Therapeutic potential of p38 MAP kinase inhibition in the management of cardiovascular disease

American Journal of Cardiovascular Drugs

Volumn 14, Issue 3, 2014, Pages 155-165

  Fisk, Marie ^a   Gajendragadkar, Parag R ^a   Mäki Petäjä, Kaisa M ^a   Wilkinson, Ian B ^a   Cheriyan, Joseph ^a,b  

^a CAMBRIDGE UNIVERSITY HOSPITALS NHS FOUNDATION TRUST   (United Kingdom)

^b ADDENBROOKE S HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; ATORVASTATIN; C REACTIVE PROTEIN; CYCLINE; DILMAPIMOD; DORAMAPIMOD; HEAT SHOCK PROTEIN; INTERLEUKIN 1; INTERLEUKIN 6; INTERLEUKIN 8; LOSMAPIMOD; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; OXIDIZED LOW DENSITY LIPOPROTEIN; TUMOR NECROSIS FACTOR ALPHA; AUTACOID; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38;

APOPTOSIS; ARTICLE; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR FUNCTION; CELL PROLIFERATION; CONFORMATIONAL TRANSITION; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; HUMAN; HYPERCHOLESTEROLEMIA; INTRACELLULAR SIGNALING; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN DEPLETION; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); SIGNAL TRANSDUCTION; ANTAGONISTS AND INHIBITORS; CARDIOVASCULAR DISEASES; CLINICAL TRIAL (TOPIC); INFLAMMATION; METABOLISM; PATHOPHYSIOLOGY;

ATHEROSCLEROSIS; CARDIOVASCULAR DISEASES; CLINICAL TRIALS AS TOPIC; HUMANS; INFLAMMATION; INFLAMMATION MEDIATORS; MITOGEN-ACTIVATED PROTEIN KINASES; P38 MITOGEN-ACTIVATED PROTEIN KINASES;

EID: 84904265663     PISSN: 11753277     EISSN: 1179187X     Source Type: Journal    
DOI: 10.1007/s40256-014-0063-6     Document Type: Article

References (86)

1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442.
2. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor Study 2010. Lancet. 2012;380(9859):2224-60.
3. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917): 868-74 (Review). (Pubitemid 36019640)
4. Spagnoli LG, Bonanno E, Sangiorgi G, Mauriello A. Role of inflammation in atherosclerosis. J Nucl Med. 2007;48(11): 1800-15. (Pubitemid 350099325)
5. Libby P, Nahrendorf M, Swirski FK. Monocyte heterogeneity in cardiovascular disease. Semin Immunopathol. 2013;35(5): 553-62.
6. del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44:2737-45. (Pubitemid 34016192)
7. Goodson NJ, Symmons DP, Scott DG, Bunn D, Lunt M, Silman AJ. Baeline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year follow up study of a primary care-based inception cohort. Arthritis Rheum. 2005;52:2293-9. (Pubitemid 41117412)
8. Hingorani AD, Cross J, Kharbanda RK, Mullen MJ, Bhagat K, Taylor M, Donald AE, Palacios M, Griffin GE, Deanfield JE, MacAllister RJ, Vallance P. Acute systemic inflammation inpairs endothelium-dependent dilatation in humans. Circulation. 2000; 102:994-9. (Pubitemid 30657515)
9. Yasmin, McEniery CM, Wallace S, Mackenzie IS, Cockcroft JR, Wilkinson IB. C-reactive protein is associated with arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol. 2004;24:969-974.
10. McEniery CM, Wilkinson IB. Large artery stiffness and inflammation. J Hum Hypertens. 2005;19(7):507-9. (Pubitemid 40946033)
11. Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity. 2013;38(6):1092-104.
12. Puri R, Nissen SE, Libby P, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, Raichlen JS, Uno K, Kataoka Y, Nicholls SJ. C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events following maximally intensive statin therapy. Circulation. 2013;128(22):2395-403
13. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFayden JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207.
14. Yoon SS, Dillon CF, Carroll M, Illoh K, Ostchega Y. Effects of statins on serum inflammatory markers: the U.S. National Health and Nutrition Examination Survey 1999-2004. J Atheroscler Thromb. 2010;17(11):1176-82.
15. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011; 162(4):597-605.
16. Marber MS, Rose B, Wang Y. The p38 mitogen-activated protein kinase pathway - a potential target for intervention in infarction, hypertrophy, and heart failure. J Mol Cell Cardiol. 2011;51 (4):485-90.
17. Martin ED, De Nicola GF, Marber MS. p38 alpha mitogen-activated protein kinase for ischemic heart disease. Circulation. 2012;126:357-68.
18. Kumar S, Boehm J, Lee JC. P38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory disease. Nat Rev Drug Discov. 2003;2(9):717-26. (Pubitemid 37361787)
19. Zarubin T, Han J. Activation and signalling of the p38 MAP kinase pathway. Cell Res. 2005;15(1):11-8. (Pubitemid 41653958)
20. Cuenda A, Rousseau S. p38 MAP-Kinases pathway regulation, function and role in human diseases. Biochimica et Biophysica Acta. 2007;1773(8):1358-75. (Pubitemid 47125981)
21. Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy - from molecular mechanisms to therapeutic benefits. Biochimica et Biophysica Acta. 2005;1754: 253-62.
22. Kumar S, Blake SM, Emery JG. Intracellular signalling pathways as a target for the treatment of rheumatoid arthritis. Curr Opin Pharmacol. 2001;1(3):307-13. (Pubitemid 33585979)
23. Barnes PJ. The cytokine network in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2009;41(6):631-8.
24. MacNee W. Pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(4):258-66. (Pubitemid 41566933)
25. Renda T, Baraldo S, Pelaia G, et al. Increased activation of p38 MAPK in COPD. Eur Respir J. 2008;31:62-9.
26. Gaffey K, Reynolds S, Plumb J, Kaur M, Singh D. Increased phosphorylated p38 mitogen activated protein kinase in COPD lungs. Eur Respir J. 2013;42(1):28-41.
27. Lu X, Kakkar V. The role of heat shock protein (HSP) in atherosclerosis: Pathophysiology and clinical opportunities. Curr Med Chem. 2010;17(10):957-73.
28. Aukrust P, Sandberg WJ, Otterdal K, Vinge LE, Gullestad L, Yndestad A, Halvorsen B, Ueland T. Tumor necrosis factor superfamily molecules in acute coronary syndromes. Ann Med. 2011;43(2):90-103.
29. Zhao M, Liu Y, Wang X, New L, Han J, Brunk UT. Activation of the p38 MAP kinase pathway is required for foam cell formation from macrophages exposed to oxidized LDL. APMIS. 2002;110 (6):458-68. (Pubitemid 34856488)
30. Hoefen RJ, Berk BC. The role of MAP kinases in endothelial activation. Vascul Pharmacol. 2002;38(5):271-3. (Pubitemid 36398260)
31. Kinlay S, Libby P, Ganz P. Endothelial function and coronary artery disease. Curr Opin Lipidol. 2001;12:383-9. (Pubitemid 32675498)
32. Goettsch C, Goettsch W, Muller G, Seebach J, Schnittler HJ, Morawietz H. Nox4 overexpression activates reactive oxygen species and p38 MAPK in human endothelial cells. Biochem Biophys Res Commun. 2009;380:355-60.
33. Ma XL, Kumar S, Gao F, Louden CS, Lopez BL, Christopher TA, Wang C, Lee JC, Feuerstein GZ, Yue TL. Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation. 1999;99(13):1685-91. (Pubitemid 29162480)
34. Kumphune S, Bassi R, Jacquet S, Sicard P, Clark JE, Verma S, Avkiran M, O'Keefe SJ, Marber MS. A chemical genetic approach reveals that p38alpha MAPK activation by diphosphorlyation aggravates myocardial infarction and is prevent by direct binding of SB203580. J Biol Chem. 2010;285:2968-75.
35. Koivisto E, Kaikkonen L, Tokola H, Pikkarainen S, Aro J, Pennanen H, Karvonen T, Rysä J, Kerkelä R, Ruskoaho H. Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms. Mol Cell Endocrinol. 2011;338(1-2): 18-27.
36. Liao P, Wang SQ, Wang S, Zheng M, Zheng M, Zhang SJ, Cheng H, Wang Y, Xiao RP. p38 mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes. Circ Res. 2002;90(2):190-6. (Pubitemid 34627088)
37. Yin H, Zhang J, Lin H, Wang R, Qiao Y, Wang B, Liu F. p38 mitogen-activated protein kinase inhibition decreased TNF-alpha secretion and protects against left ventricular remodeling in rats with myocardial ischemia. Inflammation. 2008;31:65-73. (Pubitemid 351388889)
38. Marber MS, Molkentin JD, Force T. Developing small molecules to inhibit kinases unkind to the heart: p38 MAPK as a case in point. Drug Discov Today Dis Mech. 2010;7(2):e123-7.
39. Clark JE, Sarafraz N, Marber MS. Potential of p38-MAPK inhibitors in the treatment of ischaemic heart disease. Pharmacol Ther. 2007;116(2):192-206. (Pubitemid 47451511)
40. Lee JC, Kumar S, Griswold DE, Underwood DC, Votta BJ, Adams JL. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology. 2000;47:185-201. (Pubitemid 30394538)
41. Gum RJ, McLaughlin MM, Kumar S, Wang Z, Bower MJ, Lee JC, Adams JL, Livi GP, Goldsmith EJ, Young PR. Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket. J Biol Chem. 1998;273(25):15605-10. (Pubitemid 28298174)
42. Seeger FH, Sedding D, Langheinrich AC, Haendeler J, Zeiher AM, Dimmeler S. Inhibition of the p38 MAP kinase in vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression. Basic Res Cardiol. 2010;105(3):389-97.
43. Proctor BM, Jin X, Lupu TS, Muglia LJ, Semenkovich CF, Muslin AJ. Requirement for p38 mitogen-activated protein kinase activity in neo-intima formation after vascular injury. Circulation. 2008;118:658-66.
44. Ge JJ, Zhao ZW, Zhou ZC, Wu S, Zhang R, Pan FM, Abendroth DK. p38 MAPK inhibitor, CBS3830 limits vascular remodelling in arterialised vein grafts. Heart Lung Circ. 2013;22(9):751-8.
45. Willette RN, Eybye ME, Olzinski AR, Behm DJ, Aiyar N, Maniscalco K, Bentley RG, Coatney RW, Zhao S, Westfall TD, Doe CP. Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease. J Pharmacol Exp Ther. 2009;330(3): 964-70.
46. Li M, Georgakopoulos D, Lu G, Hester L, Kass DA, Hasday J, Wang Y. p38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart. Circulation. 2005;111(19):2494-502. (Pubitemid 40696138)
47. Liu YH, Wang D, Rhaleb NE, Yang XP, Xu J, Sankey SS, Rudolph AE, Carretero OA. Inhibition of p38 mitogen-activated protein kinase protects the heart against cardiac remodeling in mice with heart failure resulting from myocardial infarction. J Card Fail. 2005;11(1):74-81. (Pubitemid 40215318)
48. Schreiber S, Feagan B, D'Haens G, Colombel JF, Geboes K, Yurcov M, Isakov V, Golovenko O, Bernstein CN, Ludwig D, Winter T, Meier U, Yong C, Steffgen J, BIRB 796 Study Group. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4(3):325-34. (Pubitemid 43343889)
49. Hammaker D, Firestein GS. "Go upstream, young man": lessons learned fromthe p38 saga. Ann Rheum Dis. 2010;69(Suppl 1):i77-82.
50. Genovese MC. Inhibition of p38: has the fat lady sung? Arthritis Rheum. 2009;60(2):317-20.
51. Goldstein DM, Kuglstatter A, Lou Y, Soth MJ. Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem. 2010;53:2345-53.
52. Li L, Li G, Yu C, Li Y. A meta-analysis of the role of p38 mitogen-activated protein kinase inhibitors in patients with active rheumatoid arthritis. Clin Rheumatol. 2013;32(12):1697-702
53. Salgado E, Maneiro JR, Carmona L, Gomez-Reino JJ. Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis. Ann Rheum Dis. 2013 (Epub ahead of print).
54. Anand P, Shenoy R, Palmer JE, Baines AJ, Lai RY, Robertson J, Bird N, Ostenfeld T, Chizh BA. Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury. Eur J Pain. 2011;15(10):1040-8.
55. Singh D, Smyth L, Borrill Z, Sweeney L, Tal-Singer R. A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. J Clin Pharmacol. 2010;50(1):94-100.
56. Ostenfeld T, Krishen A, Lai RY, Bullman J, Baines AJ, Green J, Anand P, Kelly M. Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study. Eur J Pain. 2013;17(6):844-57.
57. Lomas DA, Lipson DA, Miller BE, Willits L, Keene O, Barnacle H, et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol. 2012;52(3):416-24.
58. Elkhawad M, Rudd JH, Sarov-Blat L, Cai G, Wells R, Davies LC, Collier DJ, Marber MS, Choudhury RP, Fayad ZA, Tawakol A, Gleeson FV, Lepore JJ, Davis B, Willette RN, Wilkinson IB, Sprecher DL, Cheriyan J. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc Imaging. 2012;5(9):911-22.
59. Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Mäki-Petäjä KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011;123(5):515-23.
60. MacNee W, Allan RJ, Jones I, De Salvo MC, Tan LF. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax. 2013;68(8):738-45.
61. Cohen SB, Cheng TT, Chindalore V, Damjanov N, Burgos-Vargas R, Delora P, Zimany K, Travers H, Caulfield JP. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate- controlled study of patients with active rheumatoid arthritis. Arthritis Rheum. 2009;60(2):335-44.
62. Genovese MC, Cohen SB, Wofsy D, Weinblatt ME, Firestein GS, Brahn E, Strand V, Baker DG, Tong SE. A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J Rheumatol. 2011;38(5):846-54.
63. Sokol L, Cripe L, Kantarjian H, Sekeres MA, Parmar S, Greenberg P, Goldberg SL, Bhushan V, Shammo J, Hohl R, Verma A, Garcia-Manero G, Li YP, Lowe A, Zhu J, List AF. Randomized, dose-escalation study of the p38a MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome. Leukemia. 2013;4:977-80.
64. Tong SE, Daniels SE, Black P, Chang S, Protter A, Desjardins PJ. Novel p38a mitogen-activated protein kinase inhibitor shows analgesic efficacy in acute postsurgical dental pain. J Clin Pharmacol. 2012;52(5):717-28.
65. Damjanov N, Kauffman RS, Spencer-Green GT. Efficacy, pharmacodynamica and safety of VX-702, a novel p38 MAPK inhibitor in rheumatoid arthritis: results of two randomised, double-blind placebo-controlled clinical studies. Arthritis Rheum. 2009;60:1232-41.
66. Yang S, Lukey P, Beerahee M, Hoke F. Population pharmaco-kinetics of losmapimod in healthy subjects and patients with rheumatoid arthritis and chronic obstructive pulmonary diseases. Clin Pharmacokinet. 2013;52(3):187-98.
67. Barbour AM, Sarov-Blat L, Cai G, Fossler MJ, Sprecher DL, Graggber J, et al. Safety, tolerability, pharmacokinetics, an pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers. Br J Clin Pharmacol. 2013;76(1):99-106.
68. Yang S, Beerahee M. Losmapimod concentration-QT relationship in healthy volunteers: meta-analysis of data from six clinical trials. Eur J Clin Pharmacol. 2013;69(6):1261-7.
69. Sarov-Blat L, Morgan JM, Fernandez P, James R, Fang Z, Hurle MR, Baidoo C, Willette RN, Lepore JJ, Jensen SE, Sprecher DL. Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans. Arterioscler Thromb Vasc Biol. 2010;30(11):2256-63.
70. Elkhawad M, Rudd JH, Sarov-Blat L, Cai G, Wells R, Davies CL, et al. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc Imaging. 2012;5(9):911-22.
71. Rudd JHF, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, Johnström P, Davenport AP, Kirkpatrick PJ, Arch BN, Pickard JD, Weissberg PL. Imaging atherosclerotic plaque inflammation with 18FDG-PET. Circulation. 2002;105:2708-11.
72. Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, Yates D, et al. In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol. 2006;48:1818-24. (Pubitemid 44648622)
73. Rosito GA, Massaro JM, Hoffmann U, et al. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation. 2008;117:605-13.
74. Christen T, Sheikine Y, Rocha VZ, et al. Increased glucose uptake in visceral versus subcutaneous adipose tissue revealed by PET imaging. JACC Cardiovasc Imaging. 2010;3(8):843-51.
75. Melloni C, Sprecher DL, Sarov-Blat L, Patel MR, Heitner JF, Hamm CW, Aylward P, et al. The study of LoSmapimod treatment on inflammation and InfarCtSizE (SOLSTICE): design and rationale. Am Heart J. 2012;164(5):646-53.
76. Newby LK, Sarov-Blat L, Melloni C, Patel MR, Heitner JF, Hamm CW, Aylward P, et al. Safety and efficacy of losmapimod in non-ST-segment elevation acute myocardial infarction: results of the SOLSTICE phase 2 randomized trial. Late-breaking clinical trial abstracts. Circulation. 2012;126(23):2787-8.
77. Efficacy study of p38 kinase inhibitor to treat patients with atherosclerosis. NCT identifier: NCT00570752. http://www.clinicaltrials.gov.
78. Evaluation of losmapimod in Chronic Obstructive Pulmonary Disease (COPD) stratified by fibrinogen, ('EVOLUTION'). A phase 2a randomised placebo-controlled double-blind study. http://www.clinicaltrials.gov, search term: 'p38 MAPK inhibitor'.
79. Müllerova H, Agusti A, Erqou S, Mapel DW. Cardiovascular comorbidity in COPD: systematic literature review. Chest. 2013;144(4):1163-78.
80. Man SF, Van Eeden S, Sin DD. Vascular risk in chronic obstructive pulmonary disease: role of inflammation and other mediators. Can J Cardiol. 2012;28(6):653-61.
81. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR, Gao P, Walker M, Thompson A et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med. 2012;367(14):1310-20.
82. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993;118(12):956-63. (Pubitemid 23164134)
83. del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44:2737-45. (Pubitemid 34016192)
84. Mäki-Petäjä KM, Hall FC, Booth AD, Wallace SM, Yasmin, Bearcroft PW, Harish S, Furlong A, McEniery CM, Brown J, Wilkinson IB. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy. Circulation. 2006;114(11):1185-92. (Pubitemid 44386483)
85. Mäki-Petäjä KM, Elkhawad M, Cheriyan J, Joshi FR, Ostör AJ, Hall FC, et al. Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation. 2012;126(21):2473-80.
86. Salgado E, Maneiro JR, Carmona L, Gomez-Reino JJ. Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis. Ann Rheum Dis. 2013 (Epub ahead of print).