The GOLMePsA study protocol: an investigator-initiated, double-blind, parallel-group, randomised, controlled trial of GOLimumab and methotrexate versus methotrexate in early diagnosed psoriatic arthritis using clinical and whole body MRI outcomes

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis which impacts significantly on the quality of life and work capacity of affected individuals. Recent evidence has shown that early control of inflammation in PsA leads to improved long-term outcomes. It is postulated that prompt intervention after diagnosis using a remission-induction treatment strategy will lead to improved outcomes and optimal disease control of PsA. The aim of the present study was to compare the clinical efficacy of a treatment strategy in newly diagnosed, treatment naïve PsA subjects, using the combination of golimumab (GOL), methotrexate (MTX) and steroids versus standard care (MTX monotherapy plus steroids). Methods/design: GOLMePsA is an investigator initiated, phase IIIb, single-centre, randomised, double-blind, placebo-controlled, two-armed, parallel-group, imaging-supplemented study. Eighty-eight PsA patients, diagnosed within 24 months prior to screening and treatment naïve, will be randomised at baseline to receive: (arm 1) the combination of intramuscular/intra-articular prednisolone, MTX and GOL or (arm 2) the combination of intramuscular/intra-articular prednisolone, MTX and placebo for 24 weeks (interventional period). Primary outcome measure is clinical improvement (at least 1 unit difference) in the Psoriatic ArthritiS Disease Activity Score (PASDAS) composite index. Reflecting a “step down” therapeutic approach, all participants successfully completing the interventional period will be followed up for a further 28 weeks. During this observational period, stable maintenance MTX monotherapy will continue for both arms, unless in case of intolerance or PsA relapse. In the latter case, additional treatment will be provided. Overall, the GOLMePsA study length is planned to be 52 weeks. Discussion: The hypothesis underlining this study is that very early treatment with first-line GOL reduces disease activity in PsA, in comparison to conventional therapy. Trial registration: EudraCT 2013–004122-28. 24/09/2013

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

The effects of simulated obstructive apnea and hypopnea on arrhythmic potential in healthy subjects

Preliminary evidence supports an association between OSA and cardiac dysrhythmias. Negative intrathoracic pressure, as occurring during OSA, may provoke cardiac dysrhythmias. Thus, we aimed to study the acute effects of simulated apnea and hypopnea on arrhythmic potential and measures of cardiac repolarization [QT(C) and T (peak) to T (end) intervals ([Formula: see text])] in humans. In 41 healthy volunteers, ECG was continuously recorded prior, during and after simulated obstructive hypopnea (inspiration through a threshold load), simulated apnea (Mueller maneuver), end-expiratory central apnea and normal breathing in randomized order. The number of subjects with premature beats was significantly higher during inspiration through a threshold load (n = 7), and the Mueller maneuver (n = 7) compared to normal breathing (n = 0) (p = 0.008 for all comparisons), but not during end-expiratory central apnea (n = 3, p = 0.125). Inspiration through a threshold load was associated with a non-significant mean (SD) increase of the QT(C) interval [+5.4 (22.4) ms, 95 %CI -1.7 to +12.4 ms, p = 0.168] and a significant increase of the [Formula: see text] interval [+3.7 (8.9) ms, 95 %CI +0.9 to +6.6 ms, p = 0.010]. The Mueller maneuver induced a significant increase of the QT(C) interval [+8.3 (23.4) ms, 95 %CI 0.9 to +15.6 ms, p = 0.035] and the [Formula: see text] interval (+4.2 (8.2) ms, 95 %CI +1.6 to +6.8 ms, p = 0.002). There were no significant changes of the QT(C) and [Formula: see text] intervals during central end-expiratory apnea. These data indicate that simulated obstructive apnea and hypopnea are associated with an increase of premature beats and prolongation of QT(C) and [Formula: see text] intervals. Therefore, negative intrathoracic pressure changes may be a contributory mechanism for the association between OSA and cardiac dysrhythmias

Mechanisms of vascular damage in obstructive sleep apnea

Obstructive sleep apnea (OSA) is characterized by repetitive apnea-hypopnea cycles during sleep, which are associated with oxygen desaturation and sleep disruption. Up to 30% of the adult population in Western countries are thought to be affected by asymptomatic OSA and approximately 2-4% by symptomatic OSA (also known as obstructive sleep apnea syndrome, or OSAS). Controlled trials have demonstrated that OSAS causes hypertension and prospective epidemiological studies have indicated that OSAS might bean independent risk factor for stroke and myocardial ischemia. Three biological mechanisms are thought to underpin the association of OSA with endothelial dysfunction and arterial disease: intermittent hypoxia leading to increased oxidative stress, systemic inflammation, and sympathetic activity; intrathoracic pressure changes leading to excessive mechanical stress on the heart and large artery walls; and arousal-induced reflex sympathetic activation with resultant repetitive blood-pressure rises. More clinical interventional trials are needed to determine the magnitude of the effect OSA has on cardiovascular damage and to enable a comparison with conventional vascular risk factors

Antisense oligonucleotides: the next frontier for treatment of neurological disorders

Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs and improved clinical trial design, have provided momentum for the translation of ASO-based strategies into therapies. Many neurological conditions lack an effective treatment; however, as research progressively disentangles the pathogenic mechanisms of these diseases, they provide an ideal platform to test ASO-based strategies. This steady progress reached a pinnacle in the past few years with approvals of ASOs for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy, which represent landmarks in a field in which disease-modifying therapies were virtually non-existent. With the rapid development of improved next-generation ASOs toward clinical application, this technology now holds the potential to have a dramatic effect on the treatment of many neurological conditions in the near future