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.

Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

BACKGROUND AND PURPOSE The treatment of scleroderma‐related digital ulcers is still a therapeutic challenge. The most effective drugs are prostacyclin analogues. However, their usage is limited to an intravenous route of administration and by their frequent side effects. The objective of this study was to test whether treprostinil, iloprost and epoprostenol can induce sustained vasodilatation in rats when delivered locally using cutaneous iontophoresis. EXPERIMENTAL APPROACH Treprostinil, iloprost and epoprostenol were delivered by cathodal and anodal iontophoresis onto the hindquarters of anaesthesized rats (n= 8 for each group). Skin blood flow was quantified using laser Doppler imaging and cutaneous tolerance was assessed from day 0 to day 3. KEY RESULTS Cathodal but not anodal iontophoresis of treprostinil (6.4 mM), iloprost (0.2 mM) and epoprostenol (1.4 mM) induced a significant and sustained increase in cutaneous blood flow. The effects of treprostinil and iloprost were significantly different from those of treprostinil vehicle. Only weak effects were observed when both drugs were applied locally without current. Skin resistance was unchanged in areas treated with prostacyclin analogues. Finally, skin tolerance was good, with no evidence of epidermal damage. CONCLUSIONS AND IMPLICATIONS Cathodal iontophoresis of treprostinil and iloprost increases cutaneous blood flow with a good local tolerance. The effects of cathodal iontophoresis of these drugs should be investigated in humans, as they could have potential as new local therapies for digital ulcers in patients with scleroderma.

Background and purpose: Sildenafil, a specific inhibitor of phosphodiesterase 5A (PDE5A), is currently tested as a treatment for severe Raynaud's phenomenon. Here, we tested whether sildenafil, alone or combined with local sodium nitroprusside (SNP) delivered through skin iontophoresis, increased forearm cutaneous blood conductance in healthy volunteers, and to assess how well this combination was tolerated. Experimental approach: Ten healthy volunteers were enrolled. Variations in cutaneous vascular conductance (CVC) following oral administration of 50 or 100 mg of sildenafil with or without SNP iontophoresis were expressed as a percentage of maximal CVC, and were monitored using laser Doppler imaging. SNP iontophoresis was performed on the ventral surface of the forearm, 1 h after application of lidocaine/prilocaine cream. Key results: Sildenafil at 100 mg, but not 50 mg, increased overall responses (area under the curve) (44%) and peak responses (29%) to SNP iontophoresis. Sildenafil at 100 mg, but not 50 mg, increased baseline CVC (75%). Incidence of headache was not changed when SNP iontophoresis was combined with sildenafil. One episode of symptomatic arterial hypotension occurred in a volunteer given 50 mg sildenafil, 30 min after the beginning of SNP iontophoresis. Conclusions and implications:Oral sildenafil at 100 mg potentiated local skin hyperaemia induced by SNP iontophoresis, with no increased incidence of headaches. The combination of oral specific PDE5A inhibitor and nitrates administered through skin iontophoresis deserves further investigation in diseases such as severe Raynaud's phenomenon, with particular attention to the incidence of arterial hypotension.

Bosentan is an endothelin receptor antagonist used as a first-line treatment in pulmonary arterial hypertension (PAH). Its main adverse effect is a dose-dependent liver toxicity. CYP2C9*2 has recently been shown to be associated with hepatotoxicity in PAH patients. We conducted a nested case-control study to further explore the relationship between functional polymorphisms of gene products involved in bosentan pharmacokinetics (OATP1B1, OATP1B3, and CYP2C9) or hepatobiliary transporters affected by bosentan (ABCB11) and bosentan-induced liver toxicity.

No abstract

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.

No abstract