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Comorbidities As Risk Factors for Rheumatoid Arthritis and Their Accrual After Diagnosis

Published:November 19, 2019DOI:



      To determine the prevalence of comorbidities in rheumatoid arthritis (RA), discover which comorbidities might predispose to developing RA, and identify which comorbidities are more likely to develop after RA.

      Patients and Methods

      We performed a case-control study using a single-center biobank, identifying 821 cases of RA (143 incident RA) between January 1, 2009, and February 28, 2018, defined as 2 diagnosis codes plus a disease-modifying antirheumatic drug. We matched each case to 3 controls based on age and sex. Participants self-reported the presence and onset of 74 comorbidities. Logistic regression models adjusted for race, body mass index, education, smoking, and Charlson comorbidity index.


      After adjustment for confounders and multiple comparisons, 11 comorbidities were associated with RA, including epilepsy (odds ratio [OR], 2.13; P=.009), obstructive sleep apnea (OR, 1.49; P=.001), and pulmonary fibrosis (OR, 4.63; P<.001), but cancer was not. Inflammatory bowel disease (OR, 3.82; P<.001), type 1 diabetes (OR, 3.07; P=.01), and venous thromboembolism (VTE; OR, 1.80; P<.001) occurred more often before RA diagnosis compared with controls. In contrast, myocardial infarction (OR, 3.09; P<.001) and VTE (OR, 1.84; P<.001) occurred more often after RA diagnosis compared with controls. Analyses restricted to incident RA cases and their matched controls mirrored these results.


      Inflammatory bowel disease, type 1 diabetes, and VTE might predispose to RA development, whereas cardiovascular disease, VTE, and obstructive sleep apnea can result from RA. These findings have important implications for RA pathogenesis, early detection, and recommended screening.

      Abbreviations and Acronyms:

      BMI (body mass index), CCI (Charlson comorbidity index), DMARD (disease-modifying antirheumatic drug), EHR (electronic health record), IBD (inflammatory bowel disease), MI (myocardial infarction), OSA (obstructive sleep apnea), RA (rheumatoid arthritis), VTE (venous thromboembolism)
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        • Radner H.
        • Smolen J.S.
        • Aletaha D.
        Impact of comorbidity on physical function in patients with rheumatoid arthritis.
        Ann Rheum Dis. 2010; 69: 536-541
        • Norton S.
        • Koduri G.
        • Nikiphorou E.
        • Dixey J.
        • Williams P.
        • Young A.
        A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular manifestations in RA and their impact on outcome.
        Rheumatology (Oxford). 2013; 52: 99-110
        • Ellerby N.
        • Mattey D.L.
        • Packham J.
        • Dawes P.
        • Hider S.L.
        Obesity and comorbidity are independently associated with a failure to achieve remission in patients with established rheumatoid arthritis.
        Ann Rheum Dis. 2014; 73: e74
        • Geryk L.L.
        • Carpenter D.M.
        • Blalock S.J.
        • DeVellis R.F.
        • Jordan J.M.
        The impact of co-morbidity on health-related quality of life in rheumatoid arthritis and osteoarthritis patients.
        Clin Exp Rheumatol. 2015; 33: 366-374
        • Pedersen J.K.
        • Holst R.
        • Primdahl J.
        • Svendsen A.J.
        • Horslev-Petersen K.
        Mortality and its predictors in patients with rheumatoid arthritis: a Danish population-based inception cohort study.
        Scand J Rheumatol. 2018; 47: 371-377
        • Gabriel S.E.
        • Michaud K.
        Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases.
        Arthritis Res Ther. 2009; 11: 229
        • Jin S.
        • Li M.
        • Fang Y.
        • et al.
        Chinese Registry of rheumatoid arthritis (CREDIT): II. prevalence and risk factors of major comorbidities in Chinese patients with rheumatoid arthritis.
        Arthritis Res Ther. 2017; 19: 251
        • Jeong H.
        • Baek S.Y.
        • Kim S.W.
        • et al.
        Comorbidities of rheumatoid arthritis: results from the Korean National Health and Nutrition Examination Survey.
        PLoS One. 2017; 12: e0176260
        • Siebert S.
        • Lyall D.M.
        • Mackay D.F.
        • et al.
        Characteristics of rheumatoid arthritis and its association with major comorbid conditions: cross-sectional study of 502 649 UK Biobank participants.
        RMD Open. 2016; 2: e000267
        • Shen T.C.
        • Hang L.W.
        • Liang S.J.
        • et al.
        Risk of obstructive sleep apnoea in patients with rheumatoid arthritis: a nationwide population-based retrospective cohort study.
        BMJ Open. 2016; 6: e013151
        • Reading S.R.
        • Crowson C.S.
        • Rodeheffer R.J.
        • Fitz-Gibbon P.D.
        • Maradit-Kremers H.
        • Gabriel S.E.
        Do rheumatoid arthritis patients have a higher risk for sleep apnea?.
        J Rheumatol. 2009; 36: 1869-1872
        • Wilton K.M.
        • Matteson E.L.
        • Crowson C.S.
        Risk of obstructive sleep apnea and its association with cardiovascular and noncardiac vascular risk in patients with rheumatoid arthritis: a population-based study.
        J Rheumatol. 2018; 45: 45-52
        • Vallerand I.A.
        • Lewinson R.T.
        • Frolkis A.D.
        • et al.
        Depression as a risk factor for the development of rheumatoid arthritis: a population-based cohort study.
        RMD Open. 2018; 4: e000670
        • Chung W.S.
        • Lin C.L.
        Sleep disorders associated with risk of rheumatoid arthritis.
        Sleep Breath. 2018; 22: 1083-1091
        • Halling M.L.
        • Kjeldsen J.
        • Knudsen T.
        • Nielsen J.
        • Hansen L.K.
        Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases.
        World J Gastroenterol. 2017; 23: 6137-6146
        • Schmitt J.
        • Schwarz K.
        • Baurecht H.
        • et al.
        Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes.
        J Allergy Clin Immunol. 2016; 137: 130-136
        • Olson J.E.
        • Ryu E.
        • Johnson K.J.
        • et al.
        The Mayo Clinic Biobank: a building block for individualized medicine.
        Mayo Clin Proc. 2013; 88: 952-962
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gotzsche P.C.
        • Vandenbroucke J.P.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Int J Surg. 2014; 12: 1495-1499
        • Chung C.P.
        • Rohan P.
        • Krishnaswami S.
        • McPheeters M.L.
        A systematic review of validated methods for identifying patients with rheumatoid arthritis using administrative or claims data.
        Vaccine. 2013; 31: K41-K61
        • Kronzer V.L.
        • Crowson C.S.
        • Sparks J.A.
        • Vassallo R.
        • Davis III, J.M.
        Investigating asthma, allergic disease, passive smoke exposure, and risk of rheumatoid arthritis.
        Arthritis Rheumatol. 2019; 71: 1217-1224
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • MacKenzie C.R.
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chronic Dis. 1987; 40: 373-383
        • Holmqvist M.E.
        • Neovius M.
        • Eriksson J.
        • et al.
        Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization.
        JAMA. 2012; 308: 1350-1356
        • Kim S.C.
        • Schneeweiss S.
        • Liu J.
        • Solomon D.H.
        Risk of venous thromboembolism in patients with rheumatoid arthritis.
        Arthritis Care Res (Hoboken). 2013; 65: 1600-1607
        • Davies R.
        • Galloway J.B.
        • Watson K.D.
        • Lunt M.
        • Symmons D.P.
        • Hyrich K.L.
        Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register.
        Ann Rheum Dis. 2011; 70: 1831-1834
        • Bae J.M.
        • Choo J.Y.
        • Kim K.J.
        • Park K.S.
        Association of inflammatory bowel disease with ankylosing spondylitis and rheumatoid arthritis: a nationwide population-based study.
        Mod Rheumatol. 2017; 27: 435-440
        • Dieude P.
        • Teixeira V.H.
        • Pierlot C.
        • Cornelis F.
        • Petit-Teixeira E.
        Testing for linkage and association with rheumatoid arthritis a ptpn22 promoter polymorphism reported to be associated and linked with type 1 diabetes in the Caucasian population.
        Ann Rheum Dis. 2008; 67: 900-901
        • Hemminki K.
        • Li X.
        • Sundquist J.
        • Sundquist K.
        Familial association between type 1 diabetes and other autoimmune and related diseases.
        Diabetologia. 2009; 52: 1820-1828
        • Liao K.P.
        • Gunnarsson M.
        • Kallberg H.
        • et al.
        Specific association of type 1 diabetes mellitus with anti-cyclic citrullinated peptide-positive rheumatoid arthritis.
        Arthritis Rheum. 2009; 60: 653-660
        • Zhang P.
        • Lu Q.
        Genetic and epigenetic influences on the loss of tolerance in autoimmunity.
        Cell Mol Immunol. 2018; 15: 575-585
        • Chang K.H.
        • Hsu Y.C.
        • Chang M.Y.
        • et al.
        A large-scale study indicates increase in the risk of epilepsy in patients with different risk factors, including rheumatoid arthritis.
        Medicine (Baltimore). 2015; 94: e1485
        • Ong M.S.
        • Kohane I.S.
        • Cai T.
        • Gorman M.P.
        • Mandl K.D.
        Population-level evidence for an autoimmune etiology of epilepsy.
        JAMA Neurol. 2014; 71: 569-574
        • Gaitatzis A.
        • Carroll K.
        • Majeed A.
        • W Sandler J.
        The epidemiology of the comorbidity of epilepsy in the general population.
        Epilepsia. 2004; 45: 1613-1622
        • Rana A.
        • Musto A.E.
        The role of inflammation in the development of epilepsy.
        J Neuroinflammation. 2018; 15: 144
        • Gabriel S.E.
        • Crowson C.S.
        • O’Fallon W.M.
        Comorbidity in arthritis.
        J Rheumatol. 1999; 26: 2475-2479
        • Wright K.
        • Crowson C.S.
        • Gabriel S.E.
        Cardiovascular comorbidity in rheumatic diseases: a focus on heart failure.
        Heart Fail Clin. 2014; 10: 339-352
        • Myasoedova E.
        • Crowson C.S.
        • Kremers H.M.
        • Fitz-Gibbon P.D.
        • Therneau T.M.
        • Gabriel S.E.
        Total cholesterol and LDL levels decrease before rheumatoid arthritis.
        Ann Rheum Dis. 2010; 69: 1310-1314