA/EIA kits according to the manufacturer's protocol.The average age, distribution of females and ethnicity were comparable in patients with PM and the control group. Regarding disease status, patients with PM had a median patient visual analogue score (VAS) of 2 [0-6], physician VAS of 1 [0-3], MMT-8 of 74 [68-80] and HAQ of 0.48 [0.00-1.14]. The serum levels of HA were also significantly increased in patients with PM (390±412 ng/mL) compared to healthy subjects (129±119 ng/mL), p=0.001. In an additional analysis, the serum levels of HA did not correlate with PM demographic data (gender and ethnicity), current organ involvement or autoantibodies and were not been influenced by the use of prednisolone and/or immunosuppressives by the PM patients. However, there was a positive correlation between serum levels of HA and VAS (patient and physician), and a negative correlation between serum levels of HA and MMT-8.High serum levels of HA were observed in patients with PM and tended to correlate with PM disease activity. Additional studies are needed to assess this correlation, as well as to understand the mechanism involved in the pathogenesis of PM by HA.

The aim of the study was to evaluate the effect of the prior use of corticosteroids (CS) on the presence of inflammatory infiltrates (InI) in muscle biopsies of polymyositis (PM).We retrospectively evaluated 60 muscle biopsy samples that had been obtained at the time of the diagnosis of PM. The patients were divided into three groups according to the degree of the InI present in the muscle biopsies: (a) minimal InI present only in an interstitial area of the muscle biopsy (endomysium, perimysium) or in a perivascular area; (B) moderate InI in one or two areas of the interstitium or of the perivascular area; and (C) moderate InI throughout the interstitium or intense inflammation in at least one area of the interstitium or of the perivascular area.The three groups were comparable regarding the demographic, clinical and laboratory features (p0.05). Approximately half of the patients in each group were using CS at the time of the muscle biopsy. The median (interquartile) duration of CS use [4 (0-38), 4 (0-60) and 5 (0-60) days: groups A, B and C, respectively] and the median cumulative CS dose used [70 (0-1200), 300 (0-1470) and 300 (0-1800)mg] were similar between the groups (p0.05).Previous CS use did not influence the presence or the degree of InI found in muscle biopsies in PM with clinical and laboratory disease activity. Our study showed that muscle biopsies should be performed this population, even in individuals who have already been taking CSs.

To assess ovarian reserve markers and anti-corpus luteum (anti-CoL) antibodies in dermatomyositis (DM) patients.Forty female DM patients were invited to participate. Exclusion criteria included hormonal contraceptive use within the last six months, neoplasia associations, overlapped systemic autoimmune diseases, current pregnancy, gynaecological surgery and individual choice not to participate. The final experimental group for this cross-sectional study included 16 DM patients and 23 healthy controls, each of whom was evaluated during the early follicular phase of the menstrual cycle. Values for IgG anti-CoL (via immunoblotting), follicle stimulating hormone (FSH), estradiol, inhibin B, anti-Müllerian hormone (AMH) serum levels (via ELISA) and sonographic antral follicle count (AFC) were determined.DM patients and controls were of comparable mean age (p0.05). The mean age of DM onset was 29.1±4.7 years, with disease duration of 5.6±3.2 years. Menstrual cycle characteristics, comorbidity and lifestyle were similar amongst patients in both groups (p0.05). AMH values of ≤1ng/mL (p=0.027) and AFC values (p=0.017) were significantly reduced in DM patients relative to the control group, whereas serum estradiol levels (p0.001) were higher in DM patients compared to controls. In contrast, serum FSH and inhibin B levels, ovarian volumes, and anti-CoL antibody frequency were similar in both groups. Differences in AFC and estradiol were determined to be significant following Bonferroni correction for multiple testing.We identified a diminished ovarian reserve in DM patients of reproductive age. Further studies are necessary to assess the idiopathic inflammatory myopathy-related factors involved in the ovarian impairment of this patient population.

This paper presents characteristics of optimal routing that assigns each arriving packet to one of two heterogeneous parallel servers, each with its own queue. The characteristics are derived from numerical solutions to an optimization problem, which is to find optimal routing that minimizes the average packet delay under the condition that all of the packets' arrival times as well as all of the packets' sizes are completely known in advance. There are four characteristics: (1) Under light or moderate traffic, the average packet delay of optimal routing is almost the same as that of join the shortest delay (JSD) policy. (2) Under heavier traffic, optimal routing comes to more often use fix queue based on size (FS) policy. (3) Under heavy traffic, optimal routing assigns small packets to the slower server. (4) As the ratio of the slower server's service rate to the faster server's service rate decreases, optimal routing comes to more often use FS policy under light or moderated traffic. These characteristics are verified by the fact that a mimic optimal routing designed based on the four characteristics attains almost the same performance as optimal routing.

The problem of obtaining the material systems with more enhanced material constants characterizing physical property is considered within the framework of Suh's theory of design. The design problem is to find the mapping between the functional requirements (FR) and the design parameters (DP). The material parameters (the design parameters) for the material design are unable to move freely. Thus, our strategy is to substantially decrease the number of design parameters and to learn which directions to move the design parameters in order to efficiently enhance the material constants. To accomplish, we study the mathematical properties of the relationship, called design function, between the FRs and the DPs to find the decomposition property. The decomposition has several effective properties. We apply our method to a special case where the third-order nonlinear optical susceptibility is enhanced. We also discuss some methods for moving the material parameters as well as the scope of problems where the concept of decomposition seems to be effective.

This paper proposes a strategy of designing routing algorithms for connectionless packet-switched networks. This strategy consists of three design elements as follows: [A] the notion of ideal routings is introduced to provide the upper performance limits attained by improving routing algorithm and it serves as a standard to measure the performance of other algorithms; [B] a method of constructing simple algorithms is presented under implementation conditions from ideal routings; [C] a method is described to enhance the performance limits of [A]. By using these elements, simple algorithms with a maximum degree of performance attainment are realized. By "degree of performance attainment", we mean that we can see how much room is left for the improvement of algorithms. We develop [A] and [B] with the performance measures of throughput and average packet delay and the M/M/1 queuing network. We decide ideal static routings and their performance limits from [A]. We obtain a new simple algorithm from [B] based on the notion of the ideal routings in implementation conditions. The designed algorithm improves the throughput and the average delay, which are comparable to those from ideal static routings. This improvement is contrasted to the adaptive and distributed OSPF (Open Shortest Path First), a standard Internet routing protocol.

Takayasus arteritis (TA) is a systemic vasculitis whose clinical presentation varies from asymptomatic to serious neurovascular events, including stroke. However, few studies are currently available assessing stroke in TA. Thus, we described the clinical and laboratory characteristics and vascular imaging features in patients with TA at the time of stroke.This is a single center retrospective cohort study investigating the clinical and demographic data of 18 (15.0%) patients with a history of stroke confirmed by imaging methods, among 120 patients with TA, assessed in the 1985-2012 period.The mean age of the 18 patients at the time of stroke was 29.4+/-10.9 years, with 94.4% female and 88.9% Caucasian. Of these patients, 14 (77.8%) had previous stroke at diagnosis of TA, while in four cases the stroke occurred after confirmed TA diagnosis. Regarding the clinical course, 12 (66.7%) had peripheral neurological sequelae and one patient died as a result of cerebral hyperperfusion syndrome after carotid revascularization.Our results showed a high prevalence of stroke in TA and revealed most of these events occurred concomitantly with diagnosed TA. Moreover, although four patients had strokes after diagnosis of TA, these occurred at a young age, demonstrating they were most likely the result of vascular changes secondary to TA.

To describe a series of 30 consecutive patients with inclusion body myositis (IBM) from our tertiary center, from 1982 to 2012.All patients fulfilled the criteria of Griggs et al. (1995) for IBM.The mean age of patients at disease onset was 60.8 � 11.9 years with disease duration of 8.0 � 5.2 years. Eighty % of patients were Caucasian, with similar distribution between genders. Weight loss in early disease was present in less than a quarter of cases. The main symptom was proximal weakness of the lower limbs followed by weakness of the upper (proximal and/or distal) limbs. One third of patients had dysphagia, whereas dysphonia was present in 16.7%, arthralgias in 6.7%, moderate dyspnea symptoms in 3.3% of cases. All patients received prednisone (1mg/kg/day). Several immunosuppressives were used as corticosteroid-sparing according to tolerance, side effects and/or refractoriness. Half of the patients still in follow-up remained stable according to clinical and laboratory data during the study. There were four cases of cancer, four cases associated with viral infections (HIV and hepatitis C virus) and three deaths (two because of sepsis secondary to community bronchopneumonia, and one because of congestive heart failure).This is the first Brazilian series of cases involving large sample of IBM. The profile of the patients analyzed in this study was comparable to those profiles described in literature, except that of IBM cases of our population are equally distributed in both genders and the interval between symptoms onset and diagnosis of the disease was relatively short. It is relevant to note the high frequency of neoplastic diseases and chronic viral infections in our population, reinforcing the need for specific epidemiological studies to verify these associations, once it is poorly described in the literature.

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that are associated with increased cardiovascular diseases (CVD). MetS has been systematically evaluated in all systemic autoimmune rheumatic diseases except for polymyositis (PM). This study aimed to evaluate the frequency of MetS in PM patients and analyse the possible association of MetS with traditional risk factors of CVD and PM-related clinical and laboratory features.The present cross-sectional, single-centre study included 35 consecutive PM patients (Bohan and Peter, 1975) and 70 healthy controls. MetS diagnosis was determined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII).The age, gender and ethnicity distributions between the PM and control groups were comparable (p0.050). The median PM disease duration was 5 years. Compared with healthy subjects, PM patients had higher prevalence of MetS (45.7% vs. 20.0%, p=0.011). In an additional univariate analysis of PM patients with (n=26) and without (n=19) MetS revealed that patients with this complication were older (56.1±7.8 vs. 44.3±12.8 years; p=0.002) with more cumulative prednisolone doses, higher scores on the health assessment questionnaire and on the physician visual analogue scale (p0.050). Disease duration was comparable between both groups (p0.050).MetS and CVD risks are highly prevalent in PM. Monitoring for and early treatments of modifiable risk factors for CVD in PM patients are necessary.

System-in-silicon (SiS) is a multi-chip architecture to realize wide bandwidth communication between logic and memory with low power. The application of SiS to H.264/AVC motion estimation is presented. DRAM is integrated with 23.1 Gb/s bandwidth and 1.6pJ/b data transfer efficiency, realizing real-time 1080HDTV processing with 263.1GB/s. The authors present a system-in-silicon architecture with 1024b inter-chip bus to provide high-bandwidth low-power connectivity between logic and memory. The highly parallel architecture also allows low frequency (25MHz) operation while achieving real-time motion estimation for 1080HDTV. The solution achieves the required 23.1 Gb/s bandwidth and associated processing for motion estimation at a power level of 190mW

The smoking habit is influenced by culture, psychological traits and physical factors. Recent studies on genetic polymorphisms have demonstrated that functional polymorphisms pertaining to neurotransmitters may affect smoking behavior, as well as psychological parameters and diseases. Our recent study demonstrated the interleukin (IL)-1B gene encoding IL-1b, a pro-inflammatory cytokine, to be associated with smoking; Japanese with the IL-1B C-31T T/T genotype, an inflammation-prone trait, were less likely to be smokers than those with IL-1B C-31T C/C (J Epidemiol 2001;11:120-125). This indicates that genetically determined biochemistry may also be an important factor for smoking behavior. We have investigated this association in another population, 963 Japanese Brazilians (399 males and 564 females) aged 33-69 years from Curitiba, Mogi das Cruzes, and Mirandopolis in Brazil. Current smokers were 15.3% among males and 11.6% among females. The sex-age-adjusted odds ratio (OR) for the polymorphism in males was around unity. In females, the adjusted OR of being current smokers vs. non-current smokers was 0.68 (95% confidence interval, 0.32-1.45) for the T/T genotype relative to the C/C genotype, and the adjusted OR of being ever smokers vs. never smokers was 0.85 (0.46-1.58). Significant reduction in the OR was not observed for either males or females with the T/T genotype. Although the inconsistent result could be caused by random variation, effect dilution caused by incorporation of a group with a smoking-free culture is a possible reason for the apparent anomaly. The effect of dilution may thus have to be taken into consideration, especially for studies on the smoking habit and genetic polymorphisms.

We use the Hamiltonian algorithm to quickly align optical axes that must be precisely positioned with multiple degrees of freedom when coupling optical devices. The Hamiltonian algorithm utilizes the mixing properties of a dynamical system and efficiently searches for the global minimum of the objective function in an optimization problem. Simulations show the mixing effects when searching for the global minimum. Coupling fiber experiments show that using this algorithm optical axes with multiple degrees of freedom can be aligned efficiently and that several fibers can be aligned in parallel. The practicality of our technique is also shown by experimentally coupling array fibers.

The paper describes the characteristics of an optimal routing that assigns each arriving packet to one of two heterogeneous parallel servers. The characteristics are derived from numerical solutions to a routing problem, which finds an optimal routing that minimizes the average packet delay under the condition that the input traffic is completely deterministic. Four characteristics are presented: (1) under light or moderate traffic, the average packet delay of the optimal routing is almost the same as that of the join the shortest delay (JSD) policy; (2) as traffic becomes heavier, the optimal routing more often uses the fix queue based on size (FS) policy; (3) under heavy traffic, the optimal routing assigns small packets to a slower server; (4) as the ratio of the two servers' service rates C/sub 1//C/sub 2/ (C/sub 1//spl les/C/sub 2/) decreases, under lighter traffic the optimal routing uses the FS policy. A new adaptive routing policy based on these four characteristics outperforms the JSD policy.

Heparin and heparan sulfate fragments, obtained by bacterial heparinase and heparitinases, bearing an unsaturation at C4-C5 of the uronic acid moiety, are able to produce up to 80% reduction of the cytosolic calcium of smooth muscle cell lines. Unsaturated disaccharides from chondroitin sulfate, dermatan sulfate, and hyaluronic acid are inactive, indicating that, besides the unsaturation of the uronic acid, a vicinal 1 --4 glycosidic linkage is needed. An inverse correlation between the molecular weight and activity is observed. Thus, the ED(50) of the N-acetylated disaccharide derived from heparan sulfate (430 Da) is 88 microm compared with 250 microm of the trisulfated disaccharide (650 Da) derived from heparin. Except for enoxaparin (which contains an unsaturation at the non-reducing end and 1 --4 glycosidic linkage), other low molecular weight heparins and native heparin are practically inactive in reducing the cytosolic calcium levels. Thapsigargin (sarcoplasmic reticulum Ca(2+)-ATPase inhibitor), vanadate (cytoplasmic membrane Ca(2+)-ATPase inhibitor), and nifedipine and verapamil (Ca(2+) channel antagonists) do not interfere with the effect of the trisulfated disaccharide upon the decrease of the intracellular calcium. A significant decrease of the activity of the trisulfated disaccharide is observed by reducing extracellular sodium, suggesting that the fragments might act upon the Na(+)/Ca(2+) exchanger promoting the extrusion of Ca(2+). This was further substantiated by binding experiments and circular dichroism analysis with the exchanger inhibitor peptide.

A 66-year-old woman presented with exertional dyspnea and productive cough. Chest radiography showed ground glass opacities and patchy infiltrates in both lungs. After confirmation of pulmonary alveolar proteinosis by bronchoalveolar lavage, she underwent conventional whole-lung lavage with slight improvement, with the aid of a partial extracorporeal circulation. After aggravation for one year, a modified lavage technique using high-frequency jet ventilation was used, and persistent improvement in oxygenation was achieved. We believe that this modified technique could be a useful method for pulmonary alveolar proteinosis.