Cardiovascular diseases (CVDs) lead to higher morbidity and mortality in rheumatoid arthritis; thus, we aimed to determine whether patients who had discontinued methotrexate treatment before the study enrollment (group MTX 0) were at a higher risk of CVD than patients treated with methotrexate at the time of the data collection (group MTX 1). A retrospective, prospective, observational, cross-sectional study was conducted. A total of 125 patients were enrolled in the study. Patients from the MTX 0 group (n = 35) were not treated with methotrexate for 7.54 (SD ± 4.21) years in average. Medical documentation as well as information taken in patient examinations during regular rheumatologist visits was used to obtain the required data. The composite of any CVD occurred less frequently in patients in the MTX 1 group than in the MTX 0 group (18.8 vs. 40.0%, OR 0.35, 95% CI, 0.15 to 0.83; p = 0.017) with a non-significant trend after adjustment for other treatments, which differed between study groups at the baseline (p = 0.054). Significant difference was found for the reduction of myocardial infarction in the MTX 1 group compared to the MTX 0 group (3.5 vs. 14.3%, OR 0.22, 95% CI, 0.05 to 0.97; p = 0.046). There were 4 deaths (4.7%) in the MTX 1 group as compared with 7 (20.0%) in the MTX 0 group (OR 0.20, 95% CI, 0.05 to 0.73; p = 0.015). Our results demonstrate that patients who discontinued methotrexate treatment are at a significantly higher risk of CVD and all-cause mortality. Based on our findings, we recommend stricter control of CVD in cases of methotrexate discontinuation.

2nd Department of Internal Medicine Gastroenterology Division Rheumatology Faculty of Medicine and University Hospital in Hradec Kralove Charles University Hradec Kralove Czechia

Department of Biophysics and Physical Chemistry Faculty of Pharmacy in Hradec Kralove Charles University Prague Czechia

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Prague Czechia

Department of Social and Clinical Pharmacy Faculty of Pharmacy in Hradec Kralove Charles University Prague Czechia

Institute of Clinical Biochemistry and Diagnostics University Hospital Hradec Kralove Hradec Kralove Czechia

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Ambrosino P., Lupoli R., Di Minno A., Tasso M., Peluso R., Di Minno M. N. (2015). Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis. A Meta-Analysis of Literature Studies. Thromb. Haemost. 113 (5), 916–930. 10.1160/th14-11-0921 PubMed DOI

Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., et al. (1988). The American Rheumatism Association 1987 Revised Criteria for the Classification of Rheumatoid Arthritis. Arthritis Rheum. 31 (3), 315–324. 10.1002/art.1780310302 PubMed DOI

Atzeni F., Benucci M., Sallì S., Bongiovanni S., Boccassini L., Sarzi-Puttini P. (2013). Different Effects of Biological Drugs in Rheumatoid Arthritis. Autoimmun. Rev. 12 (5), 575–579. 10.1016/j.autrev.2012.10.020 PubMed DOI

Aviña-Zubieta J. A., Choi H. K., Sadatsafavi M., Etminan M., Esdaile J. M., Lacaille D. (2008). Risk of Cardiovascular Mortality in Patients with Rheumatoid Arthritis: A Meta-Analysis of Observational Studies. Arthritis Rheum. 59 (12), 1690–1697. 10.1002/art.24092 PubMed DOI

Bluett J., Sergeant J. C., MacGregor A. J., Chipping J. R., Marshall T., Symmons D. P. M., et al. (2018). Risk Factors for Oral Methotrexate Failure in Patients with Inflammatory Polyarthritis: Results from a UK Prospective Cohort Study. Arthritis Res. Ther. 20 (1), 50. 10.1186/s13075-018-1544-9 PubMed DOI PMC

Choi H. K., Hernán M. A., Seeger J. D., Robins J. M., Wolfe F. (2002). Methotrexate and Mortality in Patients with Rheumatoid Arthritis: A Prospective Study. Lancet 359 (9313), 1173–1177. 10.1016/s0140-6736(02)08213-2 PubMed DOI

Conroy R. M., Pyörälä K., Fitzgerald A. P., Sans S., Menotti A., De Backer G., et al. (2003). Estimation of Ten-Year Risk of Fatal Cardiovascular Disease in Europe: the SCORE Project. Eur. Heart J. 24 (11), 987–1003. 10.1016/s0195-668x(03)00114-3 PubMed DOI

Crowson C. S., Matteson E. L., Roger V. L., Therneau T. M., Gabriel S. E. (2012). Usefulness of Risk Scores to Estimate the Risk of Cardiovascular Disease in Patients with Rheumatoid Arthritis. Am. J. Cardiol. 110 (3), 420–424. 10.1016/j.amjcard.2012.03.044 PubMed DOI PMC

Crowson C. S., Liao K. P., Davis J. M., 3rd, Solomon D. H., Matteson E. L., Knutson K. L., et al. (2013). Rheumatoid Arthritis and Cardiovascular Disease. Am. Heart J. 166 (4), 622–e1. 10.1016/j.ahj.2013.07.010 PubMed DOI PMC

de Groot L., Jager N. A., Westra J., Smit A. J., Kallenberg C. G., Posthumus M. D., et al. (2015). Does Reduction of Disease Activity Improve Early Markers of Cardiovascular Disease in Newly Diagnosed Rheumatoid Arthritis Patients? Rheumatol. (Oxford) 54 (7), 1257–1261. 10.1093/rheumatology/keu459 PubMed DOI

De Vecchis R., Baldi C., Palmisani L. (2016). Protective Effects of Methotrexate against Ischemic Cardiovascular Disorders in Patients Treated for Rheumatoid Arthritis or Psoriasis: Novel Therapeutic Insights Coming from a Meta-Analysis of the Literature Data. Anatol J. Cardiol. 16 (1), 2–9. 10.5152/akd.2015.6136 PubMed DOI PMC

del Rincón I. D., Williams K., Stern M. P., Freeman G. L., Escalante A. (2001). High Incidence of Cardiovascular Events in a Rheumatoid Arthritis Cohort Not Explained by Traditional Cardiac Risk Factors. Arthritis Rheum. 44 (12), 2737–2745. 10.1002/1529-0131(200112)44:12<2737::AID-ART460>3.0.CO;2-# PubMed DOI

Gonzalez A., Maradit Kremers H., Crowson C. S., Ballman K. V., Roger V. L., Jacobsen S. J., et al. (2008). Do cardiovascular Risk Factors Confer the Same Risk for Cardiovascular Outcomes in Rheumatoid Arthritis Patients as in Non-rheumatoid Arthritis Patients? Ann. Rheum. Dis. 67 (1), 64–69. 10.1136/ard.2006.059980 PubMed DOI

Grundy S. M., Cleeman J. I., Grundy S. M., Cleeman J. I., Daniels S. R., Donato K. A., et al. (2005). Diagnosis and Management of the Metabolic Syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive Summary. Cardiol. Rev. 13(17), 322–327. 10.1161/CIRCULATIONAHA.105.169404 PubMed DOI

Heart Risk Calculator (2013). Online Calculator for 10-year Risk of Heart Disease or Stroke Using the ASCVD Algorithm Published in 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk. [Online]. Available: Available from http://www.cvriskcalculator.com/ (Accessed August 2017).

Humphreys J., Hyrich K., Symmons D. (2016). What Is the Impact of Biologic Therapies on Common Co-morbidities in Patients with Rheumatoid Arthritis? Arthritis Res. Ther. 18 (1), 282. 10.1186/s13075-016-1176-x PubMed DOI PMC

Khraishi M., Aslanov R., Doyle K. (2013). SAT0055 18-Month Cardiovascular Risk Assessment in Rheumatoid Arthritis (RA) Patients Treated by Biologic Response Modifiers. Ann. Rheum. Dis. 72 (Suppl. 3), 2–A598. 10.1136/annrheumdis-2013-eular.1781 DOI

Kisiel B., Kruszewski R., Juszkiewicz A., Raczkiewicz A., Bachta A., Tłustochowicz M., et al. (2015). Methotrexate, Cyclosporine A, and Biologics Protect against Atherosclerosis in Rheumatoid Arthritis. J. Immunol. Res. 2015, 759610. 10.1155/2015/759610 PubMed DOI PMC

Ku I. A., Imboden J. B., Hsue P. Y., Ganz P. (2009). Rheumatoid Arthritis: Model of Systemic Inflammation Driving Atherosclerosis. Circ. J. 73 (6), 977–985. 10.1253/circj.cj-09-0274 PubMed DOI

Mackey R. H., Kuller L. H., Moreland L. W. (2018). Update on Cardiovascular Disease Risk in Patients with Rheumatic Diseases. Rheum. Dis. Clin. North. Am. 44 (3), 475–487. 10.1016/j.rdc.2018.03.006 PubMed DOI

Mankad R. (2015). Atherosclerotic Vascular Disease in the Autoimmune Rheumatologic Patient. Curr. Atheroscler. Rep. 17 (4), 1–10. 10.1007/s11883-015-0497-6 PubMed DOI

Maradit-Kremers H., Crowson C. S., Nicola P. J., Ballman K. V., Roger V. L., Jacobsen S. J., et al. (2005). Increased Unrecognized Coronary Heart Disease and Sudden Deaths in Rheumatoid Arthritis: a Population-Based Cohort Study. Arthritis Rheum. 52 (2), 402–411. 10.1002/art.20853 PubMed DOI

Micha R., Imamura F., Wyler von Ballmoos M., Solomon D. H., Hernán M. A., Ridker P. M., et al. (2011). Systematic Review and Meta-Analysis of Methotrexate Use and Risk of Cardiovascular Disease. Am. J. Cardiol. 108 (9), 1362–1370. 10.1016/j.amjcard.2011.06.054 PubMed DOI PMC

NASKL (2009). Online Calculator of National Authorization Center for Clinical Laboratories at the Czech Medical Society of Jan Evangelista Purkyně. [Online]. Available: Available from http://www.naskl.cz/score-algoritmus-pro-vypocet-desetilete-pravdepodobnosti-fatalni-kardiovaskularni-prihody/ (Accessed August 2017).

Nurmohamed M. T., van Halm V. P., Dijkmans B. A. (2002). Cardiovascular Risk Profile of Antirheumatic Agents in Patients with Osteoarthritis and Rheumatoid Arthritis. Drugs 62 (11), 1599–1609. 10.2165/00003495-200262110-00003 PubMed DOI

Peters M. J., van Halm V. P., Voskuyl A. E., Smulders Y. M., Boers M., Lems W. F., et al. (2009). Does Rheumatoid Arthritis Equal Diabetes Mellitus as an Independent Risk Factor for Cardiovascular Disease? A Prospective Study. Arthritis Rheum. 61 (11), 1571–1579. 10.1002/art.24836 PubMed DOI

Reiss A. B., Grossfeld D., Kasselman L. J., Renna H. A., Vernice N. A., Drewes W., et al. (2019). Adenosine and the Cardiovascular System. Am. J. Cardiovasc. Drugs 19 (5), 449–464. 10.1007/s40256-019-00345-5 PubMed DOI PMC

Reynolds Risk Score (2013). Online Calculator of Reynolds Risk Score. [Online]. Available: Available from http://www.reynoldsriskscore.org (Accessed August 2017).

Ridker P. M., Hennekens C. H., Buring J. E., Rifai N. (2000). C-Reactive Protein and Other Markers of Inflammation in the Prediction of Cardiovascular Disease in Women. N. Engl. J. Med. 342 (12), 836–843. 10.1056/nejm200003233421202 PubMed DOI

Ridker P. M., Everett B. M., Pradhan A., MacFadyen J. G., Solomon D. H., Zaharris E., et al. (2019). Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N. Engl. J. Med. 380 (8), 752–762. 10.1056/NEJMoa1809798 PubMed DOI PMC

Schieir O., Tosevski C., Glazier R. H., Hogg-Johnson S., Badley E. M. (2017). Incident Myocardial Infarction Associated with Major Types of Arthritis in the General Population: a Systematic Review and Meta-Analysis. Ann. Rheum. Dis. 76 (8), 1396–1404. 10.1136/annrheumdis-2016-210275 PubMed DOI

Shinde C. G., Venkatesh M. P., Kumar T. M., Shivakumar H. G. (2014). Methotrexate: a Gold Standard for Treatment of Rheumatoid Arthritis. J. Pain Palliat. Care Pharmacother. 28 (4), 351–358. 10.3109/15360288.2014.959238 PubMed DOI

Singh J. A., Hossain A., Mudano A. S., Tanjong Ghogomu E., Suarez-Almazor M. E., Buchbinder R., et al. (2017). Biologics or Tofacitinib for People with Rheumatoid Arthritis Naive to Methotrexate: a Systematic Review and Network Meta-Analysis. Cochrane Database Syst. Rev. 5, Cd012657. 10.1002/14651858.Cd012657 PubMed DOI PMC

Smolen J. S., Landewé R., Bijlsma J., Burmester G., Chatzidionysiou K., Dougados M., et al. (2017). EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs: 2016 Update. Ann. Rheum. Dis. 76 (6), 960–977. 10.1136/annrheumdis-2016-210715 PubMed DOI

Solomon D. H., Karlson E. W., Rimm E. B., Cannuscio C. C., Mandl L. A., Manson J. E., et al. (2003). Cardiovascular Morbidity and Mortality in Women Diagnosed with Rheumatoid Arthritis. Circulation 107 (9), 1303–1307. 10.1161/01.cir.0000054612.26458.b2 PubMed DOI

Solomon D. H., Kremer J., Curtis J. R., Hochberg M. C., Reed G., Tsao P., et al. (2010). Explaining the Cardiovascular Risk Associated with Rheumatoid Arthritis: Traditional Risk Factors versus Markers of Rheumatoid Arthritis Severity. Ann. Rheum. Dis. 69 (11), 1920–1925. 10.1136/ard.2009.122226 PubMed DOI PMC

Soukup T., Dosedel M., Pavek P., Nekvindova J., Barvik I., Bubancova I., et al. (2015). The Impact of C677T and A1298C MTHFR Polymorphisms on Methotrexate Therapeutic Response in East Bohemian Region Rheumatoid Arthritis Patients. Rheumatol. Int. 35 (7), 1149–1161. 10.1007/s00296-015-3219-z PubMed DOI

Suissa S., Bernatsky S., Hudson M. (2006). Antirheumatic Drug Use and the Risk of Acute Myocardial Infarction. Arthritis Rheum. 55 (4), 531–536. 10.1002/art.22094 PubMed DOI

Symmons D. P., Gabriel S. E. (2011). Epidemiology of CVD in Rheumatic Disease, with a Focus on RA and SLE. Nat. Rev. Rheumatol. 7, 399–408. 10.1038/nrrheum.2011.75 PubMed DOI

Toledano E., Candelas G., Rosales Z., Martínez Prada C., León L., Abásolo L., et al. (2012). A Meta-Analysis of Mortality in Rheumatic Diseases. Reumatol Clin. 8 (6), 334–341. 10.1016/j.reuma.2012.05.006 PubMed DOI

van Breukelen-van der Stoep D. F., Klop B., van Zeben D., Hazes J. M., Castro Cabezas M. (2013). Cardiovascular Risk in Rheumatoid Arthritis: How to Lower the Risk? Atherosclerosis 231 (1), 163–172. 10.1016/j.atherosclerosis.2013.09.006 PubMed DOI

van der Kooij S. M., de Vries-Bouwstra J. K., Goekoop-Ruiterman Y. P., van Zeben D., Kerstens P. J., Gerards A. H., et al. (2007). Limited Efficacy of Conventional DMARDs after Initial Methotrexate Failure in Patients with Recent Onset Rheumatoid Arthritis Treated According to the Disease Activity Score. Ann. Rheum. Dis. 66 (10), 1356–1362. 10.1136/ard.2006.066662 PubMed DOI PMC

Wållberg-Jonsson S., Johansson H., Ohman M. L., Rantapää-Dahlqvist S. (1999). Extent of Inflammation Predicts Cardiovascular Disease and Overall Mortality in Seropositive Rheumatoid Arthritis. A Retrospective Cohort Study from Disease Onset. J. Rheumatol. 26 (12), 2562–2571. PubMed

Westlake S. L., Colebatch A. N., Baird J., Kiely P., Quinn M., Choy E., et al. (2010). The Effect of Methotrexate on Cardiovascular Disease in Patients with Rheumatoid Arthritis: a Systematic Literature Review. Rheumatol. (Oxford) 49 (2), 295–307. 10.1093/rheumatology/kep366 PubMed DOI

Xie F., Chen L., Yun H., Levitan E., Muntner P., Curtis J. R. (2018). OP0192 Methotrexate Use and the Risk for Cardiovascular Disease Among Rheumatoid Patients Initiating Biologic Disease-Modifying Antirheumatic Drugs. Ann. Rheum. Dis. 77 (Suppl. 2), 145. 10.1136/annrheumdis-2018-eular.6796 DOI