Review article: Risk of cardiovascular events in patients with inflammatory bowel disease receiving small molecule drugs

In the context of an ageing inflammatory bowel disease (IBD) population, cardiovascular comorbidities become particularly relevant. Novel small molecule drugs (SMDs) for the treatment of moderate‐to‐severe IBD have been recently approved, including Janus kinase (JAK) inhibitors and sphingosine‐1‐phosphate receptor (S1P) modulators. Data from rheumatoid arthritis population have raised concerns about the risk of cardiovascular events with the use of tofacitinib, which was extrapolated to other immune‐mediated diseases and other JAK inhibitors. S1P receptor modulation has been associated with potential cardiovascular events, especially bradycardia and cardiac conduction abnormalities.

[1]  S. Vermeire,et al.  Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies , 2023, The Lancet.

[2]  L. Peyrin-Biroulet,et al.  P476 Characterization of cardiac conduction abnormalities reported in the phase 3 ELEVATE programme , 2023, Journal of Crohn's & Colitis.

[3]  H. Huhtala,et al.  Increasing incidence of inflammatory bowel disease with greatest change among the elderly: a nationwide study in Finland, 2000-2020. , 2022, Journal of Crohn's & colitis.

[4]  C. Ponsioen,et al.  Effectiveness and safety of tofacitinib for ulcerative colitis: two‐year results of the ICC Registry , 2022, Alimentary pharmacology & therapeutics.

[5]  E. Loftus,et al.  Multicenter Real-world Experience of Upadacitinib in the Treatment of Crohn's Disease. , 2022, Journal of Crohn's & Colitis.

[6]  J. Silverberg,et al.  Safety of upadacitinib in moderate-to-severe atopic dermatitis: An integrated analysis of phase 3 studies. , 2022, The Journal of allergy and clinical immunology.

[7]  Deepak L. Bhatt,et al.  Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance , 2022, Annals of the Rheumatic Diseases.

[8]  B. Sands,et al.  Tofacitinib for the Treatment of Ulcerative Colitis: An Integrated Summary of up to 7.8 Years of Safety Data from the Global Clinical Programme , 2022, Journal of Crohn's & colitis.

[9]  Biao Zhu,et al.  Case Report: Treatment for steroid-refractory immune-related myocarditis with tofacitinib , 2022, Frontiers in Immunology.

[10]  L. Peyrin-Biroulet,et al.  Is selectivity the JAKpot winner for IBD treatment? , 2022, Gastroenterology.

[11]  M. Dubinsky,et al.  Review article: guide to tofacitinib dosing in patients with ulcerative colitis , 2022, Alimentary pharmacology & therapeutics.

[12]  M. Buttmann,et al.  OzEAN Study to Collect Real-World Evidence of Persistent Use, Effectiveness, and Safety of Ozanimod Over 5 Years in Patients With Relapsing-Remitting Multiple Sclerosis in Germany , 2022, Frontiers in Neurology.

[13]  L. Peyrin-Biroulet,et al.  Evaluating Upadacitinib in the Treatment of Moderate-to-Severe Active Ulcerative Colitis: Design, Development, and Potential Position in Therapy , 2022, Drug design, development and therapy.

[14]  K. Allin,et al.  The Risk of Type 2 Diabetes in Patients With Inflammatory Bowel Disease After Bowel Resections: A Nationwide Cohort Study , 2022, Gastro hep advances.

[15]  C. Nelson,et al.  Filgotinib: A Clinical Pharmacology Review , 2022, Clinical Pharmacokinetics.

[16]  C. J. van der Woude,et al.  Lipid Changes After Induction Therapy in Patients with Inflammatory Bowel Disease: Effect of Different Drug Classes and Inflammation , 2022, Inflammatory bowel diseases.

[17]  S. Vermeire,et al.  Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials , 2022, The Lancet.

[18]  L. Peyrin-Biroulet,et al.  Is it time to include older adults in inflammatory bowel disease trials? A call for action. , 2022, The Lancet. Healthy longevity.

[19]  S. Jung,et al.  The Comparative Risk of Serious Adverse Events With Tofacitinib and TNF Inhibitors in Patients With Ulcerative Colitis: The Korean Experience as Revealed by a National Database , 2022, Journal of Korean medical science.

[20]  D. Rubin,et al.  Ozanimod in the Treatment of Ulcerative Colitis: Initial Real World Data from A Large Tertiary Center. , 2022, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[21]  A. Cheifetz,et al.  Review article: emerging drug therapies in inflammatory bowel disease , 2022, Alimentary pharmacology & therapeutics.

[22]  Ousmane A Camara,et al.  Long-Term Effectiveness, Safety and Tolerability of Fingolimod in Patients with Multiple Sclerosis in Real-World Treatment Settings in France: The VIRGILE Study , 2022, Neurology and Therapy.

[23]  T. Cai,et al.  Comparative Risk of Thrombotic and Cardiovascular Events with Tofacitinib and Anti-TNF Agents in Patients with Inflammatory Bowel Diseases , 2022, Digestive Diseases and Sciences.

[24]  Deepak L. Bhatt,et al.  Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. , 2022, The New England journal of medicine.

[25]  B. Feagan,et al.  Janus Kinase Inhibitors for the Management of Patients With Inflammatory Bowel Disease. , 2022, Gastroenterology & hepatology.

[26]  P. Goupille,et al.  Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials , 2021, Rheumatology and Therapy.

[27]  M. Zhong,et al.  Risk for Cardiovascular Adverse Events Associated With Sphingosine-1-Phosphate Receptor Modulators in Patients With Multiple Sclerosis: Insights From a Pooled Analysis of 15 Randomised Controlled Trials , 2021, Frontiers in Immunology.

[28]  J. Ge,et al.  Case Series of Steroid-Resistant Immune Checkpoint Inhibitor Associated Myocarditis: A Comparative Analysis of Corticosteroid and Tofacitinib Treatment , 2021, Frontiers in Pharmacology.

[29]  G. D'Haens,et al.  Upadacitinib Was Efficacious and Well Tolerated Over 30 Months in Patients with Crohn's Disease in the CELEST Extension Study. , 2021, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[30]  Long Millie,et al.  P038 Ozanimod First-Dose Cardiac Effects in Patients with Moderately to Severely Active Ulcerative Colitis and Relapsing Multiple Sclerosis. , 2021, American Journal of Gastroenterology.

[31]  T. Hibi,et al.  A Phase II, Multicentre, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability and Efficacy of Amiselimod in Patients with Moderate to Severe Active Crohn's Disease. , 2021, Journal of Crohn's & colitis.

[32]  M. Genovese,et al.  Integrated safety analysis of filgotinib in patients with moderately to severely active rheumatoid arthritis receiving treatment over a median of 1.6 years , 2021, Annals of the Rheumatic Diseases.

[33]  S. Hanauer,et al.  Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. , 2021, The New England journal of medicine.

[34]  W. Miles,et al.  Physiologic Variants of Cardiac Conduction (Aberration, Gap, Supernormal Conduction). , 2021, Cardiac electrophysiology clinics.

[35]  S. Ng,et al.  International consensus on the prevention of venous and arterial thrombotic events in patients with inflammatory bowel disease , 2021, Nature Reviews Gastroenterology & Hepatology.

[36]  S. Vermeire,et al.  Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial , 2021, The Lancet.

[37]  S. Bonovas,et al.  Safety of S1P Modulators in Patients with Immune-Mediated Diseases: A Systematic Review and Meta-Analysis , 2021, Drug Safety.

[38]  C. Taxonera,et al.  Real-World Effectiveness and Safety of Tofacitinib in Patients With Ulcerative Colitis: Systematic Review With Meta-Analysis. , 2021, Inflammatory bowel diseases.

[39]  S. Vermeire,et al.  Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study , 2021, Journal of Crohn's & colitis.

[40]  S. Vermeire,et al.  Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active Ulcerative Colitis: Results From the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study , 2021, Journal of Crohn's & colitis.

[41]  M. Regueiro,et al.  Tofacitinib Treatment Safety in Moderate to Severe Ulcerative Colitis: Comparison of Observational Population Cohort Data From the IBM MarketScan® Administrative Claims Database With Tofacitinib Trial Data , 2020, Inflammatory bowel diseases.

[42]  D. Rubin,et al.  Real-World Effectiveness and Safety of Tofacitinib in Crohn's Disease and IBD-U: A Multi-Center Study from the TROPIC consortium. , 2020, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[43]  G. Kaplan,et al.  The four epidemiological stages in the global evolution of inflammatory bowel disease , 2020, Nature Reviews Gastroenterology & Hepatology.

[44]  S. Rizzo,et al.  Inflammation as a Predictor of Recurrent Ventricular Tachycardia After Ablation in Patients With Myocarditis. , 2020, Journal of the American College of Cardiology.

[45]  J. Cerqueira,et al.  REALMS study: real-world effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis in Portugal , 2020, Neurological Sciences.

[46]  J. Gisbert,et al.  Tofacitinib in Ulcerative Colitis: Real-world Evidence From the ENEIDA Registry. , 2020, Journal of Crohn's & colitis.

[47]  Hongwei Lu,et al.  The role of sphingosine 1‐phosphate and its receptors in cardiovascular diseases , 2020, Journal of cellular and molecular medicine.

[48]  S. Vermeire,et al.  JAK Inhibitors: Back to Small Molecules for the Treatment of IBD , 2020, Journal of Crohn's & colitis.

[49]  D. Rubin,et al.  Safety of Tofacitinib in a Real-World Cohort of Patients With Ulcerative Colitis. , 2020, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[50]  T. Card,et al.  Disease Activity in Inflammatory Bowel Disease Is Associated With Arterial Vascular Disease. , 2020, Inflammatory bowel diseases.

[51]  G. D'Haens,et al.  Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study. , 2020, The lancet. Gastroenterology & hepatology.

[52]  K. Ohtsuka,et al.  Rapid prediction of 1-year efficacy of tofacitinib for treating refractory ulcerative colitis , 2020, Intestinal research.

[53]  S. Danese,et al.  JAK selectivity: more precision less troubles , 2020, Expert review of gastroenterology & hepatology.

[54]  C. Campochiaro,et al.  Therapeutic strategies for virus-negative myocarditis: a comprehensive review. , 2020, European journal of internal medicine.

[55]  Xiaoxu Zhou,et al.  Evidence for Inflammation as a Driver of Atrial Fibrillation , 2020, Frontiers in Cardiovascular Medicine.

[56]  R. Weersma,et al.  Tofacitinib for ulcerative colitis: results of the prospective Dutch Initiative on Crohn and Colitis (ICC) registry , 2020, Alimentary pharmacology & therapeutics.

[57]  S. Vermeire,et al.  JAK–STAT pathway targeting for the treatment of inflammatory bowel disease , 2020, Nature Reviews Gastroenterology & Hepatology.

[58]  S. Rizzo,et al.  Ventricular Arrhythmias in Myocarditis: Characterization and Relationships With Myocardial Inflammation. , 2020, Journal of the American College of Cardiology.

[59]  M. Grabowski,et al.  Cardiac Arrhythmias in Autoimmune Diseases. , 2020, Circulation journal : official journal of the Japanese Circulation Society.

[60]  P. Higgins,et al.  Efficacy of Upadacitinib in a Randomized Trial of Patients With Active Ulcerative Colitis. , 2020, Gastroenterology.

[61]  J. Lewis,et al.  Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease. , 2020, Gastroenterology.

[62]  Stanley B. Cohen,et al.  Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme , 2019, Annals of the Rheumatic Diseases.

[63]  K. Allin,et al.  Inflammatory Bowel Disease Increases Risk of Type 2 Diabetes in a Nationwide Cohort Study. , 2020, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[64]  B. Sands,et al.  Tofacitinib Treatment Is Associated With Modest and Reversible Increases in Serum Lipids in Patients With Ulcerative Colitis. , 2020, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[65]  Zhuoli Zhang,et al.  Effect of tofacitinib on cardiovascular events and all-cause mortality in patients with immune-mediated inflammatory diseases: a systematic review and meta-analysis of randomized controlled trials , 2019, Therapeutic advances in musculoskeletal disease.

[66]  A. Amiot,et al.  Real-world evidence of tofacitinib effectiveness and safety in patients with refractory ulcerative colitis. , 2019, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[67]  S. Vermeire,et al.  Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients with Ulcerative Colitis. , 2019, Gastroenterology.

[68]  D. Gladman,et al.  Changes in Lipid Levels and Incidence of Cardiovascular Events Following Tofacitinib Treatment in Patients With Psoriatic Arthritis: A Pooled Analysis Across Phase III and Long‐Term Extension Studies , 2019, Arthritis care & research.

[69]  E. Cristiano,et al.  Real-World Effectiveness and Safety of Fingolimod in Patients With Relapsing Remitting Multiple Sclerosis: A Prospective Analysis in Buenos Aires, Argentina. , 2019, Clinical neuropharmacology.

[70]  I. McInnes,et al.  Risk Factors for Major Adverse Cardiovascular Events in Phase III and Long‐Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis , 2019, Arthritis & rheumatology.

[71]  L. Peyrin-Biroulet,et al.  Comorbidities in inflammatory bowel disease: a call for action. , 2019, The lancet. Gastroenterology & hepatology.

[72]  G. Kaplan,et al.  Evolving Epidemiology of IBD , 2019, Current Gastroenterology Reports.

[73]  C. Le Berre,et al.  JAK selectivity for inflammatory bowel disease treatment: does it clinically matter? , 2019, Gut.

[74]  S. Rizzo,et al.  Arrhythmias in myocarditis: State of the art. , 2019, Heart rhythm.

[75]  S. Rizzo,et al.  Impact of systemic immune-mediated diseases on clinical features and prognosis of patients with biopsy-proved myocarditis. , 2019, International journal of cardiology.

[76]  W. Sandborn,et al.  Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists , 2019, Front. Pharmacol..

[77]  J. S. Kim,et al.  Increased Risk of Diabetes in Inflammatory Bowel Disease Patients: A Nationwide Population-Based Study in Korea , 2019, Journal of clinical medicine.

[78]  D. Rubin,et al.  Real-World Experience with Tofacitinib in IBD at a Tertiary Center , 2019, Digestive Diseases and Sciences.

[79]  M. Floria,et al.  Cardiovascular Manifestations of Inflammatory Bowel Disease: Pathogenesis, Diagnosis, and Preventive Strategies , 2019, Gastroenterology research and practice.

[80]  B. Nordestgaard,et al.  Cardiovascular Risk Profile Among Patients With Inflammatory Bowel Disease: A Population-based Study of More Than 100 000 Individuals , 2018, Journal of Crohn's & colitis.

[81]  N. Harrison,et al.  Heart Under Attack: Cardiac Manifestations of Inflammatory Bowel Disease. , 2018, Inflammatory bowel diseases.

[82]  H. Sokol,et al.  Clinical activity is an independent risk factor of ischemic heart and cerebrovascular arterial disease in patients with inflammatory bowel disease , 2018, PloS one.

[83]  Ludwig Kappos,et al.  Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study , 2018, The Lancet.

[84]  V. van Pesch,et al.  Long-term safety and real-world effectiveness of fingolimod in relapsing multiple sclerosis , 2017, Patient related outcome measures.

[85]  U. Eriksson,et al.  Diagnosis and management of myocardial involvement in systemic immune-mediated diseases: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease , 2017, European heart journal.

[86]  E. Armstrong,et al.  Effect of tofacitinib on lipid levels and lipid-related parameters in patients with moderate to severe psoriasis. , 2017, Journal of clinical lipidology.

[87]  P. Libby,et al.  Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease , 2017, The New England journal of medicine.

[88]  F. Carrat,et al.  Increased risk of acute arterial events in young patients and severely active IBD: a nationwide French cohort study , 2017, Gut.

[89]  J. Gisbert,et al.  Cardiovascular disease in immune-mediated inflammatory diseases , 2017, Medicine.

[90]  J. L. Ruiz-Peña,et al.  The real-world effectiveness and safety of fingolimod in relapsing-remitting multiple sclerosis patients: An observational study , 2017, PloS one.

[91]  G. Keskindemirci,et al.  Prolonged P-Wave and QT Dispersion in Children with Inflammatory Bowel Disease in Remission , 2017, BioMed research international.

[92]  L. Peyrin-Biroulet,et al.  JAK inhibition in inflammatory bowel disease , 2017, Expert review of clinical immunology.

[93]  S. Vermeire,et al.  Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials , 2017, Gut.

[94]  Андрей Юрьевич Барановский Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial (статья) , 2017 .

[95]  W. Sandborn,et al.  Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. , 2017, The New England journal of medicine.

[96]  L. Peyrin-Biroulet,et al.  Next generation of small molecules in inflammatory bowel disease , 2016, Gut.

[97]  M. González-Gay,et al.  Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist. , 2016, Seminars in arthritis and rheumatism.

[98]  G. Aksan,et al.  Assessment of Atrial Electromechanical Delay and Left Atrial Mechanical Functions in Patients with Ulcerative Colitis , 2016, Echocardiography.

[99]  M. Zeegers,et al.  Epidemiology and Long-term Outcome of Inflammatory Bowel Disease Diagnosed at Elderly Age—An Increasing Distinct Entity? , 2016, Inflammatory bowel diseases.

[100]  Y. Coşkun,et al.  Atrial Electromechanical Properties in Inflammatory Bowel Disease , 2016, Echocardiography.

[101]  S. Vermeire,et al.  Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. , 2016, The New England journal of medicine.

[102]  R. Gajulapalli,et al.  Prevalence of QT interval prolongation in inflammatory bowel disease. , 2016, The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology.

[103]  S. Kapadia,et al.  Conventional risk factors and cardiovascular outcomes of patients with inflammatory bowel disease with confirmed coronary artery disease. , 2014, Inflammatory bowel diseases.

[104]  Ken Kitahara,et al.  Analysis of Onset Mechanisms of a Sphingosine 1-Phosphate Receptor Modulator Fingolimod-Induced Atrioventricular Conduction Block and QT-Interval Prolongation. , 2014, Toxicology and applied pharmacology.

[105]  Jeffrey A. Cohen,et al.  First-dose effects of fingolimod: Pooled safety data from three phase 3 studies. , 2014, Multiple sclerosis and related disorders.

[106]  W. Sandborn,et al.  A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease. , 2014, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[107]  Jennifer G. Robinson,et al.  2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines , 2014, Circulation.

[108]  Jennifer G. Robinson,et al.  2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines , 2014, Circulation.

[109]  L. Dauchet,et al.  Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: a meta-analysis of observational studies. , 2014, Journal of Crohn's & colitis.

[110]  R. Erichsen,et al.  Increased risk of atrial fibrillation and stroke during active stages of inflammatory bowel disease: a nationwide study. , 2014, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[111]  Siddharth Singh,et al.  Risk of cerebrovascular accidents and ischemic heart disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. , 2014, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[112]  Mark E Flanagan,et al.  Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. , 2014, Journal of medicinal chemistry.

[113]  Yeong-Wook Song,et al.  Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study* , 2013, Annals of the rheumatic diseases.

[114]  R. Erichsen,et al.  Disease Activity in Inflammatory Bowel Disease Is Associated with Increased Risk of Myocardial Infarction, Stroke and Cardiovascular Death – A Danish Nationwide Cohort Study , 2013, PloS one.

[115]  L. Dauchet,et al.  Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study , 2013, Gut.

[116]  H. Yorulmaz,et al.  Prolonged QT dispersion in inflammatory bowel disease. , 2013, World journal of gastroenterology.

[117]  N. Gray,et al.  The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate , 2012, British journal of pharmacology.

[118]  A. Kornbluth,et al.  Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population. , 2012, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[119]  W. Sandborn,et al.  Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. , 2012, The New England journal of medicine.

[120]  K. Sonmez,et al.  Evaluation of QT and P Wave Dispersion and Mean Platelet Volume among Inflammatory Bowel Disease Patients , 2011, International journal of medical sciences.

[121]  G. Fishman,et al.  The Cardiac Conduction System , 2011, Circulation.

[122]  M. Curione,et al.  A study on QT interval in patients affected with inflammatory bowel disease without cardiac involvement , 2010, Internal and emergency medicine.

[123]  M. Curione,et al.  Atrioventricular block associated with Crohn's relapsing colitis in a 12-year-old child. , 2010, Inflammatory bowel diseases.

[124]  David Gruben,et al.  The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. , 2009, Arthritis and rheumatism.

[125]  J. Brown,et al.  Sphingosine-1-phosphate receptor signalling in the heart. , 2008, Cardiovascular research.

[126]  B. Gersh,et al.  The Problem With Composite End Points in Cardiovascular Studies: The Story of Major Adverse Cardiac Events and Percutaneous Coronary Intervention , 2009 .

[127]  Kevin E. Kip,et al.  The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention. , 2008, Journal of the American College of Cardiology.

[128]  Paul M. Ridker,et al.  Inflammation as a Cardiovascular Risk Factor , 2004, Circulation.

[129]  Sarah Spiegel,et al.  Sphingosine-1-phosphate: an enigmatic signalling lipid , 2003, Nature Reviews Molecular Cell Biology.

[130]  I. Leodolter [Crohn's disease]. , 1967, Wiener Zeitschrift fur innere Medizin und ihre Grenzgebiete.

[131]  G PLACITELLI,et al.  [Ulcerative colitis]. , 1958, La Riforma medica.