Post-switch Effectiveness of Etanercept Biosimilar Versus Continued Etanercept in Rheumatoid Arthritis Patients with Stable Disease: A Prospective Multinational Observational Study.

INTRODUCTION: To better inform clinicians about the use of etanercept biosimilar (SB4) in patients with rheumatoid arthritis (RA), COMPANION-B, a prospective real-world observational study, evaluated the effectiveness of the voluntary switch from originator (etanercept, ETN) to SB4 in patients with stable RA (low-disease activity/remission). METHODS: The study recruited adult patients (18 years or older) with RA (2010 American College of Rheumatology criteria) prescribed ETN as their first or second biologic for at least 6 months across 14 sites in Canada and five in Australia. Patients had stable disease (Disease Activity Score-28 using erythrocyte sedimentation rate [DAS28-ESR] less than 3.2) at enrollment with no evidence of flare within the previous 3 months. Concomitant disease-modifying antirheumatic drugs (DMARDs) were permitted. Patients could elect to continue ETN or voluntarily switch to SB4 in consultation with their doctors. The primary effectiveness measure was the proportion of patients with disease worsening (defined as a DAS28-ESR increase of at least 1.2 from baseline and minimum score of at least 3.2 or a defined modification in RA treatment) during 12 months of follow-up. The secondary effectiveness measure was the proportion of patients with disease worsening at month 6. Serious adverse events (SAEs) and non-serious adverse reactions (NSARs) were recorded. RESULTS: Of 163 patients enrolled, 109 elected to continue on ETN and 54 switched to SB4; 65.8% of patients received non-biologic DMARD(s), 52.6% methotrexate, and 10.5% oral corticosteroid(s). At month 12, the proportion of patients with disease worsening was comparable in the ETN group (22.8% [95% CI 15.0-32.2]) and SB4 group (17.6% [95% CI 8.4-30.9]). Similarly, the proportions of patients with disease worsening were also comparable at month 6 (ETN: 7.9% [95% CI 3.5-15.0]; SB4: 7.8% [95% CI 2.2-18.9]). SAEs were low and similar across both groups (ETN: 8.7%; SB4: 5.7%). NSARs were slightly higher in the SB4 vs. ETN group (13.2% vs. 2.9%). CONCLUSIONS: SB4 demonstrated comparable effectiveness to ETN over 12 months in patients with stable RA who voluntarily switched to the biosimilar in a real-world setting.

Reslizumab and mepolizumab for moderate-to-severe poorly controlled asthma: an indirect comparison meta-analysis.

Aim: A systematic literature review and network meta-analysis assessed the efficacy and safety of reslizumab 3.0 mg/kg and mepolizumab 100 mg. Materials & methods: Eligible studies evaluated reslizumab and mepolizumab in patients with inadequately-controlled severe eosinophilic asthma. Using a Bayesian network meta-analysis, 95% credible intervals and posterior probabilities were reported. Results: Of 19 indirect efficacy comparisons performed in base-case (Global Initiative for Asthma 4/5 patients with ≥2 exacerbations in the previous year) and overall populations, significant differences favoring reslizumab were observed for severe exacerbations, FEV1 at 4 weeks and eosinophil counts at 4, 16 and 24 weeks, with no other significant differences including risk of adverse events. Conclusion: Indirect comparison of reslizumab and mepolizumab largely showed no significant differences in efficacy or safety.

Novel role of the renin-angiotensin system in preeclampsia superimposed on chronic hypertension and the effects of exercise in a mouse model.

Gestational hypertensive disorders, such as preeclampsia, affect 6% to 8% of all pregnancies in North America, and they are the leading cause of maternal mortality in industrialized countries, accounting for 16% of deaths. Women with hypertension have an increased risk (15% to 25%) of developing preeclampsia. Our aim was to investigate the mechanisms implicated in preeclampsia superimposed on chronic hypertension and in the protective effects of exercise in a mouse model. Female mice overexpressing human angiotensinogen and human renin were used as a model of preeclampsia superimposed on chronic hypertension. In the trained group, mothers were placed in cages with access to a wheel before mating, and they remained within these throughout gestation. Blood pressure was measured by telemetry. We found that angiotensin II type I receptor was increased, whereas the Mas receptor was decreased in the placenta and the aorta of pregnant sedentary transgenic mice. This would produce a decrease in angiotensin-(1-7) effects in favor of angiotensin II. Supporting the functional contribution of this modulation, we found that the prevention of most pathological features in trained transgenic mice was associated with a normalization of placental angiotensin II type 1 and Mas receptors and an increase in aortic Mas receptor. We also found reduced circulating and placental soluble Fms-like tyrosine kinase-1 in trained transgenic mice compared with sedentary mice. This study demonstrates that modulation of the renin-angiotensin system is a key mechanism in the development of preeclampsia superimposed on chronic hypertension, which can be altered by exercise training to prevent disease features in an animal model.

Impact of exercise training on preeclampsia: potential preventive mechanisms.

Preeclampsia is characterized by hypertension and de novo proteinuria after 20 weeks of pregnancy. It is the leading cause of perinatal morbidity and mortality in the developed world, and to date, the only means of treating the disease is by inducing delivery. Many studies have shown the benefits of exercise training on normal pregnancy. Conversely, because the impact of exercise on reducing the risk of preeclampsia has long been debated, the American College of Obstetricians and Gynecologists has yet to support the prescription of exercise training to women at risk of developing the disease. There is, however, a significant body of evidence in support of the protective role of exercise training against preeclampsia. A recent animal study demonstrated that many preeclampsia features can be eliminated with prenatal followed by gestational exercise training. Hence, the present article reviews the literature on the impact of exercise training on preeclampsia risk, as well as the mechanisms that may be involved.

Exercise training can attenuate preeclampsia-like features in an animal model.

OBJECTIVE: Exercise training benefits have been widely investigated and used as alternative treatment for different pathological conditions. Since preeclampsia is a severe pregnancy-associated disease for which no treatment is available, our aim was to investigate the protective role of exercise training on pregnancy outcome using a mouse model of the disease. METHODS: We used transgenic female mice overexpressing human angiotensinogen, which develop preeclampsia when mated with human renin-overexpressing males. Females were placed in exercise cages 4 weeks prior to mating, and remained in these throughout gestation. Blood pressure was measured by telemetry, and proteinuria was quantified by ELISA. Placentas were assessed by histology and immunohistochemistry, whereas vascular endothelial growth factor was measured by real-time PCR and immunoblot. Endothelial function was assessed in isolated mesenteric arteries. RESULTS: Conversely to sedentary transgenic females (131.20 ± 4.08 mmHg), trained dam's mean arterial pressure was no longer different from normal mice at the end of gestation (117.5 ± 10.6 vs. 112.3 ± 5.5 mmHg). Proteinuria observed in transgenic dams (3.364 ± 1.62 µg/mg) was absent in trained mice (0.894 ± 0.43 µg/mg). Placental disease and cardiac hypertrophy were also normalized, whereas vascular reactivity was significantly ameliorated. Furthermore, placental vascular endothelial growth factor was normalized in trained transgenic mice. CONCLUSIONS: To our knowledge, we are the first to clearly demonstrate that exercise training both before and during gestation can reduce preeclampsia features in a mouse model. Consequently, women at risk for this disease could benefit from exercise training to protect themselves and their future fetuses.

Mice overexpressing both human angiotensinogen and human renin as a model of superimposed preeclampsia on chronic hypertension.

Preeclampsia is the major cause of maternal and fetal mortality/morbidity. Because hypertension is an important risk factor for preeclampsia, we investigated whether hypertensive mice that overexpress human renin and angiotensinogen develop superimposed preeclampsia. Given that the mechanisms underlying this disease are still poorly understood, animal models are of great use for elucidation. Blood pressure and proteinuria were measured by telemetry and ELISA, respectively. Heart function was evaluated by echocardiography, whereas pathological cardiac hypertrophy-related genes were assessed by real-time PCR. Soluble fms-like tyrosine kinase 1 plasma concentrations were quantitated by ELISA and placental expression by real-time PCR. Transgenic mice develop de novo proteinuria during gestation and marked blood pressure elevation, which are hallmarks of superimposed preeclampsia on chronic hypertension. Abnormal placentation present in these mothers produced a significant decrease in pup and placental weight and was associated with an increased placental expression of soluble fms-like tyrosine kinase 1. We also found heightened circulating levels of this receptor, when adjusted for placental mass, as has been observed in women who suffer from preeclampsia. Cardiac hypertrophy could be observed in the transgenic mice and was exacerbated by gestation. As a result, heart function was significantly decreased, and markers of pathological hypertrophy were increased. Our data, thus, confirm the characterization of a new model of superimposed preeclampsia on chronic hypertension. Because chronically hypertensive women are at risk of developing the pathology, our model reflects a clinical reality and is, thus, an excellent tool to elucidate the molecular mechanisms triggering this disease.

Impact of diet and stress on the development of preeclampsia-like symptoms in p57kip2 mice.

The cyclin-dependent kinase inhibitor p57(kip2) regulates the cell cycle of trophoblastic cells. It has been established by a Japanese group that the heterozygous p57(kip2) knockout (p57(-/+)) mice are a good model of preeclampsia as they develop hypertension, proteinuria, and placental pathology. However, apart from the placental pathology, we could not observe these symptoms in our laboratory. Hence, we investigated the impact of diet and stress on this model. To do so, we compared the effects of the Japanese diet to that of the North American diet used by our animal facility. Furthermore, the impact of stress was determined by placing the mice in a restraining device before and at the end of gestation. Although the Japanese diet did not have any impact on blood pressure or proteinuria, the mice did develop endothelial dysfunction, left ventricular hypertrophy, as well as increased placental pathology. Also, all mice had smaller litters when fed the Japanese diet. However, stress response of these mice was not increased during gestation; in fact, a decrease was observed in the p57(-/+) mice, suggesting that this was probably not a player in the development of the pathology. Taken together, these results suggest that other environmental factors may have been implicated in the development of preeclampsia-like symptoms in this animal model. Moreover, we demonstrated that placental pathology and genetic factors are not sufficient to trigger preeclampsia-like symptoms in this model and that the diet might play an important part in the development of this multifactorial disease.

Hyperhomocysteinemia is not sufficient to cause preeclampsia in an animal model: the importance of folate intake.

OBJECTIVE: The objective of our study was to determine whether methylenetetrahydrofolate reductase (Mthfr)-deficient mice develop preeclampsia (PE). STUDY DESIGN: Mice were placed on a normal or low-folate/high-methionine (LF/HM) diet to assess the impact of mild and severe homocysteinemia. Blood pressure and proteinuria were measured throughout gestation in Mthfr-deficient and control mice on both diets, by radiotelemetry and by determining the urinary albumin/creatinine ratio by enzyme-linked immunosorbent assay, respectively. RESULTS: Although Mthfr-deficient mice have endothelial dysfunction, they do not develop hypertension or proteinuria during gestation. The LF/HM diet induced proteinuria, growth restriction, and a decrease in the number of pups per litter in all mice without any effect on the placenta. CONCLUSION: Our study clearly demonstrates that hyperhomocysteinemia is not sufficient to cause PE in this animal model. Furthermore, it confirms the importance of folate intake on pregnancy outcomes.

Celecoxib after the onset of reperfusion reduces apoptosis in the amygdala.

Reperfused myocardial infarction induces an inflammatory response that is responsible for local and systemic alterations. Among these, apoptosis observed in the amygdala following myocardial infarction has been pointed out as a consequence of such an inflammatory process. We hypothesized that inhibition of the inducible inflammatory enzyme Cox-2 during the reperfusion period may attenuate the apoptotic process in the amygdala. Anaesthetized rats were subjected to left anterior descending coronary artery occlusion for 40 min, followed by reperfusion. The Cox-2 antagonist Celecoxib (3 mg/kg i.p.) was administered 10 min after the onset of the reperfusion period. After 72 h of reperfusion, infarct size was determined and the lateral and medial amygdala were dissected from the brain. Infarct size was similar between untreated and Celecoxib-treated animals (40-45% of the area at risk). Cox-2 expression was significantly reduced in both parts of the amygdala in the Celecoxib group. Apoptosis regression was observed in the amygdala of the Celecoxib group as shown by decreased number of TUNEL positive cells and by decreased of caspase-3 activation. Bax/Bcl-2 ratio was not significantly altered by Celecoxib while Akt activation was increased in the lateral amygdala but not in the medial amygdala. This data indicates that inhibition of Cox-2 by Celecoxib is associated with regression of apoptosis in the amygdala following myocardial infarction.

Combined effects of reduced connexin 43, depressed active generator properties and energetic stress on conduction disturbances in canine failing myocardium.

To show that reductions in connexin43 (Cx43) can contribute, in association with electrophysiological alterations identified from unipolar recordings, to conduction disturbances in a realistic model of heart failure, canines were subjected to chronic rapid pacing (240/min for 4 weeks) and progressive occlusion of the left coronary circumflex artery (LCx) by an ameroid constrictor. Alterations identified from 191 epicardial recordings included abrupt activation delay, functional block, ST segment potential elevation, and reduced maximum negative slope (-dV/dt (max)). The LCx territory was divided into apical areas with depressed conduction velocity (LCx1: 0.06 +/- 0.04 m/s, mean +/- SD) and basal areas with relatively preserved conduction (LCx2: 0.28 +/- 0.01 m/s). Subepicardial Cx43 immunoblot measurements (percent of corresponding healthy heart measurements) were reduced in LCx1 ( approximately 40%) and LCx2 ( approximately 60%). In addition, -dV/dt (max) was significantly depressed (-3.8 +/- 3.3 mV/ms) and ST segment potential elevated (23.3 +/- 14.6 mV) in LCx1 compared to LCx2 (-9.5 +/- 3.4 mV/ms and 0.3 +/- 1.4 mV). Anisotropic conduction, Cx43 and ST segment potential measurements from the left anterior descending coronary artery territory, and interstitial collagen from all regions were similar to the healthy. Thus, moderate Cx43 reduction to "clinically relevant" levels can, in conjunction with regional energetic stress and depression of sarcolemmal active generator properties, provide a substrate for conduction disturbances.

The effect of lesion size and tissue remodeling on ST deviation in partial-thickness ischemia.

BACKGROUND: Myocardial ischemia causes ST segment elevation or depression in electrocardiograms and epicardial leads. ST depression in epicardium overlying the ischemic zone indicates that the ischemia is nontransmural. However, nontransmural ischemia does not always cause ST depression. Especially in animal models, ST depression is hard to reproduce. OBJECTIVE: The purpose of this study was to determine the circumstances in which ST depression could be expected. METHODS: We studied ischemia in a large-scale computer model of the human heart. A realistic representation of the ischemia-induced changes in resting membrane potential was used, which was based on diffusion of extracellular potassium. Ischemia diameter, transmural extent, and tissue conductivity were varied. RESULTS: Our simulations confirm earlier work showing that partial-thickness ischemia, like full-thickness ischemia, typically causes ST elevation in an anisotropic model of the ventricles. However, we identified three situations in which ST depression can occur in overlying leads. The first is a reduced anisotropy ratio of the intracellular conductivity, which may result from hypertrophy and gap-junctional remodeling, circumstances that are likely to accompany ischemia. Second, an increase of the extracellular anisotropy has the same effect. Third, ST depression was found, independent of the anisotropy ratios, in very large and thin ischemic regions, resembling those that may occur in left-main or multivessel disease. CONCLUSION: Both tissue remodeling and geometric factors can explain ST depression in overlying epicardial leads. We note at the same time that ST elevation is found in most circumstances, while depression occurs as a reciprocal effect, even in partial-thickness ischemia.

Post-ischemic cardioprotection by A2A adenosine receptors: dependent of phosphatidylinositol 3-kinase pathway.

Activation of myocardial A2A adenosine receptors during reperfusion has been shown to be cardioprotective. The intracellular mechanisms underlying this protection remain unknown. To understand the beneficial effects of activated A2A adenosine receptors in such a state, we investigated whether the enzymes phosphatidylinositol 3-kinase (PI3K) and caspase-3 can account for this post-ischemic cardioprotective effect in an anesthetized rabbit model of myocardial infarction (30 minutes ischemia; 5 hours reperfusion). Administration of the A2A agonist CGS21680 (0.2 microg/kg/min) 5 minutes before reperfusion began (Early) reduced infarct size expressed as a percentage of the area at risk (25.7 +/- 5.3% versus 46.5 +/- 5.3% for the control group; * P < 0.05). Treatment with the A2A agonist 5 minutes after the onset of reperfusion (Late) had no effect on infarct size (38.2 +/- 6.2%). In the presence of a selective inhibitor of PI3K (LY294002), the beneficial effects of CGS21680 on infarct size was no longer observed (43.9 +/- 7.9%). After 5 hours of reperfusion, higher PI3K activity in the ischemic region was observed in the Early group compared with the other experimental groups. Caspase-3 activity was not observed in these different groups. In another set of experiments, PI3K activity was significantly higher during the first 15 minutes of reperfusion in the Early group as compared with the Control group. Caspase-3 activity increased rapidly during the first 15 minutes of reperfusion in the Control group and remained stable in the Early group. These results indicated that post-ischemic cardioprotection afforded by A2A adenosine receptor activation is PI3K-dependent and modulate rapidly other signaling pathways such as caspase-3.