Good correlation between changes in objective and subjective signs of inflammation in patients with short- but not long duration of axial spondyloarthritis treated with tumor necrosis factor-blockers

Introduction

The aim of this study was to investigate the influence of symptom duration on treatment response and on the correlation between improvements in patient reported outcomes (PRO) and objective inflammation in patients with axial spondylarthritis (SpA) treated with etanercept (ETA) or adalimumab (ADA).

Methods

Data from 112 patients with axial SpA originally enrolled in two randomized controlled clinical trials were pooled and analyzed after one year of treatment with ETA (n = 66) or ADA (n = 46). Patients with <4 years and ≥4 years of disease were compared for improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS), C-reactive protein (CRP) and magnetic resonance imaging (MRI) score for sacroiliac joints (SIJ).

Results

Patients with <4 years of disease showed a significantly better improvement than longer diseased patients in BASDAI (3.2 (95% confidence interval (CI): 2.7 to 3.7) vs. 1.7 (1.1 to 2.2)), BASFI, BASMI and ASDAS (1.6 (1.4 to 1.8) vs. 0.9 (0.7 to 1.1)). The change in BASDAI showed a significant correlation with the change in SIJ score (Spearman’s rank correlation coefficient (rho) = 0.37, P = 0.01) and the change in CRP (rho = 0.45, P = 0.001) in patients with <4 years of disease. For long diseased patients this correlation was poor and did not achieve statistical significance (rho = 0.13, P = 0.46; rho = 0.22, P = 0.13 respectively).

Conclusion

The low correlation between change of PROs and change of objective signs of inflammation seen in axial SpA patients with longer symptom duration treated with tumor necrosis factor-blocker seems to indicate that inflammation is not the only cause of the patients’ symptoms, while inflammation seems to be the major cause in short diseased patients.

Trial registration

Clinical Trials.gov NCT00844142 (Trial 1); NCT00235105 (Trial 2)     

Safety and Immunogenicity of an AMA1 Malaria Vaccine in Malian Children: Results of a Phase 1 Randomized Controlled Trial

Background

The objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/AS02_A in children exposed to seasonal falciparum malaria.

Methodology/Principal Findings

A Phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02_A is a recombinant protein (FMP2.1) based on apical membrane antigen 1 (AMA1) from the 3D7 clone of P. falciparum, formulated in the Adjuvant System AS02_A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert®). One hundred healthy Malian children aged 1–6 years were recruited into 3 cohorts and randomized to receive either 10 µg FMP2.1 in 0.1 mL AS02_A, or 25 µg FMP2.1 in 0.25 mL AS02_A, or 50 µg FMP2.1 50 µg in 0.5 mL AS02_A, or rabies vaccine. Three doses of vaccine were given at 0, 1 and 2 months, and children were followed for 1 year. Solicited symptoms were assessed for 7 days and unsolicited symptoms for 30 days after each vaccination. Serious adverse events were assessed throughout the study. Transient local pain and swelling were common and more frequent in all malaria vaccine dosage groups than in the comparator group, but were acceptable to parents of participants. Levels of anti-AMA1 antibodies measured by ELISA increased significantly (at least 100-fold compared to baseline) in all 3 malaria vaccine groups, and remained high during the year of follow up.

Conclusion/Significance

The FMP2.1/AS02_A vaccine had a good safety profile, was well-tolerated, and induced high and sustained antibody levels in malaria-exposed children. This malaria vaccine is being evaluated in a Phase 2 efficacy trial in children at this site.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00358332","term_id":"NCT00358332"}}NCT00358332 [{"type":"clinical-trial","attrs":{"text":"NCT00358332","term_id":"NCT00358332"}}NCT00358332]     

The immunogenicity to the first anti-TNF therapy determines the outcome of switching to a second anti-TNF therapy in spondyloarthritis patients

Introduction

Anti-TNF drugs have proven to be effective against spondyloarthritis (SpA), although 30% of patients fail to respond or experience adverse events leading to treatment discontinuation. In rheumatoid arthritis, the presence of anti-drug antibodies (ADA) against the first TNF inhibitor influences the outcome after switching. Our aim was to assess whether the response to a second anti-TNF drug is related to the previous development of ADA to the first anti-TNF drug SpA patients.

Methods

Forty-two SpA patients began a second anti-TNF drug after failing to respond to the first anti-TNF therapy. Clinical activity was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline (at the beginning of the first and second anti-TNF therapy) and at 6 months after switching. The drug and ADA levels were measured by ELISA before each administration.

Results

All patients were treated with anti-TNF drugs and mainly due to inefficacy were switched to a second anti-TNF drug. Eleven of 42 (26.2%) developed ADA during the first biologic treatment. At baseline, no differences in ASDAS were found in patients with or without ADA to the first anti-TNF drug (3.52 ± 1.03 without ADA vs. 3.14 ± 0.95 with ADA, p = 0.399) and to the second anti-TNF drug (3.36 ± 0.94 without ADA vs. 3.09 ± 0.91 with ADA, p = 0.466). At 6 months after switching, patients with previous ADA had lower disease activity (1.62 ± 0.93 with ADA vs. 2.79 ± 1.01 without ADA, p = 0.002) and most patients without ADA had high disease activity state by the ASDAS (25 out of 31 (80.6%) without ADA vs. 3 out of 11 (27.3%) with ADA, p = 0.002).

Conclusions

In SpA the failure to respond to the first anti-TNF drug due to the presence of ADA predicts a better clinical response to a second anti-TNF drug.     

Evaluation of the nonsteroidal anti-inflammatory drug-sparing effect of etanercept in axial spondyloarthritis: results of the multicenter,randomized, double-blind,placebo-controlled SPARSE study

Introduction

In clinical practice, nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly discontinued after response to biologic therapy is achieved in patients with axial spondyloarthritis (axSpA), but the impact of NSAID discontinuation has not been assessed in prospective controlled trials. The aim of the SPARSE study was to evaluate the effects of the anti-tumor necrosis factor agent etanercept on NSAID intake and conventional clinical outcomes in axSpA patients.

Methods

In the double-blind, placebo-controlled period, patients with active (mini Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4) axSpA despite optimal NSAID intake were randomized to receive etanercept 50 mg or placebo once weekly for 8 weeks. All patients were advised to taper/discontinue their NSAID intake during the treatment period. NSAID intake was self-reported by diary and Assessment of SpondyloArthritis International Society (ASAS)-NSAID scores calculated based on ASAS recommendations. The primary endpoint was change from baseline to week 8 in ASAS-NSAID score (analysis of covariance).

Results

In 90 randomized patients at baseline, mean age (standard deviation) was 38.9 (11.8) years; disease duration, 5.7 (8.1) years; 59/90 (66%) were human leukocyte antigen-B27 positive; 51/90 (57%) had radiographic sacroiliitis; and 45/90 (50%) were magnetic resonance imaging sacroiliitis-positive. Mean ASAS-NSAID scores were similar between etanercept and placebo groups at baseline (98.2 (39.0) versus 93.0 (23.4)), as were BASDAI (6.0 (1.7) versus 5.9 (1.5)), and Bath Ankylosing Spondylitis Functional Index (5.2 (2.1) versus 5.1 (2.2)). Mean changes (SE) in ASAS-NSAID score from baseline to week 8 were –63.9 (6.1) and –36.6 (5.9) in the etanercept and placebo groups (between-group difference, –27.3; P = 0.002). Significantly higher proportions of patients receiving etanercept versus placebo had an ASAS-NSAID score <10 (46% versus 17%; P = 0.008) and ASAS-NSAID score of 0 (41% versus 14%; P = 0.013) at this time point. Significantly more patients in the etanercept versus placebo group achieved BASDAI50 (39% versus 18%; P = 0.032) and ASAS40 (44% versus 21%; P = 0.028) at week 8.

Conclusions

In patients with axSpA, etanercept was associated with clinically relevant NSAID-sparing effects in addition to significant improvements in conventional clinical outcomes.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01298531","term_id":"NCT01298531"}}NCT01298531. Registered 16 February 2011.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0481-5) contains supplementary material, which is available to authorized users.     

Azithromycin and cough-specific health status in patients with chronic obstructive pulmonary disease and chronic cough: a randomised controlled trial

Background

Macrolides reduce exacerbations in patients with COPD. Their effects on health status has not been assessed as primary outcome and is less clear. This study assessed the effects of prophylactic azithromycin on cough-specific health status in COPD-patients with chronic productive cough.

Methods

In this randomised controlled trial 84 patients met the eligibility criteria: age of ≥40 years, COPD GOLD stage ≥2 and chronic productive cough. The intervention-group (n = 42) received azithromycin 250 mg 3 times a week and the control-group (n = 42) received a placebo. Primary outcome was cough-specific health status at 12 weeks, measured with the Leicester Cough Questionnaire (LCQ). Secondary outcomes included generic and COPD-specific health status and exacerbations. Changes in adverse events and microbiology were monitored.

Results

Mean age of participants was 68 ± 10 years and mean FEV1 was 1.36 ± 0.47 L. The improvement in LCQ total score at 12 weeks was significantly greater with azithromycin (difference 1.3 ± 0.5, 95% CI 0.3;2.3, p = 0.01) and met the minimal clinically important difference. Similar results were found for the domain scores, and COPD-specific and generic health status questionnaires. Other secondary endpoints were non-significant. No imbalances in adverse events were found.

Conclusions

Prophylactic azithromycin improved cough-specific health status in COPD-patients with chronic productive cough to a clinically relevant degree.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01071161","term_id":"NCT01071161"}}NCT01071161     

Endothelial Dysfunction and Specific Inflammation in Obesity Hypoventilation Syndrome

Background

Obesity hypoventilation syndrome (OHS) is associated with increased cardiovascular morbidity. What moderate chronic hypoventilation adds to obesity on systemic inflammation and endothelial dysfunction remains unknown.

Question

To compare inflammatory status and endothelial function in OHS versus eucapnic obese patients.

Methodology

14 OHS and 39 eucapnic obese patients matched for BMI and age were compared. Diurnal blood gazes, overnight polysomnography and endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), were assessed. Inflammatory (Leptin, RANTES, MCP-1, IL-6, IL-8, TNFα, Resistin) and anti-inflammatory (adiponectin, IL-1Ra) cytokines were measured by multiplex beads immunoassays.

Principal Findings

OHS exhibited a higher PaCO₂, a lower forced vital capacity (FVC) and tended to have a lower PaO₂ than eucapnic obese patients. _HS-CRP, RANTES levels and glycated haemoglobin (HbA1c) were significantly increased in OHS (respectively 11.1±10.9 vs. 5.7±5.5 mg.l⁻¹ for _HS-CRP, 55.9±55.3 vs 23.3±15.8 ng/ml for RANTES and 7.3±4.3 vs 6.1±1.7 for HbA1c). Serum adiponectin was reduced in OHS (7606±2977 vs 13660±7854 ng/ml). Endothelial function was significantly more impaired in OHS (RH-PAT index: 0.22±0.06 vs 0.51±0.11).

Conclusions

Compared to eucapnic obesity, OHS is associated with a specific increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin and impaired endothelial function. These three conditions are known to be strongly associated with an increased cardiovascular risk.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00603096","term_id":"NCT00603096"}}NCT00603096     

The Potential of a High Protein-Low Carbohydrate Diet to Preserve Intrahepatic Triglyceride Content in Healthy Humans

Background

Protein supplementation has been shown to reduce the increases in intrahepatic triglyceride (IHTG) content induced by acute hypercaloric high-fat and high-fructose diets in humans.

Objective

To assess the effect of a 12-wk iso-energetic high protein-low carbohydrate (HPLC) diet compared with an iso-energetic high carbohydrate-low protein (HCLP) diet on IHTG content in healthy non-obese subjects, at a constant body weight.

Design

Seven men and nine women [mean ± SD age: 24±5 y; BMI: 22.9±2.1 kg/m²] were randomly allocated to a HPLC [30/35/35% of energy (En%) from protein/carbohydrate/fat] or a HCLP (5/60/35 En%) diet by stratification on sex, age and BMI. Dietary guidelines were prescribed based on individual daily energy requirements. IHTG content was measured by ¹H-magnetic resonance spectroscopy before and after the dietary intervention.

Results

IHTG content changed in different directions with the HPLC (CH₂H₂O: 0.23±0.17 to 0.20±0.10; IHTG%: 0.25±0.20% to 0.22±0.11%) compared with the HCLP diet (CH₂H₂O: 0.34±0.20 vs. 0.38±0.21; IHTG%: 0.38±0.22% vs. 0.43±0.24%), which resulted in a lower IHTG content in the HPLC compared with the HCLP diet group after 12 weeks, which almost reached statistical significance (P = 0.055).

Conclusions

A HPLC vs. a HCLP diet has the potential to preserve vs. enlarge IHTG content in healthy non-obese subjects at a constant body weight.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01551238","term_id":"NCT01551238"}}NCT01551238     

Safety and Immunogenicity of a Recombinant Plasmodium falciparum AMA1 Malaria Vaccine Adjuvanted with Alhydrogel?, Montanide ISA 720 or AS02

Background

Plasmodium falciparum Apical Membrane Antigen 1 (PfAMA1) is a candidate vaccine antigen expressed by merozoites and sporozoites. It plays a key role in red blood cell and hepatocyte invasion that can be blocked by antibodies.

Methodology/Principal Findings

We assessed the safety and immunogenicity of recombinant PfAMA1 in a dose-escalating, phase Ia trial. PfAMA1 FVO strain, produced in Pichia pastoris, was reconstituted at 10 µg and 50 µg doses with three different adjuvants, Alhydrogel™, Montanide ISA720 and AS02 Adjuvant System. Six randomised groups of healthy male volunteers, 8–10 volunteers each, were scheduled to receive three immunisations at 4-week intervals. Safety and immunogenicity data were collected over one year. Transient pain was the predominant injection site reaction (80–100%). Induration occurred in the Montanide 50 µg group, resulting in a sterile abscess in two volunteers. Systemic adverse events occurred mainly in the AS02 groups lasting for 1–2 days. Erythema was observed in 22% of Montanide and 59% of AS02 group volunteers. After the second dose, six volunteers in the AS02 group and one in the Montanide group who reported grade 3 erythema (>50 mm) were withdrawn as they met the stopping criteria. All adverse events resolved. There were no vaccine-related serious adverse events. Humoral responses were highest in the AS02 groups. Antibodies showed activity in an in vitro growth inhibition assay up to 80%. Upon stimulation with the vaccine, peripheral mononuclear cells from all groups proliferated and secreted IFNγ and IL-5 cytokines.

Conclusions/Significance

All formulations showed distinct reactogenicity profiles. All formulations with PfAMA1 were immunogenic and induced functional antibodies.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00730782","term_id":"NCT00730782"}}NCT00730782     

Concentrations of the Stress Hormone Copeptin Increase upon Hypoglycaemia in Patients with Type 1 Diabetes Dependent of Hypoglycaemia Awareness

Objective

Copeptin, a marker for stress mirroring vasopressin concentrations, has been shown to increase upon insulin-induced hypoglycaemia in patients after transsphenoidal surgery of pituitary adenomas. Patients with type 1 diabetes mellitus are prone to hypoglycaemia, but no data about copeptin levels upon hypoglycaemia are available. Furthermore, the perception of hypoglycaemia can vary from total unawareness to disabling episodes. The aim of this study was to investigate whether copeptin increases upon hypoglycaemia in patients with type 1 diabetes mellitus and is associated with the degree of hypoglycaemia awareness.

Materials and Methods

In this prospective observational study, 17 patients with type 1 diabetes underwent a standardized insulin infusion test. Blood sampling for glucose and copeptin was performed at baseline and after 60 minutes (min). To assess hypoglycaemia associated symptoms the Mood and Symptom Questionnaire (MSQ) was conducted at baseline and after 60 min.

Results

During insulin infusion, blood glucose decreased from 5.1 (SD±0.2) to 3.0 (±0.5) mmol/L at 60 min (p<0.001). Copeptin concentrations increased from 3.2 (±1.7) to 3.8 (±1.9) pmol/L (p = 0.03). Mood and Symptoms Questionnaire scores increased from 14 (±3.0) to 18 (±5.8), (p = 0.006). Patients with good hypoglycaemia awareness had an increase in copeptin from 3.0 (±1.8) to 4.2 (±2.4) pmol/L (p = 0.03) in contrast to patients more unaware of hypoglycaemia who only showed an increase in copeptin from 3.3 (±1.6) to 3.6 (±1.4) pmol/L (p = 0.4). There was a trend to a larger copeptin increase in patients aware of hypoglycemia compared to patients unaware of hypoglycemia (p = 0.074).

Conclusion

Copeptin increases in patients with type 1 diabetes upon insulin induced hypoglycaemia. Interestingly, the copeptin increase seems associated with the degree of hypoglycaemia awareness. This hypothesis warrants further verification.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00515801","term_id":"NCT00515801"}}NCT00515801     

Hawthorne Effect with Transient Behavioral and Biochemical Changes in a Randomized Controlled Sleep Extension Trial of Chronically Short-Sleeping Obese Adults: Implications for the Design and Interpretation of Clinical Studies

Objective

To evaluate the effects of study participation per se at the beginning of a sleep extension trial between screening, randomization, and the run-in visit.

Design

Subjects were screened, returned for randomization (Comparison vs. Intervention) after 81 days (median), and attended run-in visit 121 days later.

Setting

Outpatient.

Patients

Obese (N = 125; M/F, 30/95; Blacks/Whites/Other, N = 73/44/8), mean weight 107.6±19.7 kg, <6.5 h sleep/night.

Intervention

Non-pharmacological sleep extension.

Measurements

Sleep duration (diaries and actigraphy watch), sleep quality (Pittsburgh Sleep Quality Index), daily sleepiness (Epworth Sleepiness Scale), fasting glucose, insulin and lipids.

Results

Prior to any intervention, marked improvements occurred between screening and randomization. Sleep duration increased (diaries: 357.4 ±51.2 vs. 388.1±48.6 min/night; mean±SD; P<0.001 screening vs. randomization; actigraphy: 344.3 ±41.9 vs. 358.6±48.2 min/night; P<0.001) sleep quality improved (9.1±3.2 vs. 8.2±3.0 PSQI score; P<0.001), sleepiness tended to improve (8.9±4.6 vs. 8.3±4.5 ESS score; P = 0.06), insulin resistance decreased (0.327±0.038 vs. 0.351±0.045; Quicki index; P<0.001), and lipids improved, except for HDL-C. Abnormal fasting glucose (25% vs. 11%; P = 0.007), and metabolic syndrome (42% vs. 29%; P = 0.007) both decreased. In absence of intervention, the earlier metabolic improvements disappeared at the run-in visit.

Limitations

Relatively small sample size.

Conclusions

Improvements in biochemical and behavioral parameters between screening and randomization changed the “true” study baseline, thereby potentially affecting outcome. While regression to the mean and placebo effect were considered, these findings are most consistent with the “Hawthorne effect”, according to which behavior measured in the setting of an experimental study changes in response to the attention received from study investigators. This is the first time that biochemical changes were documented with respect to the Hawthorne effect. The findings have implications for the design and conduct of clinical research.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00261898","term_id":"NCT00261898"}}NCT00261898.     

Platelet Expression of Stromal Cell-Derived Factor-1 Is Associated with the Degree of Valvular Aortic Stenosis

Background and Purpose

Platelet surface expression of stromal-cell-derived factor-1 (SDF-1) is increased during platelet activation and constitutes an important factor in hematopoetic progenitor cell trafficking at sites of vascular injury and ischemia. Enhanced platelet SDF-1 expression has been reported previously in patients suffering from acute coronary syndrome (ACS). We hypothesized that expression of platelet associated SDF-1 may also be influenced by calcified valvular aortic stenosis (AS).

Methods

We consecutively evaluated 941 patients, who were admitted to the emergency department with dyspnea and chest pain. Platelet surface expression of SDF-1 was determined by flow cytometry, AS was assessed using echocardiography and hemodynamic assessment by heart catheterization. A 1∶1 propensity score matching was implemented to match 218 cases with 109 pairs adjusting for age, sex, cardiovascular risk factors, and medication including ACE inhibitors, angiotensin receptor blockers, beta blockers, statins, aspirin, clopidogrel, GPIIb/IIIa antagonists, and vitamin K antagonists.

Results

Patients with valvular AS showed enhanced platelet SDF-1 expression compared to patients without AS (non-valvular disease, NV) independent of ACS and stable coronary artery disease (SAP) [mean fluorescence intensity (MFI) for ACS (AS vs. NV): 75±40.4 vs. 39.5±23.3; P = 0.002; for SAP (AS vs. NV): 54.9±44.6 vs. 24.3±11.2; P = 0.008]. Moreover, the degree of AS significantly correlated with SDF-1 platelet surface expression (r = 0.462; P = 0.002).

Conclusions

Valvular AS is associated with enhanced platelet-SDF-1 expression; moreover the degree of valvular AS correlates with SDF-1 platelet surface expression. These findings may have clinical implications in the future.     

Comparison of Corneal Epithelial and Stromal Thickness Distributions between Eyes with Keratoconus and Healthy Eyes with Corneal Astigmatism ≥2.0 D

Purpose

To identify corneal epithelial- and stromal-thickness distribution patterns in keratoconus using spectral-domain optical coherence tomography (SD-OCT).

Patients and Methods

We analyzed SD-OCT findings in 20 confirmed cases of keratoconus (group 1) and in 20 healthy subjects with corneal astigmatism ≥2 D (group 2). Epithelial and stromal thicknesses were measured at 11 strategic locations along the steepest and flattest meridians, previously located by corneal topography. Vertical mirrored symmetry superimposition was used in the statistical analysis.

Results

The mean maximum keratometry measurements in groups 1 and 2 were 47.9±2.9 D (range, 41.8–52.8) and 45.6±1.1 D (range, 42.3–47.5), respectively, with mean corneal cylinders of 3.3±2.2 D (range, 0.5–9.5) and 3.6±1.2 D (range, 2.0–6.4), respectively. The mean epithelial thickness along the steepest meridian in group 1 was the lowest (37.4±4.4 µm) at 1.2 mm inferotemporally and the highest (59.3±4.4 µm) at 1.4 mm supranasally from the corneal vertex. There was only a small deviation in thickness along the steepest meridian in group 2, as well as along the flattest meridians in both groups. The stromal thickness distribution in the two groups was similar to the epithelial, while the stromal thickness was generally lower in group 1 than in group 2.

Conclusions

SD-OCT provides details about the distribution of corneal epithelial and stromal thicknesses. The epithelium and stroma in keratoconic eyes were thinner inferotemporally and thicker supranasally compared with control eyes. The distribution pattern was more distinct in epithelium than in stroma. This finding may help improve the early diagnosis of keratoconus.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02023619","term_id":"NCT02023619"}}NCT02023619     

Effect of Arginase Inhibition on Ischemia-Reperfusion Injury in Patients with Coronary Artery Disease with and without Diabetes Mellitus

Background

Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes (Clinical trial registration number: {"type":"clinical-trial","attrs":{"text":"NCT02009527","term_id":"NCT02009527"}}NCT02009527).

Methods

Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (N^ω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline.

Results

The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). N^ω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions.

Conclusions

Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.     

Aerobic and Combined Exercise Sessions Reduce Glucose Variability in Type 2 Diabetes: Crossover Randomized Trial

Purpose

To evaluate the effects of aerobic (AER) or aerobic plus resistance exercise (COMB) sessions on glucose levels and glucose variability in patients with type 2 diabetes. Additionally, we assessed conventional and non-conventional methods to analyze glucose variability derived from multiple measurements performed with continuous glucose monitoring system (CGMS).

Methods

Fourteen patients with type 2 diabetes (56±2 years) wore a CGMS during 3 days. Participants randomly performed AER and COMB sessions, both in the morning (24 h after CGMS placement), and at least 7 days apart. Glucose variability was evaluated by glucose standard deviation, glucose variance, mean amplitude of glycemic excursions (MAGE), and glucose coefficient of variation (conventional methods) as well as by spectral and symbolic analysis (non-conventional methods).

Results

Baseline fasting glycemia was 139±05 mg/dL and HbA1c 7.9±0.7%. Glucose levels decreased immediately after AER and COMB protocols by ∼16%, which was sustained for approximately 3 hours. Comparing the two exercise modalities, responses over a 24-h period after the sessions were similar for glucose levels, glucose variance and glucose coefficient of variation. In the symbolic analysis, increases in 0 V pattern (COMB, 67.0±7.1 vs. 76.0±6.3, P = 0.003) and decreases in 1 V pattern (COMB, 29.1±5.3 vs. 21.5±5.1, P = 0.004) were observed only after the COMB session.

Conclusions

Both AER and COMB exercise modalities reduce glucose levels similarly for a short period of time. The use of non-conventional analysis indicates reduction of glucose variability after a single session of combined exercises.

Trial Registration

Aerobic training, aerobic-resistance training and glucose profile (CGMS) in type 2 diabetes (CGMS exercise). ClinicalTrials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT00887094","term_id":"NCT00887094"}}NCT00887094.     

Incidence and predictors of morphometric vertebral fractures in patients with ankylosing spondylitis

Introduction

Ankylosing spondylitis (AS) is associated with an increased incidence of vertebral fractures (VFs); however the actual incidence and predictors of morphometric VFs are unknown. The present study examined the incidence and predictors of new VFs in a large AS cohort.

Methods

In total, 298 AS patients who fulfilled the modified New York criteria were enrolled and spinal radiographs were evaluated biennially. Clinical and laboratory data and radiographic progression were assessed according to the Bath AS Disease Activity Index, erythrocyte sedimentation rate, C-reactive protein (CRP), and the Stoke AS spine score (SASSS). VF was defined according to the Genant criteria. The incidence of VFs at 2 and 4 years was evaluated using the Kaplan-Meier method. The age-specific standardized prevalence ratio (SPR) for AS patients in comparison with the general population was calculated.

Results

Of 298 patients, 31 (10.8%) had previous VFs at baseline. A total of 30 new VFs occurred in 26 patients over 4 years. The incidence of morphometric VFs was 4.7% at 2 years and 13.6% at 4 years. Multivariate logistic regression analysis showed that previous VFs at baseline and increased CRP levels at 2 years were predictors of new VFs (odds ratio (OR) =12.8, 95% confidence interval (CI) = 3.6-45.3 and OR = 5.4, 95% CI = 1.4–15.9). The age-specific specific standardized prevalence ratio of morphometric VFs in AS was 3.3 (95% CI 2.1–4.5).

Conclusions

The incidence of morphometric VFs increased in AS. Previous VFs and increased CRP levels predicted future VFs. Further studies are needed to identify the effects of treatment interventions on the prevention of new VFs.     

Similar Trends in Serum VEGF-D Levels and Kidney Angiomyolipoma Responses with Longer Duration Sirolimus Treatment in Adults with Tuberous Sclerosis

Context

We have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up.

Objective

To compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS).

Design and Intervention(s)

Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0–12 months. During months 12–24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus.

Setting

Adult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1).

Patients

There were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients.

Main Outcome Measure(s)

We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups.

Results

At 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787±426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971±4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p = 0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed.

Trial Registration

Clinical trials.gov {"type":"clinical-trial","attrs":{"text":"NCT00126672","term_id":"NCT00126672"}}NCT00126672.     

The Effect of Aerobic Exercise on Intrahepatocellular and Intramyocellular Lipids in Healthy Subjects

Background

Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass).

Aim

To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy.

Methods

Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO_2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO_2max) using ¹H-MR-spectroscopy.

Results

Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO_2max, 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (−22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity.

Conclusions

IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions.

Trial Registration

ClinicalTrial.gov {"type":"clinical-trial","attrs":{"text":"NCT00491582","term_id":"NCT00491582"}}NCT00491582     

Effectiveness of adalimumab in treating patients with ankylosing spondylitis associated with enthesitis and peripheral arthritis

Introduction

The purpose of this study was to investigate the effectiveness of adalimumab in enthesitis and peripheral arthritis in patients with ankylosing spondylitis (AS).

Methods

Adults with active AS (Bath ankylosing spondylitis disease activity index [BASDAI] ≥ 4) received adalimumab 40 mg every other week with standard antirheumatic therapies in a 12-week, open-label study. Effectiveness in enthesitis was assessed using the Maastricht ankylosing spondylitis enthesitis score (MASES, 0-13) and by examining the plantar fascia in patients with enthesitis (≥ 1 inflamed enthesis) at baseline; effectiveness in peripheral arthritis was evaluated using tender and swollen joint counts (TJC, 0-46; SJC, 0-44) in patients with peripheral arthritis (≥ 1 swollen joint) at baseline. Overall effectiveness measures included Assessment of SpondyloArthritis International Society 20% response (ASAS20).

Results

Of 1,250 patients enrolled, 686 had enthesitis and 281 had peripheral arthritis. In 667 patients with MASES ≥ 1 at baseline, the median MASES was reduced from 5 at baseline to 1 at week 12. At week 12, inflammation of the plantar fascia ceased in 122 of 173 patients with inflammation at baseline. The median TJC in 281 patients with SJC ≥ 1 at baseline was reduced from 5 at baseline to 1 at week 12; the median SJC improved from 2 to 0. ASAS20 responses were achieved by 70.5% of 457 patients with no enthesitis and no arthritis; 71.0% of 512 patients with only enthesitis; 68.0% of 107 patients with only arthritis; and 66.7% of 174 patients with both.

Conclusions

Treatment with adalimumab improved enthesitis and peripheral arthritis in patients with active AS.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00478660","term_id":"NCT00478660"}}NCT00478660.     

Visualization of Coronary Wall Atherosclerosis in Asymptomatic Subjects and Patients with Coronary Artery Disease Using Magnetic Resonance Imaging

Background

Magnetic resonance imaging (MRI) is sensitive to early atherosclerotic changes such as positive remodeling in patients with coronary artery disease (CAD). We assessed prevalence, quality, and extent of coronary atherosclerosis in a group of healthy subjects compared to patients with confirmed CAD.

Methodology

Twenty-two patients with confirmed CAD (15M, 7F, mean age 60.4±10.4 years) and 26 healthy subjects without history of CAD (11M, 15F, mean age 56.1±4.4 years) underwent MRI of the right coronary artery (RCA) and vessel wall (MR-CVW) on a clinical 1.5T MR-scanner. Wall thickness measurements of both groups were compared.

Principal Findings

Stenoses of the RCA (both < and ≥50% on CAG) were present in all patients. In 21/22 patients, stenoses detected at MRI corresponded to stenoses detected with conventional angiography. In 19/26 asymptomatic subjects, there was visible luminal narrowing in the MR luminography images. Fourteen of these subjects demonstrated corresponding increase in vessel wall thickness. In 4/26 asymptomatic subjects, vessel wall thickening without luminal narrowing was present. Maximum and mean wall thicknesses in patients were significantly higher (2.16 vs 1.92 mm, and 1.38 vs 1.22 mm, both p<0.05).

Conclusions

In this cohort of middle-aged individuals, both patients with stable angina and angiographically proven coronary artery disease, as well as age-matched asymptomatic subjects. exhibited coronary vessel wall thickening detectable with MR coronary vessel wall imaging. Maximum and mean wall thicknesses were significantly higher in patients. The vast majority of asymptomatic subjects had either positive remodeling without luminal narrowing, or non-significant stenosis.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00456950","term_id":"NCT00456950"}}NCT00456950     

A Comparative Study on the Efficacy of Solifenacin Succinate in Patients with Urinary Frequency with or without Urgency

Objectives

Patients with overactive bladder (OAB) often have trouble perceiving urgency because of difficulties in distinguishing between urgency and desire to void. Empirical antimuscarinic treatment of patients with frequency only may be reasonable if conservative management has failed. We compared the efficacy of solifenacin in patients with frequency with or without urgency.

Materials and Methods

This multicenter, 12-week, open-label, comparative, non-inferiority clinical trial assessed whether the solifenacin efficacy for frequency without urgency is non-inferior to its efficacy for frequency with urgency. All patients had micturition frequency ≥8 voids/day with or without urgency. Primary efficacy variable: daily frequency change at 12 weeks relative to baseline. Secondary efficacy variables: change at 12 weeks relative to baseline in Patients'' Perception of Bladder Condition (PPBC), OAB Symptom Score (OABSS), and Benefit, Satisfaction, Willingness to continue (BSW) questionnaire.

Results

Of the 286 enrolled patients, 240 (83.9%) completed the study (without urgency n = 115; with urgency n = 125). Full dataset analysis revealed that the groups without and with urgency exhibited significant reductions in daily micturition frequency of −2.49±0.35 (mean ± standard error) and −2.63±0.37, respectively. The lower limit of the 95% two-sided CI of the comparison of the two group means was −1.14, which is smaller than the −0.8 margin of clinical equivalence. The two groups did not differ in improvement in PPBC, OABSS, or BSW scores. Both tolerated the treatment well.

Conclusions

It was not possible to verify that the solifenacin efficacy for frequency alone was non-inferior to its efficacy for OAB. Nevertheless, solifenacin tended to be effective for frequency regardless of urgency.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00979472","term_id":"NCT00979472"}}NCT00979472