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Objective We aimed at testing if a correlation between adverse drug reactions relative risks estimated from meta-analyses and disproportionality analyses calculated from pharmacovigilance spontaneous reporting systems databases exist, and if methodological choices modify this correlation. Study design We extracted adverse drug reactions (ADR) odds ratios (ORs) from meta-analyses used as reference and calculated corresponding Reporting Odds Ratios (RORs) from the WHO pharmacovigilance database according to five different designs. We also calculated the relative bias and agreement of ROR compared to ORs. Results We selected five meta-analyses which displayed a panel of 13 ADRs. A significant correlation for 7 out of the 13 ADRs studied in the primary analysis was found. The methods for ROR calculation impacted the results but none systematically improved the correlations. Whereas correlation was found between OR and ROR, agreement was poor and relative bias was important. Conclusion Despite the large variation in disproportionality analyses results due to design specification, this study provides further evidence that relative risks obtained from meta-analyses and from disproportionality analyses correlate in most cases, in particular for objective ADR not associated with the underlying pathology.

According to previous reports, diabetes seems to be a risk factor which worsens the serious clinical events caused by COVID-19. But is diabetes per se a risk factor that increases the probability of getting the virus? This paper will discuss this point. There are not many research data on antidiabetic drugs in this context. The potential influence of glucose-lowering agents on the severity of COVID-19 has not been described yet. Dipeptidylpeptidase-4 (DPP-4) is a cell surface protein ubiquitously expressed in many tissues and it is also a soluble molecule found in serum/plasma fluids. DPP-4 is involved in infection of cells by some viruses. This paper reviews data about the use of DPP-4 inhibitors and others diabetes drugs on COVID-19 patients. As such, no available evidence has yet suggested that glucose-lowering drugs - including those targeting DPP4-related pathways - produce any significant harm or benefit in the context of human infections. However, insulin must remain the first-choice agent in the management of critically ill-hospitalized patients, while it is recommended to suspend other agents in unstable patients. This paper provides related French and international recommendations for people with diabetes who got infected by COVID-19 and upholds that infections may alter glucose control and may require additional vigilance., D’après les dernières analyses de cas notamment en Chine et en Italie, le diabète semble être un facteur de risque d’aggravation de l’état clinique d’un patient atteint par le COVID-19 mais est-il un facteur de susceptibilité ? Une analyse de la littérature à la date du 6 mai 2020 tente de répondre à la question. Les données concernant le type de traitement antidiabétique à utiliser dans ces circonstances et son impact éventuel sur l’état clinique d’un patient infecté par le COVID-19 sont très rares. La dipeptidylpeptidase 4 (DPP-4), glycoprotéine membranaire ubiquitaire présente à la surface de nombreuses cellules et existant aussi sous forme soluble, est impliquée dans les réponses immunitaires inflammatoires en modifiant la production de plusieurs cytokines. La DPP-4 est impliquée dans l'infection des cellules par certains virus. Nous abordons la question de l’utilisation des inhibiteurs des DPP-4 chez les patients diabétiques et il n’y a pas à ce jour de données qui indiquent que l’état clinique des patients dépend de leur utilisation. De la même façon, l’utilisation de la metformine, des sulfamides hypoglycémiants, des analogues du GLP1 comme de l’insuline n’ont pas fait l’objet d’études dans ce contexte. Il nous parait prudent en phase aigüe de la maladie, en particulier chez les patients nécessitant un séjour en unités de soins intensifs de privilégier l’insuline chez eux. A la lumière d’une revue des recommandations sur la prise en charge des diabétiques,l’optimisation du contrôle glycémique est à privilégier et plusieurs messages clefs délivrés par les Sociétés savantes concluent ce travail.

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease affecting predominantly sacroiliac joints and axial skeleton. axSpA progression being irregular and hardly predictable, identifying functional decline is particularly important in patient with axSpA to allow delivery of timely and targeted interventions. Pain, reduced range of motion or altered posture can have adverse consequences on gait. Although gait has previously been used as a sensitive measure of physical outcomes in elderly and pathological populations, to the best of our knowledge, no study has used gait as a predictor of physical function in patients with axSpA. The objective of our study is hence to determine if gait parameters measured in patients with axSpA could predict the evaluation at 18 months of physical function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). This is a prospective and longitudinal study. Sixty patients with axSpA and 30 healthy age- and sex-matched controls will be included. Patients should be aged 18–65 years at time of their first evaluation, followed at Grenoble Alpes University Hospital for axSpA or ankylosing spondylitis, able to walk 180 m without technical help and with stable treatment for at least 12 months. Clinical characteristics, BASFI, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), clinical and laboratory measurements of gait will be assessed during four visits (at baseline and at months 6, 12, and 18). Similar assessments will be performed once for the healthy control group. A linear mixed model at 6, 12 and 18 months will be constructed to answer to the first objective, with the BASFI as dependent variable and gait parameters as explanatory variables. The data collection started in August 2018 and will be completed with the inclusion and follow-up of all the participants. We believe that the combination of clinical and laboratory measurements of gait in patients with axSpA could strengthen the capacity to monitor disease’s evolution and to predict changes in patients’ physical function. Results of the present study could ultimately allow delivering targeted, timely, personalized interventions and treatment in patients with axSpA. Trial registration: The study was approved by local ethic committee (CPP Ile De France 1, RCB: 2017-A03468-45, date of agreement: July 17th, last version: V4.0, 2018, March 5th, 2019) and is retrospectively registered in Clinical trials (NCT03761212).

Erythromelalgia is a recurrent and paroxysmal syndrome characterized by the clinical triad of bilateral redness, heat, and paroxysmal burning pain, mostly localized on the feet. This disorder can be primary, as a consequence of mutations in the genes encoding the voltage gated sodium channels. It can also be secondary to an underlying disease or drugs. Its pathophysiology involves either an abnormal microvascular arteriovenous shunting together with a decreased nutritional blood flow responsible for the pain , and/or a state of increase blood viscosity.

Aims: A particularly high burden of sleep apnea is reported in patients treated with cardiac implants such as pacemakers and defibrillators. Sleep apnea diagnosis remains a complex procedure mainly based on sleep and respiratory indices captured by polysomnography (PSG) or respiratory polygraphy (PG). We aimed to evaluate whether implantable cardiac devices are reliable for sleep apnea diagnosis compared to reference methods. Method and results: We performed a systematic literature search (PubMed, Cochrane Library) to identify relevant studies and finally included 13 studies involving 647 patients in the meta-analysis. The majority of patients were men, of mean age of 70.5 ± 4.8 years. Sensitivity of cardiac implants for sleep apnea diagnosis ranged from 60 to 100%, specificity from 50 to 100% with a prevalence of sleep apnea varying from 22 to 91%. The overall performance of cardiac implants for sleep apnea diagnosis was assessed by a randomized bivariate meta-analysis and completed by pre-specified sensitivity analyses for different implant types and brands. For an apnea-hypopnea index threshold ≥30 events/hour during polysomnography (corresponding to severe sleep apnoea), the optimal respiratory event threshold for cardiac implants was 31.5/hour with a sensitivity of 80% (61-91%) and specificity of 70% (53-83%). Subgroup analyses on implant type and brand provided no additional information owing to the small number of studies. Conclusions: The respiratory disturbance index provided by cardiac implants is clinically relevant and might improve access to sleep apnea diagnosis in at risk cardiovascular populations.

International audience; Insulin resistance (IR), currently called prediabetes (PD), affects more than half of the adult population worldwide. Type 2 diabetes (T2D), which often follows in the absence of treatment, affects more than 475 million people and represents 10–20% of the health budget in industrialized countries. A preventive public health policy is urgently needed in order to stop this constantly progressing epidemic. Indeed, early management of prediabetes does not only strongly reduce its evolution toward T2D but also strongly reduces the appearance of cardiovascular comorbidity as well as that of associated cancers. There is however currently no simple and reliable test available for the diagnosis or screening of prediabetes and it is generally estimated that 20–60% of diabetics are not diagnosed. We therefore developed an ELISA for the quantitative determination of serum Insulin-Regulated AminoPeptidase (IRAP). IRAP is associated with and translocated in a stoechiometric fashion to the plasma membrane together with GLUT4 in response to insulin in skeletal muscle and adipose tissue which are the two major glucose storage sites. Its extracellular domain (IRAPs) is subsequently cleaved and secreted in the blood stream. In T2D, IRAP translocation in response to insulin is strongly decreased. Our patented sandwich ELISA is highly sensitive (≥10.000-fold “normal” fasting concentrations) and specific, robust and very cost-effective. Dispersion of fasting plasma concentration values in a healthy population is very low (101.4 ± 15.9 μg/ml) as compared to those of insulin (21–181 pmol/l) and C-peptide (0.4–1.7 nmol/l). Results of pilot studies indicate a clear correlation between IRAPs levels and insulin sensitivity. We therefore think that plasma IRAPs may be a direct marker of insulin sensitivity and that the quantitative determination of its plasma levels should allow large-scale screening of populations at risk for PD and T2D, thereby allow the enforcement of a preventive health policy aiming at efficiently reducing this epidemic.

Many drugs are responsible, through different mechanisms, for peripheral oedema. Severity is highly variable, ranging from slight oedema of the lower limbs to anasarca pictures as in the capillary leak syndrome. Although most often noninflammatory and bilateral, some drugs are associated with peripheral oedema that is readily erythematous (eg, pemetrexed) or unilateral (eg, sirolimus). Thus, drug-induced peripheral oedema is underrecognized and misdiagnosed, frequently leading to a prescribing cascade. Four main mechanisms are involved, namely precapillary arteriolar vasodilation (vasodilatory oedema), sodium/water retention (renal oedema), lymphatic insufficiency (lymphedema) and increased capillary permeability (permeability oedema). The underlying mechanism has significant impact on treatment efficacy. The purpose of this review is to provide a comprehensive analysis of the main causative drugs by illustrating each pathophysiological mechanism and their management through an example of a drug.

Awada and colleagues recently published in the European Respiratory Journal an interesting pre-clinical study suggesting that crizotinib may exacerbate and predispose to pulmonary arterial hypertension (PAH) [1]. Crizotinib is a first-in-class anaplastic lymphocyte kinase (ALK) inhibitor and is now a standard first-line therapy for advanced ALK-positive non-small cell lung cancer (NSCLC) [2]. Its inconsistent efficacy and its limited ability to control brain metastases pushed the development of second-generation ALK tyrosine kinase inhibitors (TKI) (ceritinib, alectinib and brigatinib) which are characterised by higher selectivity and distribution to the central nervous system. Furthermore, third-generation ALK-TKI such as lorlatinib or entrectinib have been recently developed to overcome acquired resistance due to secondary ALK mutations, which concern more than half of patients treated by second-generation ALK-TKI [3]. Cases of PAH onset have also been reported in patients with metastatic NSCLC who received other ALK-TKI such as brigatinib and lorlatinib [4, 5]. Subsequently, one can ask if this adverse event is specific to crizotinib or a class effect of ALK-TKI, and whether on-target or off-target tyrosine kinases are implicated in its pathophysiology. To further add knowledge on this potential adverse drug reaction (ADR), we aimed to comprehensively characterise PAH reported with ALK-TKI use, using the WHO pharmacovigilance database to describe cases clinical features and to assess its causality. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: Charles Khouri has nothing to disclose. Conflict of Interest: Alex Hlavaty has nothing to disclose. Conflict of Interest: Matthieu Roustit reports grants to institution (Grenoble University Hospital) for a clinical research on diabetic foot ulcers from United Therapeutics; patent for Grenoble University PCT/EP2014/065093, device using treprostinil (Remodulin®) to treat cutaneous ulcers; outside the submitted work. Conflict of Interest: Jean-Luc Cracowski has nothing to disclose. Conflict of Interest: Marie-Camille Chaumais has nothing to disclose. Conflict of Interest: Marc Humbert reports grants paid to institution, consulting fees for steering committee, speaker fees, and advisory board membership from Acceleron, Janssen, Merck; speaker fees from AOP; outside the submitted work. Conflict of Interest: David Montani reports grants paid to institution from Acceleron, Janssen, Merck; consulting fees for steering committee from Acceleron; speaker fees from Bayer, Janssen, Merck; outside the submitted work. Conflict of Interest: All other authors have nothing to disclose.

Background The vagus nerve has anti-inflammatory properties. We aimed to investigate vagus nerve stimulation (VNS) as a new therapeutic strategy targeting an intrinsic anti-inflammatory pathway in a pilot study in Crohn's disease patients. The main objectives addressed the questions of long-term safety, tolerability, and anti-inflammatory effects of this therapy. This study is the continuation of previous reported findings at 6 months. Methods Nine patients with moderate active disease underwent VNS. An electrode wrapped around the left cervical vagus nerve was continuously stimulated over 1 year. Clinical, biological, endoscopic parameters, cytokines (plasma, gut), and mucosal metabolites were followed-up. Key results After 1 year of VNS, five patients were in clinical remission and six in endoscopic remission. C-reactive protein (CRP) and fecal calprotectin decreased in six and five patients, respectively. Seven patients restored their vagal tone and decreased their digestive pain score. The patients' cytokinergic profile evolved toward a more "healthy profile": Interleukins 6, 23, 12, tumor necrosis factor α, and transforming growth factorβ1 were the most impacted cytokines. Correlations were observed between CRP and tumor necrosis factor α, and some gut mucosa metabolites as taurine, lactate, alanine, and beta-hydroxybutyrate. VNS was well tolerated. Conclusion & inferences Vagus nerve stimulation appears as an innovative and well-tolerated treatment in moderate Crohn's disease. After 12 months, VNS has restored a homeostatic vagal tone and reduced the inflammatory state of the patients. VNS has probably a global modulatory effect on the immune system along with gut metabolic regulations. This pilot study needs replication in a larger randomized double-blinded control study.

International audience; Objective: Finger systolic blood pressure measurement (FSBP) has been shown helpful in the detection of distal arterial insufficiency in upper limbs. This work assesses the possibility to measure FSBP on the 2nd phalanx instead of the first one in order to improve its sensitivity and to verify this would not alter the repeatability of the measurement.Methods: In this multicenter study, FSBP was measured twice in all fingers but the thumbs in consecutive systemic sclerosis patients on the first phalanx and the second phalanx in alternate order using laser-Doppler flowmetry.Results: Thirty-seven patients were enrolled. The repeatability of FSBP was excellent and similar on the first and 2nd phalanxes with coefficients of variation respectively of 7.1% and 7.6%. While the correlation between the FSBP at the two sites was fair (Pearson coefficient 0.69; p < 0.001). The agreement was poor, with a mean difference of 14 mm Hg between the two sites. Significantly higher differences were found in fingers with digital ulcers. The ROC curves showed a better prediction of the 2nd phalanx measurements.Conclusion: FSBP has an excellent repeatability whatever the site of phalanx. However, measurements performed on the 2nd phalanx have a better sensitivity for the prediction of digital ulcers.

From before the coronavirus disease 2019 (COVID-19) pandemic, the effect of dipeptidyl peptidase 4 inhibitors (DPP-4i) on respiratory infections (RI) remains unclear. The meta-analysis of Yang et al. (1) specifically assessed the risk of infection with DPP-4i. However, cardiovascular outcomes trials (CVOTs) did not appear in their meta-analysis for RI (1). In addition, the meta-analyses of CVOTs did not report assessment of RI for DPP-4i. Meta-analyses and pharmacovigilance studies showed some discrepancies (2). Recently published practical recommendations did not suggest discontinuation of DPP-4i because of the COVID-19 pandemic (3,4). The dipeptidyl peptidase 4 enzyme could be a target for treating COVID-19 (2). We aimed to provide a powerful and less biased estimate of the effect of DPP-4i on the overall risk of RI and thus verify the validity of the recent recommendations for the management of diabetes during the COVID-19 pandemic (3,4). We updated a previous systematic review and meta-analysis, focusing our primary analysis on RI in placebo-controlled CVOTs assessing a DPP-4i in patients with type 2 diabetes, using PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), up to 27 January 2020. In line with the previous meta-analysis of Yang et al. (1), our primary outcome was “any respiratory infection” (defined as influenza, nasopharyngitis, sinusitis, pharyngotonsillitis, pharyngitis, bronchitis, respiratory tract infection [RTI], upper RTI, lower RTI, or pneumonia). Secondary outcomes …

Objective To assess the long-term analgesic effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex in patients with chronic pain syndrome. Methods The study included 57 patients (orofacial pain, n = 26, pudendal neuralgia, n = 18, and neuropathic limb pain, n = 13) with an “induction phase” of 12 daily rTMS sessions for 3 weeks, followed by a “maintenance phase” of bi-monthly sessions for the next five months. Results All pain measures significantly decreased from baseline to the end of the induction phase. Analgesic response, defined as pain intensity decrease ≥ 30% compared to baseline, was observed in 39 patients (68%), who could be differentiated from non-responders from the 7th rTMS session. At the end of the maintenance phase (D180), 27 patients (47%) were still responders. Anxio-depressive symptoms and quality of life also improved. The analgesic response at the end of the induction phase was associated with lower pain score at baseline, and the response at the end of the maintenance phase was associated with lower anxio-depressive score at baseline. Conclusion The analgesic efficacy of motor cortex rTMS can be maintained in the long term in various chronic pain conditions. Patients with high pain level and severe anxio-depressive symptoms may have a less favorable profile to respond to the procedure. Significance The overall impact of rTMS treatment on daily life requires a multidimensional evaluation that goes beyond the analgesic effect that can be achieved.

SummaryBackgroundAssociation between DPP4 inhibitors and respiratory infection remains unclear. CardioVascular Outcomes Trials (CVOTs) conducted before the COVID-19 pandemic are available. We aimed to estimate the effect of DPP4 inhibitors on the risk of respiratory infections.MethodsWe updated a previous systematic review and meta-analysis, searching for CVOTs assessing a DPP4 inhibitor in patients with type 2 diabetes mellitus. We focused on placebo-controlled CVOTs. Our primary outcome was ‘any respiratory infection’. We added a sensitivity analysis integrating non-CVOTs and active-controlled CVOTs.FindingsWe included 47 714 patients in five placebo-controlled CVOTs. Median follow-up ranged from 1·5 years to 3 years. 4 369 events of overall respiratory infection were reported (rate of 9·2%). DPP4 inhibitors were not associated with a different risk compared to placebo (RR = 0·99 [95% CI: 0·93; 1·04]). The sensitivity analysis integrating the non-CVOTs studies and the active-controlled CVOT reached 11 349 events among 82 644 participants (rate of 13·7%). DPP4 inhibitors were not associated with a different risk of overall respiratory infection (RR = 1·00 [95% CI: 0·97; 1·03]).InterpretationOur up-dated meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. We did not find any effect of the DPP4 inhibitors on the risk of respiratory infection. Our results support the recently published practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic.FundingNo source of fundingPanel: Research in contextEvidence before this studyFrom before the COVID19 pandemic, respiratory infections are considered potential adverse effects of DPP4 inhibitors. Randomized trials assessing DPP4 inhibitors in patients with type 2 diabetes (T2D), their meta-analyses and pharmacovigilance studies reported conflicting results. Since the last meta-analyses assessing the risk of infections with DPP4 inhibitors, powerful cardiovascular outcomes randomized trials (CVOTs) became available. Recent practical recommendations for the management of diabetes during COVID-19 suggested that DPP4 inhibitors could be continued. We updated our previous meta-analysis of CVOTs and focused to the overall risk of respiratory infection associated with DPP4 inhibitors. We searched for published and unpublished CVOTs in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov, up to January 27, 2020, using key word as “diabetes mellitus”, “hypoglycemic agents”, “glucose control”, “randomized controlled trial”, “cardiovascular diseases”.Added value of this studyWe included CVOTs comparing a DPP4 inhibitor versus placebo, in people with T2D, and analysed the risk of respiratory infection with DPP4 inhibitors. We focused on placebo-controlled CVOTs to avoid the pitfalls of small study effect and heterogeneous comparators. We added a sensitivity analysis integrating non-CVOTs and non-placebo CVOTs to challenge our results and to increase the statistical power. Our meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. Our analyses integrated 11 349 events of any respiratory infections through 82 644 patients from randomized trials. Our results did not find any association between DPP4 inhibitors use and risk of non-COVID respiratory infections.Implications of all the available evidenceThe current COVID-19 pandemic has raised some questions about pros and cons of certain cardiovascular drugs. Our results support the recent practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic.

Bronchial diseases are characterised by the weak efficiency of mucus transport through the lower airways, leading in some cases to the muco-obstruction of bronchi. It has been hypothesised that this loss of clearance results from alterations in the mucus rheology, which are reflected in sputum samples collected from patients, making sputum rheology a possible biophysical marker of these diseases and their evolution. However, previous rheological studies have focused on quasi-static viscoelastic (linear storage and loss moduli) properties only, which are not representative of the mucus mobilisation within the respiratory tract. In this paper, we extend this approach further, by analysing both quasi-static and some dynamic (flow point) properties, to assess their usability and relative performance in characterising several chronic bronchial diseases (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) and distinguishing them from healthy subjects. We demonstrate that pathologies influence substantially the linear and flow properties. Linear moduli are weakly condition-specific and even though the corresponding ranges overlap, distinct levels can be identified. This directly relates to the specific mucus structure in each case. In contrast, the flow point is found to strongly increase in muco-obstructive diseases, which may reflect the complete failure of mucociliary clearance causing episodic obstructions. These results suggest that the analysis of quasi-static and dynamic regimes in sputum rheology is in fact useful as these regimes provide complementary markers of chronic bronchial diseases.

Background Recent guidelines recommend riociguat, a soluble guanylate cyclase (sGC) stimulator, and the type 5 phosphodiesterase inhibitor (PDE5i) tadalafil or sildenafil as treatments for pulmonary arterial hypertension. We compared the safety profiles of sildenafil, tadalafil, and riociguat in pulmonary hypertension. Methods We combined two approaches. First, we performed a meta-analysis of safety data extracted from randomized controlled trials. Second, we conducted a disproportionality analysis of data from VigiBase, the World Health Organization's global database of individual case safety reports, to compare the safety profiles with real-life data. Results In the meta-analysis, a significant difference between the three drugs was only detected for gastrointestinal disorders, in disfavor of riociguat ( P Conclusions The safety profiles of PDE5is and sGC stimulators significantly differ in pulmonary hypertension. Accordingly, there is a safety rationale in switching between PDE5is and sGC stimulators because of their different side effects. Trial Registry PROSPERO; No.: CRD42016051986; URL: https://www.crd.york.ac.uk/prospero/.

This disproportionality analysis uses the World Health Organization pharmacovigilance database to explore the potential safety signal of facial paralysis after COVID-19 vaccination.

Ischaemic digital ulcers (DUs) are an indicator of the severity of the microangiopathy in patients with systemic sclerosis (SSc). DUs are a frequent complication, affecting about 50% of patients with SSc, and are often recurrent. In cross-sectional studies involving patients with SSc, the frequency of ischaemic DUs was 12-16% with a major impact on hand function and quality of life. Effective therapy for DUs remains elusive. Intravenous iloprost has been demonstrated to have a positive effect on healing of active DUs. Bosentan, an oral endothelin receptor antagonist, only showed a benefit in preventing the occurrence of new DUs. Despite limited evidence, recent guidelines have recommended phosphodiesterase type 5 inhibitors as an option. Injection of botulinum toxin and digital sympathectomy have been increasingly used for ischaemic DUs. Here we present the complex case of a SSc patient already treated with sildenafil and bosentan in whom an active DU was successfully treated with botulinum toxin A. Despite the lack of a randomised controlled trial, results are encouraging for the use of botulinum toxin in the treatment of DUs and could perhaps help to avoid some amputations, as in the present case.

International audience; The impact of the local inhibition of soluble epoxide hydrolase, which metabolizes vasodilator and anti-inflammatory epoxyeicosanoids, on diabetic skin microvascular dysfunction was assessed. In diabetic db/db mice, basal skin blood flow assessed using laser Doppler imaging was similar to that of control mice, but thermal hyperemia was markedly reduced. At 2 h after the topical administration of an aqueous gel containing the soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB: 400 mg/L), the peak concentration of t-AUCB was detected in the skin of diabetic mice, which quickly decreased thereafter. In parallel, 2 h after application of t-AUCB treatment, thermal hyperemia was increased compared to the control gel. Quantification of t-AUCB in plasma of treated animals showed no or low systemic diffusion. Furthermore, haematoxylin and eosin histological staining of skin biopsies showed that skin integrity was preserved in t-AUCB-treated mice. Finally, for pig ear skin, a surrogate for human skin, using Franz diffusion cells, we observed a continuous diffusion of t-AUCB from 2 h after application to beyond 24 h. A single topical administration of a soluble epoxide hydrolase inhibitor improves microcirculatory function in the skin of db/db mice and might represent a new therapeutic approach for preventing the development of skin complications in diabetic patients.

OBJECTIVE Fibromyalgia (FM) is a chronic painful condition partly due to alterations in pain modulation by the central nervous system. Multicomponent therapy (MT) and repetitive transcranial magnetic stimulation (rTMS) have both been reported as pain modulators in patients with FM. The aim of this study was to compare the effects of rTMS on pain with a combination of MT and rTMS versus MT alone. METHODS Thirty-nine FM patients with visual analog scale (VAS) results for pain of ≥40 mm were randomized to active or sham rTMS (high-frequency, primary motor cortex M1) plus 12 weeks of MT (3 sessions per week combining aerobic training, pool-based exercises, and relaxation). Repetitive TMS was started 2 weeks prior to MT and maintained until the end of the program (week 14). Assessments were achieved at baseline, at week 14, and at 6 months (week 40) after completion of the program. The main criterion was pain reduction, as assessed by the weekly mean self-reported level of pain (reported daily). Secondary outcomes were cardiorespiratory fitness (graded maximal exercise test), cardiac autonomic adaptations, and FM impact (using scales for FM impact, depression, sleep efficiency, and pain catastrophizing). RESULTS The reduction of the weekly mean of pain reported daily did not differ significantly between groups (using repeated measures of analysis of variance [ANOVA]). Two-way ANOVAs showed that pain VAS results, as well as cardiorespiratory fitness, quality of life, depression, and catastrophizing, improved significantly at week 14 and remained stable until week 40. Neither cardiac autonomic adaptations nor sleep efficiency changed significantly. CONCLUSION Repetitive TMS did not reduce pain in patients with FM who followed the MT program.

Background:Inhibiting a specific JAK may impede more than one pathway, explaining both the efficacy and adverse effects observed with JAK inhibitors (JAKi). Among those, there have been recent concerns about potential thromboembolic risks with these drugs. As patients enrolled are not representative of all patients who may receive JAKi, data from trials are unlikely to provide definitive answers. Real impact of JAKi in real life on major cardiovascular events is not known.Objectives:To evaluate the risk of venous and arterial thromboembolic events with the use of JAKi in a real-world setting.Methods:A self-controlled case series analysis (method in which individuals act as their own control) was performed using data from the French national healthcare insurance system SNDS (“Système National des Données de Santé”), which included all anonymized individual level data about sociodemographic data, outpatient healthcare dispensed, hospital discharge summaries, and registration status for a list of 30 long term diseases. All patients treated by JAKi (baricitinib or tofacitinib) for rheumatoid arthritis, psoriasis arthritis and/or inflammatory bowel disease, and with at least one thromboembolic event (venous (VTE): deep vein thrombosis (DVT), pulmonary embolism (PE), arterial (ATE): acute coronary syndrome (ACS), myocardial infarction (MI), transient ischemic attack (TIA) and stroke) between 2017/11/01 and 2019/06/30 were included in the study. Associations were evaluated by incidence rate ratios (IRR), which compare the rate of events during exposed periods with rate of event during all other observed time periods. Exposed periods were defined as i) exposure to JAKi, ii) the month following exposure (post-exposure 1-30 days), and iii) long-term post-exposure (31 to 60 days). A pre-exposure period of 7 days was individualized to identify event-dependent probabilities of exposure and potential reverse causality bias, and all other periods were considered as non-exposed periods.Results:Among the 5,870 patients treated with JAKi between 2017/11/01 and 2019/06/30, 94 presented an incident thromboembolic event and were included. Almost two thirds were female (n=61, 64.9%), and median age was 65.4 [IQR: 55.5; 75.8] years. Most of patients have a rheumatoid arthritis (n=91, 96.8%), 62 (66.0%) were treated by baricitinib, and 32 (34.0%) by tofacitinib. Almost half (n=42, 44.7%) presented a venous thromboembolism, mainly DVT (n=31, 33.0%), and 52 (55.3%) presented an arterial thromboembolism, mainly MI (n=16, 17.0%) and stroke (n=14, 14.9%). Eleven patients (11.7%) died during the study period. The median time of occurrence of VTE was 4.3 [IQR: 2.5; 8.9] months, and 6.1 [IQR: 3.3; 9.2] months for ATE.The median duration of exposure was 6.0 [IQR: 3.3; 10.1] months for VTE, and 12.0 [IQR: 4.8; 15.3] months for ATE. The IRR for VTE and ATE were increased during exposure, and during the 30 days following exposure (Table 1). The IRR for VTE was only increased during exposure and in the early post-exposure phase contrary to the IRR for ATE that was also increased in the pre-exposure 7-Day period. Analysis conducted on survival patients confirmed results.Table 1.NPatient-yearsIRR95%CIVenous thromboembolic eventsNon-exposure (reference)83975.01-Pre-exposure to JAK-i1135.24.70.6-38.0Exposure to JAK-i272090.59.84.1-23.3Post-exposure 1-30 d5369.06.21.9-19.9Post-exposure 31-60 d1139.01.50.2-12.6Arterial thromboembolic eventsNon-exposure (reference)74076.81-Pre-exposure to JAK-i3344.111.52.8-46.8Exposure to JAK-i326363.87.42.9-18.7Post-exposure 1-30 d8659.211.53.8-34.6Post-exposure 31-60 d2132.24.30.8-22.0Conclusion:The present study found an increased risk of VTE and ATE for baricitinib and tofacitinib. The risk persists in the month following the discontinuation of treatment but disappears after day 30 post-exposure.Disclosure of Interests:Amandine Gouverneur: None declared, Jérôme Avouac Consultant of: JA has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis from (last three years): Abbvie, Galapagos, Pfizer, Bristol Myers Squibb, Sanofi, Nordic Pharma, Chugai and MSD., Grant/research support from: JA has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis from (last three years): Abbvie, Galapagos, Pfizer, Bristol Myers Squibb, Sanofi, Nordic Pharma, Chugai and MSD., Clément Prati: None declared, Jean-Luc Cracowski: None declared, Thierry Schaeverbeke Consultant of: TS consultancy and/or research fundings: Abbvie, Lilly, Pfizer, Galapagos, Novartis, BMS, Medac, NordicPharma, Biogen, Mylan, Janssen., Grant/research support from: TS consultancy and/or research fundings: Abbvie, Lilly, Pfizer, Galapagos, Novartis, BMS, Medac, NordicPharma, Biogen, Mylan, Janssen., Antoine Pariente Grant/research support from: AP reports acting as an independant expert towards the French Medicines Agency (Agence Nationale de Securité du Médicament et des Produits de Santé, ANSM) and the European Medicines Agency (EMA). AP coordinates the DRUGS Systematised Assessment in real-liFe EnviRonment (DRUGS-SAFER) programme funded by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM)., Marie-Elise Truchetet Consultant of: has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis and spondyloarthritis and their complications from (last three years): Abbvie, Galapagos, Lilly, Medac, Novartis, Pfizer, and Roche., Grant/research support from: has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis and spondyloarthritis and their complications from (last three years): Abbvie, Galapagos, Lilly, Medac, Novartis, Pfizer, and Roche.

Summary Objective We evaluated the feasibility and the tolerance of repeated fluorescent indocyanine green angiography in free flap monitoring, and determined the intraoperative predictive values of flap vitality. Background The free flap failure rate has been significantly reduced, but free flap loss still occurs and remains a costly disaster. Repeated clinical examinations are commonly used for flap monitoring, but they can be unreliable because of their subjectivity. Laser-induced fluorescence of indocyanine green is a new method for assessing tissue perfusion. Methods 20 patients undergoing microsurgical reconstruction were monitored by indocyanine green fluorescence angiography, intraoperatively, and during 4 days after surgery, with 18 injections. Monitoring was made by clinical examination, and then compared to angiographic findings. Results The vascular complication rate was 15% (3/20) with 2 cases of venous thrombosis and one case of partial necrosis of the flap skin paddle. Both cases of venous thrombosis were salvaged by secondary surgery. There was no total flap loss. ICG angiography allowed detecting each intra and postoperative complication, earlier than clinical examination. The mean per-operative intensity of fluorescence was significantly lower in flaps with vascular complications (23.8 GL/ms; p = 0.008). The postoperative slope (p = 0.02) and amplitude (p = 0.03) of the fluorescent signal were both significantly lower than for uncomplicated flaps, before surgical revision. These 2 parameters came back to normal values after secondary surgery. There was no adverse effect of ICG despite the repeated injections. Conclusion ICG angiography is a feasible and safe technique for the detection of free flap vascular complications.

Background Pulmonary arterial hypertension (PAH) is a rare progressive disease with a 3-year mortality rate of approx. 45% in incident patients. The prostacyclin, endothelin-1 (ET-1), and nitric oxide (NO) pathways are validated therapeutic targets, however the underlying pathomechanisms are not yet fully understood. In the present study, we investigated metabolites of the NO pathway (e.g. l-arginine, asymmetric dimethylarginine (ADMA), and homoarginine), which are potentially involved in the pathophysiology of PAH. Methods Newly diagnosed, treatment-naive incident PAH patients were recruited from six centers and followed for three years. In longitudinal analyses we investigated the prognostic potential of these markers. Cross-sectional analysis was later used to study associations between prognostic relevant markers and clinical phenotypes of PAH. Results Among 108 enrolled patients (53±17years, mean±SD), 76 had idiopathic (i)PAH. Kaplan–Meier survival analysis and adjusted Cox proportional hazard models identified homoarginine as an independent predictor of mortality (HR:0.51, CI:0.28–0.94 for PAH and HR:0.41 CI:0.19–0.88 for iPAH), but not l-arginine or ADMA. Homoarginine was lower in 27 patients who died during the follow-up, i.e. 1.26±0.48 vs. 1.64±0.69μmol/L, P P Conclusion Homoarginine was found an independent predictor for mortality in newly diagnosed PAH and iPAH patients. Further experimental studies are necessary to elucidate the involvement of homoarginine in the pathophysiology of PAH and its potential role as a therapeutic option for these patients.

Aim Drug-induced Raynaud's phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or β-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. Methods A systematic review of English and French language articles was performed through Medline (1946–2015) and Embase (1974–2015). Further relevant papers were identified from the reference lists of retrieved articles. Results We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by β-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. Conclusion Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.

Introduction Diabetes is associated with impairment of cutaneous wound healing and can lead to lower limb amputation. The cutaneous microcirculation in diabetes is impaired due to alterations of the nitric oxide and prostacyclin pathways that can be therapeutic targets. Topical application of lipid nanoparticles can increase drug delivery through improved stability and controlled delivery compared to classical formulations. Objective We tested the efficacy of topical delivery of the prostacyclin analogue treprostinil and the IP receptor agonist ACT-333679 (active metabolite of selexipag), encapsulated in lipid nanoparticles, on wound healing in a diabetic mice model. Method We used 80 nm cationic (C80) or neutral (N80) lipid nanoparticles. Cationic emulsions (EM) were also formulated. For the wound healing study, 12-week-old males db/db mice were used. Two 8 mm2 diameter ulcers were made on the back of each animal and protected using a transparent, occlusive dressing. Each treatment was evaluated on 12 mice with one ulcer treated with the treatment and the contralateral ulcer treated with the vehicle. Wounds were treated daily over 24 days and evaluated daily using planimetry (ImageJ, NIH). Area under the curve (AUC) of the wound surface (expressed as a % of day 0 size) was calculated and compared between treatments and their vehicles. Results Encapsulation of ACT-333679 was stable in C80 and N80 for 6 months at 4 °C. Encapsulation of ACT-333679 was stable for 3 months at 4 °C. Encapsulation of Treprostinil was stable for 3 months in C80 while encapsulation was not stable in EM (1 month stability). Both Treprostinil and ACT-333679 increased the rate of wound healing in the db/db mice model. There was no major difference between lipid nanoparticles and emulsions. Conclusion Stable lipid nanoparticles loaded with IP receptors agonists can be formulated in a topical gel, are stable over time and result in an improved wound healing in a diabetic mouse model.

Objectives:To investigate alterations in the serum proteome of patients with systemic sclerosis (SSc)-associated pulmonary hypertension (PAH), to identify proteins that correlated with hemodynamic severity and to determine their possible pathogenic role.Methods:Patients were included if they fulfilled the following criteria: diagnosis of limited cutaneous SSc, no extensive interstitial lung disease (ILD), and no treatment with PAH-specific therapy. Patients were classified as cases if they had a definitive diagnosis of PAH confirmed by right heart catheterization (RHC) and a serum sample collected on the same day as RHC. They were classified as controls if they had no sign suggestive of PAH on echocardiography.Results:In a first exploratory step, serum expression of 1129 proteins was assessed in 15 cases and 16 controls by a high-throughput proteomic assay (SOMAscan). We identified 53 proteins differentially expressed between the 2 groups. Among these 53 candidates, only 2 correlated significantly with pulmonary vascular resistance (PVR): chemerin (p=0.01,ρ=0.62) and SET nuclear proto-oncogen (SET) (p=0.01,ρ=0.62).To validate these results, serum levels of chemerin and SET were measured by ELISA assay in 25 additional cases and 19 additional controls. Chemerin levels were confirmed to be significantly higher in cases (p=0.01) and correlated with PVR (p=0.01,ρ=0.46).In a second step, to study the potential pathophysiological role of chemerin, we performed confocal immunofluorescence analyses on explanted lungs of healthy controls, SSc-ILD without PAH and SSc-PAH patients. Chemerin receptor, CMKLR1, was significantly increased on SSc-ILD and SSc-PAH pulmonary artery smooth muscle cells (PA-SMC).We then tested the effect of chemerin on PA-SMC proliferation by stimulating PA-SMCs from idiopathic pulmonary arterial hypertension (iPAH) patients with serum from SSc patients with and without PH, in the presence or absence of a CMKLR1 inhibitor. PA-SMCs from iPAH were confirmed to have higher mRNA expression of CMKLR1 than controls (p=0.03). Serum from SSc-PH patients induced a significantly higher PA-SMC proliferation (p=0.005) than serum from controls. This difference was no longer significant (p=0.69) when adding the CMKLR1 inhibitor α–NETA.Conclusion:Chemerin is a surrogate biomarker for PVR in SSc-PAH. Increased chemerin and its receptor, CMKLR1, contribute to the SSc-PAH pathogenesis by inducing PA-SMC proliferation.Acknowledgments:NoneDisclosure of Interests:Sebastien SANGES: None declared, Lisa Rice: None declared, Ly Tu: None declared, Jean-Luc Cracowski Grant/research support from: JL Cracowski received grants from United Therapeutic, Bioprojet and Topadur, David Montani Grant/research support from: Dr. MONTANI reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, personal fees from MSD, personal fees from Chiesi, outside the submitted work, Julio Mantero: None declared, Camille Ternynck: None declared, Guillemette Marot: None declared, Eric Hachlla: None declared, David Launay Grant/research support from: Dr. Launay reports personal fees from Actelion, grants and personal fees from Takeda, grants and personal fees from CSL Behring, outside the submitted work., Marc Humbert Grant/research support from: Dr. Humbert reports personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, from United Therapeutics, personal fees from Acceleron, outside the submitted work., Christophe Guignabert: None declared, Robert Lafyatis Grant/research support from: RL holds research grants from Formation, Elpidera and Kiniksa., Consultant of: R.L. has served as a consultant for Bristol Myers Squibb, Boehringer-Mannheim, Merck, Magenta and Genentech/Roche

Summary The Raynaud's condition score is a 11-point scale severity score used in Raynaud's phenomenon clinical trials since 1998. The Raynaud's condition score diary has been recommended for use in clinical trials assessing efficacy of interventions on scleroderma related Raynaud's phenomenon. However, this score has never been formally validated in French. We thus performed a translation and a linguistic validation of the Raynaud's condition score through a forward/backward translations process followed by an expert review and cognitive patient interviews. The translations led to a French version of the Raynaud's condition score that was linguistically valid, and conceptually equivalent to the original English version. This “Score de Raynaud” will be usable to perform and harmonize clinical trials in French-speaking patients with secondary Raynaud's phenomenon.

Introduction & Background: Due to the structural similarity between gabapentin and baclofen, gabapentin was reported to produce ‘baclofen-like’ effects. Baclofen is linked to sleep apnea syndrome (SAS), aggravating sleep-disordered breathing by depressing central ventilatory drive and/or increasing upper airway obstruction. Aims & Objectives: We hypothesized that gabapentinoids might be associated with SAS. Methods: We performed a disproportionality analysis within Vigibase, the large WHO pharmacovigilance database. The relationship between the use of each antiepileptic and the occurrence of adverse drug reaction (i.e. SAS) was assessed by calculating the reported odds ratio (ROR) [95% confidence intervals] in a case-noncase model. Results: Of the 17 519 277 Individual Case Safety Reports reported to Vigibase between December 1970 and July 2018, 8915 (0.05%) were SAS cases; 76 cases of SAS for gabapentin and 123 for pregabalin. The ROR for both drugs were significant: 2.61 [2.08 to 3.27] for gabapentin and 2.42 [2.02 to 2.89] for pregabalin, whereas no other antiepileptic drugs had a ROR with lower boundary > 2. The ROR was also significant for benzodiazepines: 3.07 [2.58 to 3.66] (Figure 1). Conclusions: Rates of gabapentinoids use in the USA tripled between 2002 and 2015, especially in opioid crisis context leading to the emergence of pregabalin and gabapentin misuse and abuse. Physicians need to be aware that sleep apnea might affect patients treated with gabapentinoids.

Diabetic foot ulcers are one of the most common and serious complications of diabetes mellitus. Few drugs are effective in enhancing the healing of microvascular skin ulcers. The main objective of the present study was to determine whether iontophoresis of treprostinil, a prostacyclin analog, increases skin microvascular blood flux in the malleolus area of healthy subjects and diabetic patients. We recruited 12 healthy subjects and 12 type 2 diabetic patients. Cathodal iontophoresis (40 mC/cm²) of treprostinil 250 µM and NaCl 0.9% was performed in the malleolus area. Skin hyperemia was quantified using non-invasive laser speckle contrast imaging, and expressed as the area under the curve (AUC) of cutaneous vascular conductance (CVC). In healthy controls and diabetic patients, treprostinil 250 µM induced a significant increase in CVC compared with NaCl (for diabetic patients, AUC 0–6 h was 19970±8697; versus 2893±5481%BL.min, respectively; P =0.002). In both groups, the peak flux was obtained between 30 min and 1 h after the end of treprostinil iontophoresis and flux remained higher than baseline up to 6 h after ending of iontophoresis. No significant side-effect occurred. Cutaneous iontophoresis of 250 µM treprostinil increases microvascular blood flux in the malleolus area in healthy volunteers and diabetic patients, without inducing systemic or local side-effects. Treprostinil cathodal iontophoresis should be further investigated as a new local therapy for diabetic ulcers.

Inhibitors of the sodium-glucose co-transporter-2 (SGLT-2) are a novel class of glucose-lowering agents that show promising results. However, the use of canagliflozin has been associated with an increased risk of lower-limb amputation. Whether this risk concerns other SGLT-2 inhibitors is unclear, and our objective was to address this issue. We performed a disproportionality analysis using the WHO global database of individual case safety reports (VigiBase). Among the 8 293 886 reports available between January 2013 and December 2017, we identified 79 reports of lower-limb amputation that were associated with SGLT-2 inhibitors. Among all blood glucose lowering drugs, the proportional reporting ratio (PRR) was increased only for SGLT-2 inhibitors (5.55 [4.23, 7.29]). While we observed an expected signal for canagliflozin (7.09 [5.25, 9.57]), the PRR was also high for empagliflozin (4.96 [2.89, 8.50]) and, for toe amputations only, for dapagliflozin (2.62 [1.33, 5.14]). In conclusion, our results reveal a positive disproportionality signal for canagliflozin, and also for empagliflozin, and, for toe amputations only, for dapagliflozin. However, our analysis relies on a limited number of cases and is exposed to the biases inherent to pharmacovigilance studies. Further prospective data are therefore needed to better characterize the risk of amputations with different SGLT-2 inhibitors.

Introduction: Rheology can be a tool to diagnose COPD and assess the efficiency of treatments on market or in development, by evaluating the consistency of sputum. Rheology allows a better understanding of the expectoration deficiencies in patients with COPD. The study aims to find out whether rheology can be used in a clinical context. Material & Methods: The Rheomuco device was used to measure the viscoelastic properties in a clinical study (NCT02682290) called “ Assessment of Rheological Parameters of Human Sputum ”. Two properties are mainly extracted: elastic modulus (G’) at 1Hz and viscous modulus (G’’) at 1Hz. The study was led by and in the Grenoble University Hospital (France) with 3 groups: 10 COPD, 10 ASH and 10 HV. The study is still going on and will end by late July 2017. During the visits, COPD, ASH and HV have a spontaneous expectoration and an induced expectoration with hypertonic saline solution (4.5%). Partial Results & Analysis: The Figure shows that COPD group is significantly different from HV and ASH.s Extra results show that hypertonic saline solution reduces G’ by 56% and G’’ by 48% for COPD, and the rheological behavior tends to HV one. Sputum in general are more viscous than elastic, and those properties can cluster COPD patients. Conclusion: Rheology can be used as a tool to diagnose and monitor treatment efficiency for COPD.

We investigated the effect of neuromuscular electrical stimulation (NMES) training prior to endurance training in patients with cystic fibrosis (CF) and severe pulmonary obstruction.Fourteen patients with CF (FEV(1) = 35% ± 11% predicted) were prospectively randomized to either a 6-week NMES training program (n = 7) or a 6-week control period (n = 7) both followed by ergocycle (ERGO) training (8 weeks) (NMES + ERGO and control + ERGO groups). Measurements were pulmonary function, mid-thigh circumference, quadriceps strength, 6-min walk distance, maximal exercise capacity on a cycloergometer, plasma biomarkers, insulin resistance (homeostasis model assessment indexes), and quality of life (CF questionnaire for adults and teenagers14 years of age [CFQ14 + ], Baseline Dyspnea Index-Transition Dyspnea Index).NMES + ERGO training greatly improved mid-thigh circumference ( + 2.6 ± 0.9 cm vs - 0.4 ± 1.4 cm), quadriceps strength ( + 6 ± 5 kg vs - 2 ± 2 kg), and BMI ( + 0.6 ± 0.6 kg/m(2) vs - 0.5 ± 0.7 kg/m(2) ) compared with control + ERGO training ( P.05). No differences between groups were found in exercise-induced changes in 6-min walk distance and maximal exercise capacity. However, dyspnea after the 6-minute walk test, the fasting glucose/insulin ratio (calculated as an index of insulin resistance), and physical function and health perception domains of the CFQ14 + improved after NMES + ERGO training compared with control + ERGO training ( P.05). Significant correlations were found between changes in mid-thigh circumference and muscle strength, ventilation requirements during exercise, insulin sensibility, and the physical function section of CFQ14 + ( P.05).NMES training performed prior to endurance training is useful for strengthening peripheral muscles, which in turn may augment gains in body weight and quality of life, further reductions in ventilation requirements during exercise, and retard insulin resistance in patients with CF with severe pulmonary obstruction.

Recent technical developments enable skin fluorescence to be quantified in vivo in humans. The present study aimed at determining whether flow mediated skin fluorescence was reproducible, sensitive to changes within an individual, and if it could differ between patients with coronary artery disease and healthy volunteers.First, forearm flow mediated skin fluorescence recorded during and after brachial artery occlusion was assessed following successive forearm occlusion periods (1, 2, 3 and 5min) and expressed as ischemic and hyperemic responses (as % of baseline). Secondly, 3min flow mediated skin fluorescence was assessed before and after 10min local cooling to 15°C. In a third protocol, the inter-day reproducibility of ischemic and hyperemic responses to 3min occlusion was tested at an interval of 7days, and compared between healthy controls and patients with coronary artery disease (CAD).In the first protocol, we observed a time dependent increase in the ischemic and hyperemic responses to occlusion. Next, we observed a lower hyperemic response after local cooling (9.8±4.2 versus 17.8±2.5% respectively, P0.001), while in contrast, the ischemic response was higher and exhibited greater variability (23±15 versus 11.8±6.4%; P=0.028). In the third protocol, the inter-day reproducibility of flow mediated skin fluorescence for a 3min occlusion period was excellent. The ischemic response was significantly lower in CAD patients than in healthy controls (6.7±4.8% vs 14.7±6.8% respectively, P0.001). Similarly, the hyperemic response was significantly decreased in the CAD group compared to healthy controls (11.6±3.6% vs 19.5±5.4% respectively, P0.001).We show that quantifying the ischemic and hyperemic flow mediated skin fluorescence is feasible, reproducible, sensitive to acute changes in skin blood flow, and distinguishes patients populations. However, more data are needed to evaluate the correlation with other methods or specific biochemical endothelial markers.

Pioneering work demonstrated that an unstable substance isolated from rabbit and pig aortas could relax arterial smooth muscle and inhibit platelet aggregation. Since then, prostacyclin (prostaglandin I2, PGI2) and its analogs have raised much pharmacological interest. In this review we detail how the PGI2 signaling pathway is much more complex than was initially anticipated, involving peroxisome proliferator-activated receptors (PPARs), prostaglandin transporters (PGTs), and PGI2-thromboxane A2 (TXA2) receptor (IP TP) heterodimerization. We discuss the distinct affinities of PGI2 analogs for prostanoid receptors. In addition, we introduce the new direct and indirect pharmacological approaches to targeting the PGI2 pathway within the systemic circulation, including non-prostanoid agonists of the prostacyclin receptor (IP) and PGT inhibitors, as well as transcutaneous pathways using iontophoresis and nanostructured lipid carriers.

International audience; The vagus nerve (VN) is a link between the brain and the gut. The VN is a mixed nerve with anti-inflammatory properties through the activation of the hypothalamic-pituitary-adrenal axis by its afferents and by activating the cholinergic anti-inflammatory pathway through its efferents. We have previously shown that VN stimulation (VNS) improves colitis in rats and that the vagal tone is blunted in Crohn's disease (CD) patients. We thus performed a pilot study of chronic VNS in patients with active CD. Seven patients under VNS were followed up for 6 months with a primary endpoint to induce clinical remission and a secondary endpoint to induce biological (CRP and/or fecal calprotectin) and endoscopic remission and to restore vagal tone (heart rate variability). Vagus nerve stimulation was feasible and well-tolerated in all patients. Among the seven patients, two were removed from the study at 3 months for clinical worsening and five evolved toward clinical, biological, and endoscopic remission with a restored vagal tone. These results provide the first evidence that VNS is feasible and appears as an effective tool in the treatment of active CD.

Raynaud's phenomenon (RP) is defined as episodic ischemia of the extremities in response to cold. Although the structure of skin capillaries is normal in primary RP, some data suggest impairment of microvascular function. We aimed at testing whether digital skin blood flow was lower in RP than in controls while cooling locally. We further evaluated the contribution of sensory nerves in the response. We recruited 21 patients with primary RP and 20 healthy volunteers matched on age and gender. After a 10-min baseline at 33°C, skin temperature was cooled at 15 or 24°C during 30 min on the forearm and the finger while monitoring perfusion with a custom-design laser Doppler flowmetry probe. Perfusion was also assessed after topical anesthesia. Blood flow was expressed as cutaneous vascular conductance (CVC). Data were subsequently expressed as area above the curve (AAC0–30) of the percentage decrease from baseline CVC (%BL). CVC on the dorsum of the finger was lower in RP patients compared with controls at 15°C (AAC0–30 were 106,237.2 and 69,544.3%BL·s, respectively; P = 0.02) and at 24°C (AAC0–30 were 86,915 and 57,598%BL·s, respectively; P = 0.04) whereas we observed no significant difference on the finger pad and the forearm. Topical anesthesia increased CVC in patients with RP ( P = 0.05), whereas it did not affect reactivity in controls ( P = 0.86). Our study shows exaggerated skin microvascular vasoconstriction to local cooling on the dorsum of the finger in primary RP compared with controls. Part of this abnormal response in primary RP depends on sensitive nerves.

Please cite this paper as: Blaise, Roustit, Millet, and Cracowski (2011). Effect of Oral Sildenafil on Skin Postocclusive Reactive Hyperemia in Healthy Volunteers. Microcirculation 18(6), 448–451. Abstract Objective: Sildenafil is a type 5 phosphodiesterase inhibitor that has a theoretical ability to increase hyperemia following a short bout of ischemia. We tested if oral sildenafil increases skin PORH in healthy volunteers. Methods: We assessed forearm skin PORH (occlusion of blood flow for five minutes) in ten healthy volunteers 120 minutes following the oral administration of 50 or 100 mg of sildenafil. Cutaneous blood flow on the forearm was monitored using LDF. Results: The PORH peak, expressed as a percentage of baseline, was clearly increased with 100 mg sildenafil: 746% (95% CI 447–1044) versus 484% (95% CI 354–613) with 50 mg sildenafil, and 468% (95% CI 347–588) without sildenafil (p = 0.03 for 100 mg versus 50 mg and control). Oral sildenafil at 50 mg increased the AUC of PORH on the forearm compared with control: 4568 PU.sec (95% CI: 2252–6883) with 50 mg sildenafil versus 1030 PU.sec (95% CI 737–1322) without sildenafil (p = 0.006). Likewise, 100 mg sildenafil increased the AUC (5271 PU.sec (95% CI −81–10,623), albeit bordering on significance (p = 0.07). Neither dose increased maximal LTH. Conclusions: Acute sildenafil administration at 50 and 100 mg enhances skin hyperemia following a short bout of ischemia.

Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk-benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative.To assess the efficacy and safety of on-demand sildenafil in RP.Series of randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov: NCT02050360).Outpatients at a French university hospital.Patients with primary or secondary RP.Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily.Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy.38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients.The response to sildenafil was substantially heterogeneous among patients.Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP.GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rhône-Alpes (academic funding) and Pfizer.

Objective There is now growing evidence that connective tissue diseases, including systemic sclerosis (SSc), share a common genetic background. Microarray studies support a pivotal role of type I interferon (IFN) in the pathophysiology of connective tissue diseases. Interferon regulatory factors coordinate the expression of type I IFNs, and the IRF5 gene has been identified as a susceptibility gene of systemic lupus and Sjogren's syndrome. The aim of this study was to determine whether the IRF5 rs2004640 single-nucleotide polymorphism is associated with SSc. Methods The IRF5 rs2004640 (GT) functional polymorphism was genotyped in 1,641 subjects of French European Caucasian origin: a discovery set comprising 427 patients with SSc and 380 control subjects and a replication set comprising 454 patients with SSc and 380 control subjects. Results In both the discovery set and the replication set, the TT genotype was significantly more common in patients with SSc than in control subjects, with an odds ratio (OR) for the combined populations of 1.58 (95% confidence interval [95% CI] 1.18–2.11 [P for trend 0.002]). Analyses of the whole SSc population showed a significant association between homozygosity for the T allele and the presence of antinuclear antibodies (corrected P [Pcorr] = 0.04, OR 1.59, 95% CI 1.16–2.17) and fibrosing alveolitis (Pcorr = 0.001, OR 2.07, 95% CI 1.38–3.11). In a multivariate analysis model including the diffuse cutaneous subtype of SSc and positivity for anti–topoisomerase I antibodies, the IRF5 rs2004640 TT genotype remained associated with fibrosing alveolitis (P = 0.029, OR 1.92, 95% CI 1.07–3.44). Conclusion The IRF5 rs2004640 GT substitution is associated with susceptibility to SSc. These data provide new insight into the pathogenesis of SSc, including clues to the mechanisms leading to fibrosing alveolitis.

OBJECTIVES: Endothelial dysfunction is an early event and a critical step in the pathogenesis of systemic sclerosis. Accurate and sensitive tests are needed to correctly assess the degree of microvascular endothelial dysfunction. Spectral analysis of skin blood flow contains a characteristic low frequency reported to be associated with endothelial function in healthy subjects. We hypothesized that the relative amplitude of the oscillation recorded for this low frequency spectrum (0.008 to 0.021 Hz) would be less pronounced in patients with systemic sclerosis than in healthy subjects and in patients with primary Raynaud's phenomenon. PATIENTS AND METHOD: Twenty-one patients with systemic sclerosis, twenty patients with primary Raynaud phenomenon and eleven healthy subjects were enrolled. Skin perfusion was recorded at rest for 30 minutes using laser Doppler flowmetry on the pad of the left third left. Fourier transform spectral analysis was applied to obtain the mean amplitude of the cutaneous blood perfusion signal of the total spectrum from 0.008 to 1.6 Hz and the mean amplitude of each characteristic frequency in the laser Doppler flowmeter blood flow oscillations. RESULTS: The relative amplitudes of each characteristic frequency in the laser Doppler flowmeter blood flow oscillations were not statistically different in the three groups, particularly for frequency spectrum from 0.008 Hz to 0.021 Hz. CONCLUSION: Fourier transform spectral analysis of baseline cutaneous blood flow does not provide significant information. Further studies are required, perhaps using wavelet spectral analysis or stimulated conditions.

The specific mechanisms by which skin blood flow increases in response to a rise in core body temperature via cutaneous active vasodilation are poorly understood. The primary purpose of this study was to determine whether the cyclooxygenase (COX) pathway contributes to active vasodilation during whole body heat stress ( protocol 1; n = 9). A secondary goal was to verify that the COX pathway does not contribute to the cutaneous hyperemic response during local heating ( protocol 2; n = 4). For both protocols, four microdialysis fibers were placed in forearm skin. Sites were randomly assigned and perfused with 1) Ringer solution (control site); 2) ketorolac (KETO), a COX-1/COX-2 pathway inhibitor; 3) NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor; and 4) a combination of KETO and l-NAME. During the first protocol, active vasodilation was induced using whole body heating with water-perfused suits. The second protocol used local heaters to induce a local hyperemic response. Red blood cell flux (RBC flux) was indexed at all sites using laser-Doppler flowmetry, and cutaneous vascular conductance (CVC; RBC flux/mean arterial pressure) was normalized to maximal vasodilation at each site. During whole body heating, CVC values at sites perfused with KETO (43 ± 9% CVCmax), l-NAME (35 ± 9% CVCmax), and combined KETO/l-NAME (22 ± 8% CVCmax) were significantly decreased with respect to the control site (59 ± 7% CVCmax) ( P < 0.05). Additionally, CVC at the combined KETO/l-NAME site was significantly decreased compared with sites infused with KETO or l-NAME alone ( P < 0.05). In the second protocol, the hyperemic response to local heating did not differ between the control site and KETO site or between the l-NAME and KETO/l-NAME site. These data suggest that prostanoids contribute to active vasodilation, but do not play a role during local thermal hyperemia.

OBJECTIVES Thermal hyperaemia is impaired in patients with systemic sclerosis (SSc). The objective of these studies was to determine whether this was consecutive to skin fibrosis, microangiopathy or macroangiopathy. METHODS Using laser Doppler flowmetry, we first compared the thermal hyperaemia on the third left finger pad and on the left forearm in 21 patients with non-diffuse systemic sclerosis (SSc), in comparison with primary Raynaud's phenomenon and healthy volunteers. Second, we tested whether the altered thermal hyperaemia correlated to the digital pressure index at baseline, and following the thermal challenge. RESULTS In the first study, thermal hyperaemia of the finger pad was impaired in terms of both amplitude and kinetics, but not on the forearm in patients with SSc. In the seven SSc patients without cutaneous fibrosis, the response was similarly altered in terms of amplitude and kinetics. In the second study, we observed a weak correlation between the digital systolic blood pressure index. However, in the 15 SSc patients tested at 44 degrees C, the median digital systolic blood pressure index was 1.04 (0.84-1.24) at baseline vs 1.08 (0.87-1.29) at 44 degrees C (NS), while seven of them had an abnormal response in terms of kinetic. Furthermore, only one patient showed a clear-cut decrease in digital systolic blood pressure at 44 degrees C. CONCLUSION In patients with SSc, digital thermal hyperaemia is impaired, but does not relate to the skin fibrosis or to an associated macroangiopathy in most cases. Further studies are required to determine whether its impairment reflects a functional or structural microvascular damage.

Objective Diabetes mellitus is associated with inflammatory state and increased cardiovascular mortality. Leukotrienes are arachidonic acid metabolites derived from the 5-lipoxygenase pathway that possess vasoactive, chemotactic and proinflammatory properties. The aim of this study was to evaluate (1) the urinary excretion of leukotriene E4 (LTE4) in type 1 diabetic subjects and healthy volunteers and (2) the influence of glycemic control attested by HbA1C on LTE4 excretion. Methods and results Urinary excretion of LTE4, measured by liquid chromatography–tandem mass spectrometry, was significantly (P = 0.033) increased in diabetic patients (median [10th–90th percentiles]: 42.1 pg/mg creatinine [16.7–71.4], n = 34), compared to healthy subjects (25.5 pg/mg creatinine [13.9–54.1], n = 28). Subgroup analysis indicated a trend towards increased LTE4 excretion in patients with poor glycemic control [(HbA1C ≥ 9% or plasma glucose >18 mmol/L): 43.3 pg/mg creatinine [21.6–70.5], n = 14], whereas no difference was observed between patients with good metabolic control [(HbA1C ≤ 7.5%): 36.4 pg/mg creatinine [15.8–83.4], n = 20] and healthy subjects. Conclusions This study suggested that increased LTE4 excretion in type 1 diabetic state might reflect systemic activation of the 5-lipoxygenase pathway. It could be a determinant of underlying inflammatory state and vascular disease.

1. Myocardial ischaemia-reperfusion in humans is associated with increased formation of 15-F 2 t -isoprostane and 5-F 2 t -isoprostane (15-F 2 t -IsoP and 5-F 2 t -IsoP, respectively). Whether this formation is relevant clinically remains controversial. The present study was performed in order to evaluate the ability of the isoprostanes 15-F 2 t -IsoP and 5-F 2 t -IsoP to reduce myocardial ischaemic injury in rat isolated heart. 2. Rats were divided into six groups. Hearts were excised, perfused retrogradely and pretreated with vehicle (ethanol 5.10 - 7 and 2.10 - 9 mol/L; n = 6), subjected to ischaemic preconditioning (n = 8) or pretreated with the isoprostanes 15-F 2 t -IsoP (3.10 - 1 0 and 3.10 - 7 mol/L; n = 8) or 5-F 2 t -IsoP (10 - 9 mol/L; n = 8). After a 5 min treatment-5 min washout period, hearts were submitted to 30 min global ischaemia, followed by a 120 min reperfusion period. 3. The infarct-to-ventricle zone ratio was significantly reduced in ischaemic preconditioned (20.6 ′ 2.6%) compared with vehicle groups (44.5 ′ 4.3 and 51.3 ′ 2.5% in groups pretreated with 5.10 - 7 or 2.10 - 9 mol/L ethanol, respectively). Pretreatment with either isoprostane had no cardio-protective effect; the infarct-to-ventricle ratios were 43.1 ′ 2.2, 49.4 ′ 5.9 and 44.5 ′ 5.0% for groups treated with 3.10 - 1 0 mol/L 15-F 2 t -IsoP, 3.10 - 7 mol/L 15-F 2 t -IsoP or 10 - 9 mol/L 5-F 2 t -IsoP, respectively. 4. These data provide evidence that the isoprostanes 15-F 2 t -IsoP and 5-F 2 t -IsoP are not implicated in early myocardial preconditioning at concentrations similar to those found in the human coronary sinus following coronary angioplasty.

Recent studies have shown that F2-isoprostane levels-a marker for lipid peroxidation-are increased in human renovascular hypertension but not in essential hypertension. Angiotensin II specifically stimulates F2-isoprostane production through activation of the AT1 receptor. The objective was to determine whether there is a relationship between the level of oxidative stress evaluated by measuring urinary F2-isoprostanes levels and polymorphisms of genes involved in the renine angiotensin aldosterone system (RAAS) regulation. The population studied included 100 subjects, 65 of whom were healthy normotensives; the other 35 were suffering from untreated, essential hypertension. The polymorphisms studied concern the genes encoding angiotensin I-converting enzyme (ACE/in16del/ins), angiotensin II receptor type I (AGTR1/A+39C[A+1166C] and AGTR1/A-153G), angiotensinogen (AGT/M235T), and aldosterone synthase (CYP11B2/T344C). Oxidative stress was evaluated by measuring urinary F2-isoprostanes levels. The characteristics of the population were as follows: men/women = 46/56; age = 50 +/- 10 years; BMI = 24 +/- 3 kg/m2; SBP = 131.7 +/- 17.2 mm Hg; DBP = 84.6 +/- 10.4 mm Hg. In univariate analysis, urinary F2-isoprostane levels were significantly lower in the presence of the G allele of AGTR1/A-153G (56 +/- 17 vs 76 +/- 39 pmol/mmol creatinine; P0.001, and P0.01 after Bonferroni correction for 10 tests). In multivariate analysis, taking into account BP, age, gender, BMI, plasma glucose, and total cholesterol, the G allele of AGTR1/A-153G is linked independently to urinary F2-isoprostanes level (P0.01). Our data suggest that F2-isoprostane level depends at least in part on the A-153G polymorphism of the angiotensin II AT1 receptor gene. The clinical and prognostic relevance of this polymorphism requires further investigation.

To the Editor: Recent data suggest that inflammatory processes play a major role in pulmonary vascular remodelling in patients with idiopathic, heritable, and drug- or toxin-induced (ihd) pulmonary arterial hypertension (PAH) [1, 2]. Besides gaining insight into the mechanisms of PAH, understanding the link between inflammation and PAH may help to identify future therapeutic targets. Different studies have shown increased levels of cytokines in ihdPAH, including the proinflammatory cytokines interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-12p70, tumour necrosis factor (TNF)-α, monocyte chemoattractant protein-1 [2, 3], and the cytokine-like hormone leptin [4]. Advances in highly sensitive multiplex detection technologies present new opportunities to rapidly and specifically measure many cytokines using a limited sample volume [5]; the potential of combining markers rather than focusing on any single biomarker is of considerable interest [3, 6]. Using such an approach, Soon et al. [7] recently suggested that IL-2, IL-6, IL-8, IL-10 and IL-12p70 levels were associated with mortality in patients with ihdPAH. The French Network of Pulmonary Hypertension recently conducted a multicentre prospective cohort study of incident cases of PAH followed up for 3 years [8], from which a biobank of plasma stored as microstraws at -180°C was available. Therefore, we tested our prospective cohort to determine whether cytokines quantified using a highly sensitive multiplex assay predict mortality in patients with ihdPAH. Briefly, consecutive incident cases of PAH presenting at the University Pulmonary Vascular Departments in Clamart (Paris), Marseille, …