Myositis-specific and myositis-associated autoantibodies in Indian patients with inflammatory myositis

We aimed to study the prevalence and clinical associations of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) in a large cohort of Indian patients with idiopathic inflammatory myositis (IIM). Clinical details and serum samples were collected from patients with IIM (satisfying Bohan and Peter Criteria, 1975) and CTD-associated myositis. Sera were analysed for antibodies against SRP, Mi2, Jo1, PL7, PL12, EJ, OJ, Ro52, Ku, Pm-Scl 75 and PM-Scl 100, using immunoblot assay. The cohort comprised 124 patients with IIM (M:F = 1:3.6). Fifty-five of them had dermatomyositis (DM), 22 had juvenile dermatomyositis (JDM), 25 had polymyositis (PM) and 22 had connective tissue disease-associated myositis (CTD myositis). Mean disease duration was 10.9 months. ANA was positive in 84 (68.9 %), and MSAs in 61 (49.2 %) patients. Among MSAs, autoantibodies to Mi2, synthetase (Jo1, PL7, PL12, EJ) and SRP were present in 26 (20.9 %), 29 (23.4 %) and 6 (4.8 %) patients, respectively. Prevalence of MAAs was as follows: antibodies to Ro52 in 45 (36.3 %), Ku and PM-Scl 75 in 13 (10.5 %) and PM-Scl 100 in 5 (4 %) patients. Anti-Mi2 antibodies were positively associated with DM (21/55, 38.2 %; p < 0.0001) and pharyngeal weakness (13/34, 38.2 %; p = 0.004) and negatively associated with ILD (0/28; p = 0.001). ILD and mechanics’ hands were significantly more in patients with anti-synthetase antibodies (16/28, 57 % and 14/22, 63.6 %; p < 0.0001). Four of six patients with anti-SRP antibody showed poor response to multiple drugs. Higher prevalence of anti-Mi2 is probably related to higher proportion of patients with DM. Absence of ILD in patients with anti-Mi2 antibody suggests that it may protect against ILD. In Indian population also, anti-synthetase antibodies are associated with ILD, and anti-SRP antibodies with poor response to treatment.     

The clinical utility of serum IL-35 in patients with polymyositis and dermatomyositis

The objectives of this study are to assess the levels of serum Interleukin-35 (IL-35) in patients with idiopathic inflammatory myopathies (IIMs) and to evaluate the association between IL-35 levels and IIM-related features. Serum IL-35 was detected in 76 patients with dermatomyositis (DM), 28 patients with polymyositis (PM), 98 disease controls (40 rheumatoid arthritis (RA), 34 systemic lupus erythematosus (SLE), 12 systemic sclerosis (SSc), and 12 sjogren syndrome (SS)), and 43 healthy controls by ELISA. Follow-up was conducted on 34 patients. Serum IL-35 was higher in myositis (PM/DM) patients than in healthy controls (median 76.6 pg/ml [interquartile range (IQR) 57.9–136.2] vs. 29.9 pg/ml (IQR 21.9–65.5), P < 0.001) and disease controls. Serum IL-35 in IIM patients negatively correlated with disease duration moderately (r = ?0.35, P < 0.01). Patients with dysphagia had higher IL-35 than those without (median149.35 pg/ml (IQR 87.97–267.32) vs. 70.72 pg/ml (IQR 54.49–123.42), P = 0.001). Cross-sectional correlation analysis showed a weak positive correlation between serum IL-35 and CK (r = 0.293, P = 0.003), moderate positive correlation with erythrocyte sedimentation rate (ESR) (r = 0.304, P = 0.002), serum ferritin (SF) (r = 0.467, P = 0.001) and LDH levels (r = 0.401, P < 0.001). Additionally, serum IL-35 was higher in patients who were positive for anti-HMGCR (median 292.04 pg/ml (IQR 67.9–442.86) vs. 74.66 pg/ml (IQR 57.24–131.32), P = 0.038) and anti-SRP antibody (median 130.33 pg/ml (IQR 88.04–481.28) vs. 73.06 pg/ml (IQR 56.78–134.28), P = 0.009) than in negative patients, respectively. Follow-up study showed that changes in IL-35 levels after treatment correlated with changes in MYOACT scores moderately (r = 0.375, P = 0.029). These data indicate that increased serum IL-35 could act as a disease activity marker and as a risk factor for esophageal involvement in IIM. IL-35 may participate in the pathophysiological processes of IIM, but it still needs further study to confirm.     

Abnormally increased low-density granulocytes in peripheral blood mononuclear cells are associated with interstitial lung disease in dermatomyositis

Objective: We previously found that neutrophil extracellular traps (NETs) were associated with interstitial lung disease (ILD) in dermatomyositis (DM) patients. However, it is unclear whether low-density granulocytes (LDGs), endowed with enhanced NET formation capabilities, contribute to the pathogenesis of ILD. This study aims to elucidate the relationship between LDGs and DM-associated ILD.

Methods: We recruited 48?DM patients (28 with ILD) as well as 19 healthy volunteers for this study. The percentage of LDGs in peripheral blood mononuclear cells (PBMCs) was ascertained by flow cytometry. Plasma cfDNA was measured by using the Quant-iT PicoGreen dsDNA Kit and plasma LL-37 was tested by using the LL-37 ELISA kit.

Results: The percentage of LDGs was 7.1 times higher in DM patients than in healthy controls. LDG percentage was 2.7 times higher in DM patients with ILD than in DM patients without ILD. Additionally, LDG percentage positively correlated with MYOACT lung disease activity scores, and NET/neutrophil-related marker levels (LL-37, cfDNA, MPO, and MMP-8) in the DM group were significantly higher than those in the control group.

Conclusion: The abnormal increase of LDGs may exacerbate abnormal NET regulation and further contribute to the pathogenesis of ILD in DM patients by abnormally forming NETs.     

ADAM-17 is expressed in the inflammatory myopathy and is involved with interstitial lung disease

The “A disintegrin and metalloprotease” (ADAM) family is thought to play an important role in tissue destruction and inflammatory reactions. ADAM-17 was first described as the protease responsible for tumor necrosis factor (TNF)-α shedding. Here, we have shown the expression of ADAM-17 in inflammatory myopathy and demonstrated the role of inflammation in interstitial lung diseases (ILD). ADAM-17 in inflammatory myopathy serum [polymyositis (n?=?26), dermatomyositis (n?=?34), and clinically amyopathic dermatomyositis (n?=?10)] and healthy control (n?=?19) was measured using enzyme-linked immunosorbent assay. The relationship between ADAM-17 and clinical data was examined. Finally, we performed immunohistological analysis to investigate the expression of ADAM-17 on the muscles of the inflammatory myopathy patients. ADAM-17 in inflammatory myopathy was significantly higher than that in healthy control (mean ± SEM, 1048?±?312 and 36?±?18 pg/ml, respectively; p?<?0.05). ADAM-17 in post-treatment with corticosteroid and/or immunosuppressant serum was significantly decreased compared with that in pre-treatment serum (1465?±?562 and 1059?±?503 pg/ml, respectively; p?<?0.01). ADAM-17 was significantly positively correlated with fractalkine/CX3CL1 and CXCL16. In addition, ADAM-17 in inflammatory myopathy with ILD patients (n?=?46) was significantly higher than that in non-ILD patients (n?=?24) (1379?±?454 and 413?±?226 pg/ml, respectively; p?<?0.05). We found the expression of ADAM-17 on muscle biopsy tissue. ADAM-17 is expressed in inflammatory myopathies especially ILD, suggesting that ADAM-17 plays a role in lung fibrosis. ADAM-17 may be a potential target in inflammatory myopathies with ILD.     

Anti-MDA5 Antibody Spectrum in Western World

Purpose of Review

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) is a novel and highly specific myositis-associated autoantibody, which defines a unique phenotype among patients with dermatomyositis (DM).

Recent Findings

Anti-MDA5 was originally characterized in Japan in DM patients with hallmark cutaneous features and no proximal muscle weakness and termed clinically amyopathic DM (CADM). Anti-MDA5 has characteristic cutaneous manifestations which include tender palmar papules and cutaneous ulcerations, along with an increased frequency of interstitial lung disease (ILD) that can be rapidly progressive (RPILD) and fatal.

Summary

This review will highlight the clinical significance of anti-MDA5 autoantibodies in Caucasian DM patients.

     

Lack of correlation between platelet reactivity and glycaemic control in type 2 diabetes mellitus patients treated with aspirin and clopidogrel

The relationship between glycaemic control and platelet reactivity in patients with type 2 diabetes mellitus (DM) on dual antiplatelet therapy is still unclear. A total of 155 consecutive stable angina patients with type 2 DM scheduled for elective percutaneous coronary intervention (PCI) were recruited. All patients were taking aspirin and received a 600-mg loading dose of clopidogrel at least 12 h before intervention. Platelet reactivity was assessed prior to PCI using the VerifyNow^® device (Accumetrics Inc., San Diego, California). High platelet reactivity on clopidogrel (HPR_Clopidogrel) was defined as a PRU value ≥240. HPR on aspirin (HPR_Aspirin) defined as an ARU value ≥550. Poor glycaemic control was defined as a HbA1C value >7 mg/dL. There was no significant difference in either PRU or ARU values in patients with poor glycaemic control compared to those with good glycaemic control (PRU: 230 ± 92 vs. 228 ± 110, P = 0.90; ARU: 440 ± 63 vs. 435 ± 60, P = 0.61). Patients with and without poor glycaemic control did not show significantly different prevalence of HPR_Aspirin (8 vs. 6%; P = 0.23) or HPR_Clopidogrel (46 and 44%; P = 0.80). There was no significant correlation found between HbA1C and either ARU values (r = 0.040, P = 0.71) or PRU values (r = 0.018, P = 0.87). Overall these data suggest that glycaemic control does not appear to influence platelet reactivity in patients with type 2 DM following a loading dose of 600 mg of clopidogrel and aspirin treatment.     

The relationship of nitric oxide synthesis capacity,oxidative stress,and albumin-to-creatinine ratio in black and white men: the SABPA study

Inadequate substrate availability and increased nitric oxide synthase inhibitor levels attenuate nitric oxide (NO) synthesis, whereas increased vascular oxidative stress may lead to inactivation of NO. We compared markers of NO synthesis capacity and oxidative stress in a bi-ethnic male population. Inter-relationships of ambulatory blood pressure and urinary albumin-to-creatinine ratio with NO synthesis capacity and oxidative stress markers were investigated. NO synthesis capacity markers (L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)) and oxidative stress markers (serum peroxides, total glutathione, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase) were measured. Black men displayed higher blood pressure and albumin-to-creatinine ratio (all p < 0.001), while NO synthesis capacity was more favorable (higher L-arginine and lower ADMA (p ≤ 0.003)). Antioxidant enzyme activities were similar except for the redox status markers (GR activity and GR/GPx ratio), which were upregulated in black men (p < 0.001). In black men, ADMA was inversely related to GPx activity (R ² = 0.15; β = ?0.20; p = 0.050) and GPx/SOD ratio (R ² = 0.24; β = ?0.37; p < 0.001), but none of these markers related to blood pressure or albumin-to-creatinine ratio. In white men, albumin-to-creatinine ratio was positively associated with ADMA (R ² = 0.18; β = 0.39; p < 0.001) while ADMA was inversely related to GR activity (R ² = 0.26; β = ?0.29; p = 0.002) and GR/GPx ratio (R ² = 0.25; β = ?0.28; p = 0.003). Black men with elevated blood pressure and albumin-to-creatinine ratio displayed a favorable NO synthesis capacity. This may be counteracted by increased inactivation of NO, although it was not linked to vascular or renal phenotypes. In white men, reduced NO synthesis capacity may lower NO bio-availability, thereby influencing the albumin-to-creatinine ratio.     

Diagnostic approach to neurotransmitter monoamine disorders: experience from clinical,biochemical, and genetic profiles

Background and aim

To improve the diagnostic work-up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns.

Methods

Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified.

Results

We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folate metabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2-IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post-traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non-genetic etiologies (n = 3) were also identified.

Conclusion

We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.

     

Predictors of changes in disease activity among children with juvenile dermatomyositis enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry

Determinants of changes in disease activity among patients with juvenile dermatomyositis (JDM) are unknown. Our objective was to develop predictive models to predict changes in disease activity using the CARRA Legacy Registry. The CARRA Legacy Registry included 658 subjects with definite or probably JDM with 297 subjects with a one follow-up visit after baseline, and we studied the 65 subjects with active disease at baseline. Linear regression models were used to build risk scores for changes in disease activity adjusted for baseline disease activity, age, sex, and disease duration. Disease activity improved from baseline to 6-month follow-up as measured by patient/parent global health score (median 4; p = 0.008), patient pain score (median 2; p = 0.014), physician global (median 4; p < 0.001), and Childhood Myositis Assessment Scale (CMAS) (median 41, p < 0.001). Anti-nuclear antibodies (p = 0.013) and hydroxychloroquine use (p = 0.045) were significant predictors of less improvement in patient/parent global and baseline patient/parent global. Anti-nuclear antibodies (p = 0.001) and V/shawl sign (p = 0.005) were significant predictors of less improvement in patient pain (R-square improved from 0.29 for adjustors alone to 0.46 for the full model). Small joint arthritis (p < 0.01) predicted less improvement and dysphagia/dysphonia (p = 0.033) predicted greater improvement in CMAS and baseline CMAS (R-square improved from 0.73 for adjustors alone to 0.86 for the full model). Disease characteristics can help identify patients who are less likely to improve over time. Risk scores to predict future changes in disease activity could be used to trigger more aggressive treatment earlier in the disease course.     

Cardiovascular risk assessment in patients with rheumatoid arthritis: a correlative study of noninvasive arterial health testing

This study aimed to determine the relationship between noninvasive measures of arterial health and both estimated 10-year cardiovascular risk and measures of disease activity over time in established rheumatoid arthritis. Fifty rheumatoid arthritis patients underwent noninvasive arterial health testing (brachial artery reactivity, aortic augmentation index [AIx], pulse wave velocity, carotid artery intima-media thickness, and carotid artery plaque presence) and assessment of clinical disease activity (tender or swollen joint counts, Clinical Disease Activity Index [CDAI], and Health Assessment Questionnaire II [HAQ-II]). Clinical measures during 3 years before the study visit were averaged. Arterial health testing was compared with the American Heart Association/American College of Cardiology (AHA/ACC) Pooled Cohort Equation. Spearman methods identified correlations between disease activity measures, cardiac biomarkers, and arterial health parameters. Among the patients (mean age, 57.5 years), disease activity was moderate (mean [SD] CDAI, 16.9 [15.3]). At the study visit, corrected aortic augmentation index correlated with CDAI (r = 0.37, P = .009) and HAQ-II (r = 0.33, P = .02). AIx correlated with time-averaged tender joint count (r = 0.37, P = .008), CDAI (r = 0.36, P = .01), HAQ-II (r = 0.36, P = .01), swollen joint count (r = 0.36, P = .10), patient global assessment (r = 0.33, P = .02), physician global assessment (r = 0.35, P = .01), and pain score (r = 0.38, P = .007). The AHA/ACC low-risk group (<5% 10-year risk) had highest prevalence of carotid plaques. Arterial health testing may identify increased risk of cardiovascular disease compared with risk obtained through AHA/ACC Pooled Cohort Equation. Measures of arterial stiffness correlate with the burden of disease activity over time.     

Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of <Emphasis Type="Italic">PDGFRB</Emphasis> in chronic or blast phase

We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20–80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×10⁹/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0–13)?. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3–34) and 19 months (range 7–110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1–135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia, (c) presentation in chronic or blast phase, (d) rapid responses and long-term remission on low-dose imatinib, and (e) possible adverse prognostic impact of a complex karyotype.     

Correlations of the changes in bioptic findings with echocardiographic,clinical and laboratory parameters in patients with inflammatory cardiomyopathy

Patients with myocarditis and left ventricular (LV) dysfunction may improve after standard heart failure therapy. This improvement seems to be related to retreat of myocardial inflammation. The aim of the present study was to assess changes in clinical, echocardiographic and some laboratory parameters and to correlate them with changes in the number of inflammatory infiltrating cells in endomyocardial biopsy (EMB) samples during the 6-month follow-up, and to define predictors of LV function improvement among baseline parameters. Forty patients with biopsy-proven myocarditis and impaired LV function (LV ejection fraction—LVEF <40 %) with heart failure symptoms ≤6 months were evaluated. Myocarditis was defined as the presence of >14 mononuclear leukocytes/mm² and/or >7 T-lymphocytes/mm² in the baseline EMB. The EMB, echocardiography and clinical evaluation were repeated after 6 months of standard heart failure therapy. LVEF improved on average from 25 ± 9 to 42 ± 12 % (p < 0.001); LV end-systolic volume and LV end-diastolic volume (LVEDV) decreased from 158 ± 61 to 111 ± 58 ml and from 211 ± 69 to 178 ± 63 ml (both p < 0.001). NYHA class decreased from 2.6 ± 0.5 to 1.6 ± 0.6 (p < 0.001) and NTproBNP from 2892 ± 3227 to 851 ± 1835 µg/ml (p < 0.001). A decrease in the number of infiltrating leukocytes (CD45+/LCA+) from 23 ± 15 to 13 ± 8 cells/mm² and in the number of infiltrating T lymphocytes (CD3+) from 7 ± 5 to 4 ± 3 cells/mm² (both p < 0.001) was observed. The decline in the number of infiltrating CD45+ cells significantly correlated with the change in LVEF (R = ?0.43; p = 0.006), LVEDV (R = 0.39; p = 0.012), NYHA classification (R = 0.35; p = 0.025), and NTproBNP (R = 0.33; p = 0.045). The decrease in the number of CD3+ cells correlated with the change of systolic and diastolic diameters of the left ventricle (R = ?0.33; p = 0.038 and R = ?0.45; p = 0.003) and with the change in LVEDV (R = ?0.43; p = 0.006). Tricuspid annular plane systolic excursion (TAPSE) (OR 0.61; p = 0.005) and early transmitral diastolic flow velocity (E wave) (OR 0.89; p = 0.002) were identified as predictors of LVEF improvement. Improvements in clinical status, LV function and NTproBNP levels correlated with decrease in the number of infiltrating inflammatory cells. TAPSE and E wave velocity were significant predictors of improvement in multivariate regression. Our observations suggest that contemporary guidelines-based therapy of heart failure is an effective treatment option in patients with recent onset biopsy-proven inflammatory cardiomyopathy.     

Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation

An abnormally high number of macrophages are present in human brain arteriovenous malformations (bAVM) with or without evidence of prior hemorrhage, causing unresolved inflammation that may enhance abnormal vascular remodeling and exacerbate the bAVM phenotype. The reasons for macrophage accumulation at the bAVM sites are not known. We tested the hypothesis that persistent infiltration and pro-inflammatory differentiation of monocytes in angiogenic tissues increase the macrophage burden in bAVM using two mouse models and human monocytes. Mouse bAVM was induced through deletion of AVM causative genes, Endoglin (Eng) globally or Alk1 focally, plus brain focal angiogenic stimulation. An endothelial cell and vascular smooth muscle cell co-culture system was used to analyze monocyte differentiation in the angiogenic niche. After angiogenic stimulation, the Eng-deleted mice had fewer CD68⁺ cells at 2 weeks (P = 0.02), similar numbers at 4 weeks (P = 0.97), and more at 8 weeks (P = 0.01) in the brain angiogenic region compared with wild-type (WT) mice. Alk1-deficient mice also had a trend toward more macrophages/microglia 8 weeks (P = 0.064) after angiogenic stimulation and more RFP⁺ bone marrow-derived macrophages than WT mice (P = 0.01). More CD34⁺ cells isolated from peripheral blood of patients with ENG or ALK1 gene mutation differentiated into macrophages than those from healthy controls (P < 0.001). These data indicate that persistent infiltration and pro-inflammatory differentiation of monocytes might contribute to macrophage accumulation in bAVM. Blocking macrophage homing to bAVM lesions should be tested as a strategy to reduce the severity of bAVM.     

Fostamatinib,an oral spleen tyrosine kinase inhibitor,in the treatment of rheumatoid arthritis: a meta-analysis of randomized controlled trials

Fostamatinib is a selective inhibitor of spleen tyrosine kinase which has a role in the pathogenesis of RA. Multiple RCTs have been performed to study the effects of fostamatinib. The objective of this study was to perform a meta-analysis to analyze the efficacy and safety of fostamatinib in the management of RA. We searched PubMed, EMBASE and Cochrane CENTRAL through 11/9/15. Random effect model was used to estimate odds ratio (OR) and 95 % confidence interval. We measured outcomes with efficacy analysis using ACR20/50/70 response criteria and safety with adverse events. Five studies were included in the meta-analysis with total of 2105 patients including 1419 in fostamatinib group and 686 in placebo. Fostamatinib was effective in achieving ACR20, ACR50 and ACR70 responses compared to placebo (48 vs. 32.8 %, OR 1.86, 95 % CI 1.32–2.62, P = 0.0004, I ² 63 %; 26.4 vs. 12.5 %, OR 2.50, 95 % CI 1.93–3.23, P < 0.00001, I ² 0 % and 12.7 vs. 4.4 %, OR 3.00, 95 % CI 1.99–4.51, P < 0.00001, I ² 0 %, respectively). Response to fostamatinib was rapid and significant effect on ACR20 response was seen by week 1 (OR 3.70, 95 % CI 2.33–5.87, P < 0.00001, I ² 42 %). Safety analysis showed an increased risk of infection (OR 1.59, 95 % CI 1.2–2.11; P = 0.001; I ² 0 %), diarrhea (OR 3.54; 95 % CI 2.43–5.16; P < 0.00001; I ² 2 %), hypertension (OR 2.55, 95 % CI 1.54–4.22, P = 0.0003; I ² 42 %) and neutropenia (OR 5.68, 95 % CI 1.97–16.42, P = 0.001, I ² 35 %) and showed a trend toward the increase in ALT ≥3 times ULN (OR 1.76, 95 % CI 0.99–3.13; P = 0.05; I ² 0 %). This meta-analysis concludes that fostamatinib has moderate effect in the treatment of RA with mostly mild-to-moderate adverse events and dose-dependent, transient neutropenia and hypertransaminasemia.     

Effect of CPAP therapy on cardiovascular events and mortality in patients with obstructive sleep apnea: a meta-analysis

Purpose

Continuous positive airway pressure (CPAP) therapy may decrease the risk of mortality and cardiovascular events in patients with obstructive sleep apnea. However, these benefits are not completely clear.

Methods

We undertook a meta-analysis of randomized clinical trials identified in systematic searches of MEDLINE, EMBASE, and the Cochrane Database.

Results

Eighteen studies (4146 patients) were included. Overall, CPAP therapy did not significantly decrease the risk of cardiovascular events compared with the control group (odds ratio (OR), 0.84; 95 % confidence intervals (CI), 0.62–1.13; p = 0.25; I ² = 0 %). CPAP was associated with a nonsignificant trend of lower rate of death and stroke (for death: OR, 0.85; 95 % CI, 0.35–2.06; p = 0.72; I ² = 0.0 %; for stroke: OR, 0.56; 95 % CI, 0.18–1.73; p = 0.32; I ² = 12.0 %), a significantly lower Epworth sleepiness score (ESS) (mean difference (MD), ?1.78; 95 % CI, ?2.31 to ?1.24; p < 0.00001; I ² = 76 %), and a significantly lower 24 h systolic and diastolic blood pressure (BP) (for 24 h systolic BP: MD, ?2.03 mmHg; 95 % CI, ?3.64 to ?0.42; p = 0.01; I ² = 0 %; for diastolic BP: MD, ?1.79 mmHg; 95 % CI, ?2.89 to ?0.68; p = 0.001; I ² = 0 %). Daytime systolic BP and body mass index were comparable between the CPAP and control groups. Subgroup analysis did not show any significant difference between short- and mediate-to-long-term follow-up groups with regard to cardiovascular events, death, and stroke.

Conclusions

CPAP therapy was associated with a trend of decreased risk of cardiovascular events. Furthermore, ESS and BP were significantly lower in the CPAP group. Larger randomized studies are needed to confirm these findings.

     

Relationship between HRV measurements and demographic and clinical variables in a population of patients with atrial fibrillation

Little is known about the role of HRV in atrial fibrillation (AF) patients. Aim of our study was to assess the relationship between HRV measurements and demographic and clinical variables in a population of 274 AF patients. We selected all consecutive patients with persistent/permanent AF among whom had performed a Holter ECG in our Department from April 2010 to April 2015. Time-domain analysis of HRV was evaluated. Demographic and clinical variables were collected for each patient. At multivariable logistic regression, a higher pNN50 was associated with ACE inhibitors/ARBs (p = 0.016) and a lower pNN50 with obesity (p = 0.037) and higher heart rate (HR) (p < 0.0005). A higher RMSSD was associated with ACE inhibitors/ARBs (p = 0.001), digitalis (p < 0.0005) and beta-blockers (p = 0.002) and a lower RMSSD with a higher HR (p < 0.0005). A higher SDNN_i was associated with ACE inhibitors/ARBs (p < 0.0005), digitalis (p < 0.0005) and beta-blockers (p = 0.002) and a lower SDNN_i with dysthyroidism (p = 0.048) and higher HR (p < 0.0005). A higher SDANN was associated with non-dihydropyiridine calcium-channel-blockers (p = 0.002) and ACE inhibitors/ARBs (p = 0.002) and a lower SDANN with hypertension (p = 0.034), obesity (p = 0.011), stroke (p = 0.031), pneumonia (p = 0.005) and higher HR (p < 0.0005). A higher SDNN was associated with ACE inhibitors/ARBs (p < 0.0005), digitalis (p < 0.0005) and beta-blockers (p = 0.022) and a lower SDNN with obesity (p = 0.012), pneumonia (p = 0.049) and higher HR (p < 0.0005). Our study showed that, in AF patients, there is a direct relationship between some clinical variables and HRV measurements; as for patients with sinus rhythm, even in AF patients this relationship seemed to reflect the autonomic nervous system activity.     

Assessment of risk factors and left ventricular function in patients with slow coronary flow

Slow coronary flow (SCF) is characterized by delayed distal vessel opacification in the absence of significant epicardial coronary disease. Life-threatening arrhythmias and sudden cardiac death can occur; however, the pathological mechanism and influence on left ventricular function remain undetermined. We aimed to assess the risk factors and left ventricular (LV) function in SCF and evaluate the relationships between thrombolysis in myocardial infarction frame count (TFC) and the number of involved coronary arteries with LV function in patients with SCF. We included 124 patients who underwent coronary angiography because of symptoms of angina; 71 patients with angiographically proven SCF and 53 cases with normal coronary flow pattern. SCF was diagnosed as TFC >27 in at least one coronary artery. Complete blood count and biochemical parameters were compared between the two groups. Conventional echocardiography and tissue Doppler imaging were used to assess LV systolic and diastolic function. Platelet aggregation rate induced by ADP was an independent predictor of SCF and positively correlated with coronary artery mean TFC (mTFC) (r = 0.514, P < 0.001) and the number of coronary arteries with SCF (r = 0.628, P < 0.001). Early diastolic mitral inflow velocity (E) (0.66 ± 0.15 vs. 0.74 ± 0.17, P = 0.008), ratio of early to late diastolic mitral inflow velocity (E/A) (0.95 ± 0.29 vs. 1.15 ± 0.35, P = 0.002), global myocardial peak early diastolic velocity (gVe) (4.41 ± 1.25 vs. 4.96 ± 1.45, P = 0.037), and ratio of global myocardial peak early to late diastolic velocity (gVe/gVa: 1.09 ± 0.45 vs. 1.36 ± 0.58, P = 0.006) were decreased in patients with SCF compared with controls. gVe (3 vs. 0 branches, 4.08 ± 1.14 vs. 4.97 ± 1.45, respectively, P = 0.008) deteriorated significantly in patients with SCF involving three coronary arteries. mTFC negatively correlated with E and E/A (r = ?0.22, P = 0.02; r = ?0.20, P = 0.04, respectively). The number of coronary arteries with SCF negatively correlated with E, E/A, gVe and gVe/gVa (r = ?0.23, P = 0.02; r = ?0.25, P = 0.009; r = ?0.25, P = 0.008; r = ?0.21, P = 0.03, respectively). Platelet aggregation rate induced by ADP was an independent predictor of SCF and positively correlated with coronary artery TFC and the number of affected coronary arteries. Left ventricular global and regional diastolic function was impaired in SCF patients. Furthermore, the number of coronary arteries involved rather than coronary artery TFC determined the severity of left ventricular dysfunction in patients with SCF.     

Dual X-ray absorptiometry body composition and its associated factors in children and adolescence with type 1 diabetes mellitus in South of Iran,a case-control study

To date, limited studies have been conducted for evaluation of the body composition with the dual X-ray energy absorptiometry (DEXA) method in children with type 1 diabetes mellitus (T1DM). Also, there are lack of data about factors associated with body composition parameters in T1DM children. This case-control study was performed on T1DM children whom had referred to Diabetes Clinics of Shiraz University of Medical Sciences, 2013–2014. Weight, height, physical activity, sun exposure, insulin regimen, and the Tanner stage of children were recorded by a trained physician. Serum lipids and glycemic tests were assessed. Body composition was assessed by the DEXA Hologic system. Statistical analysis was carried out using SPSS 18.0 software. Eighty-seven T1DM children (39 male and 48 females) and 87 age- and sex-matched healthy controls with a mean age of 12.4 ± 4.2 years were enrolled in this study. Fat mass index was more in T1DM (P = 0.012), and lean mass index was more in non-diabetic children (P = 0.013). The android/gynecoid fat ratio in T1DM children was less than that of controls (P = 0.002). On multiple regression analysis, there was an independent effect of Tanner stage (P < 0.001) and FBS (P = 0.045) on total fat, an independent positive effect of age onset of T1DM (P < 0.001) on total lean mass. This study revealed an increase in the body fat index and a decrease in the lean mass index in T1DM children.     

Autoantibodies against myelin sheath and S100β are associated with cognitive dysfunction in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) has been associated with cognitive impairment and peripheral production of autoantibodies. Autoantibodies against central nervous system (CNS) proteins and S100 calcium-binding β (S100β) were found increased in diseases characterized by cognitive impairment like Alzheimer disease and Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). The aim of this study was to investigate the plasma levels of autoantibodies against myelin basic protein (anti-MBP), myelin oligodendrocyte glycoprotein (anti-MOG) and S100β, and their relationships with cognitive performance in RA patients. Twenty patients with active rheumatoid arthritis and 19 age-, sex-, and schooling-matched healthy controls were recruited. Multiple dimensions of cognitive function were evaluated by structured clinical questionnaires. Autoantibodies and S100β levels were assessed by ELISAs. Patients had significantly higher levels of anti-MBP IgG (17.51 ± 1.36 vs. 5.24 ± 0.53 ng/mL), anti-MOG IgG (5.68 ± 1.34 vs. 0.51 ± 0.49 ng/mL), and S100β protein (2.24 ± 0.50 vs. 0.47 ± 0.06) than controls (all p < 0.0001). After adjusting for potential confounders, RA group presented worse cognitive performance involving the working memory and executive functions such as inhibition, flexibility, and mental control in parallel to higher autoantibodies and S100β levels than healthy controls (all p < 0.001). Levels of anti-MBP were negatively associated with delayed verbal recall (DVR; r = ?0.42, p = 0.005), Stroop Color-Word (r = ?0.48, p = 0.004), and N-Back Total scores (r = ?0.59, p < 0.0001) and positively with Trail Making Test B (TMB, r = 0.53, p = 0.001). Negative correlation was found between levels of anti-MOG and DVR (r = ?0.64, p < 0.0001), N-Back Total scores (r = ?0.35, p = 0.03), Stroop Color-Word (r = ?0.51, p = 0.001), and positively with TMB (r = 0.50, p = 0.003). S100β levels were associated with DVR (r = ?0.51, p = 0.002), TMB (r = 0.46, p = 0.008), Stroop Color-Word (r = ?0.67, p < 0.0001), and N-Back Total (r = ?0.52, p = 0.003). RA is associated with impaired cognitive performance associated with higher levels of CNS-related autoantibodies and S100β levels. Given the importance of myelin integrity to cognition, our data indicate that these autoantibodies may be harmful to proper cognitive function.     

CTLA-4 +49A/G gene polymorphism and type 1 diabetes mellitus in the Chinese population: a meta-analysis of 2238 subjects

Previous studies reported that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) +49A/G gene polymorphism is correlated with type 1 diabetes mellitus (T1DM) risk. However, their results remain disputable. This study aims to discuss the relationship between CTLA-4 +49A/G gene polymorphism and T1DM in a Chinese population. The current meta-analysis involved 2238 participants from seven individual studies. The pooled odds ratio (OR) and its corresponding 95 % confidence interval (95 % CI) were assessed by the random- or fixed-effects model. A significant relationship between CTLA-4 +49A/G gene polymorphism and T1DM was detected under allelic (OR: 1.84, 95 % CI: 1.62–2.10, P?<?0.00001), dominant (OR: 1.152, 95 % CI: 1.062–1.249, P?=?0.001), recessive (OR: 1.631, 95 % CI: 1.443–1.844, P?<?0.00001), and additive (OR: 1.292, 95 % CI: 1.224–1.363, P?<?0.00001) genetic models. A significant relationship exists between CTLA-4 +49A/G gene polymorphism and increased T1DM risk in the Chinese population. Individuals having the G allele of CTLA-4 +49A/G gene polymorphism have a higher risk for T1DM in the Chinese population.