Advertisement

Clinical assessment of endothelial function in patients with rheumatoid arthritis: A meta-analysis of literature studies

Published:November 04, 2015DOI:https://doi.org/10.1016/j.ejim.2015.10.016

      Highlights

      • Rheumatoid arthritis (RA) patients show impaired flow-mediated dilation (FMD).
      • A more severe inflammatory status determines a more significant impairment in FMD.
      • RA is associated with endothelial dysfunction.
      • Endothelial dysfunction may contribute to the increased cardiovascular risk in RA.

      Abstract

      Background

      Several studies reported an increased cardiovascular (CV) morbidity and mortality in patients with rheumatoid arthritis (RA). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are considered non-invasive methods to assess endothelial function and surrogate markers of subclinical atherosclerosis.

      Methods

      We performed a systematic review with meta-analysis and meta-regression of literature studies evaluating the impact of RA on FMD and NMD. Studies evaluating the relationship between RA and markers of CV risk (FMD and NMD) were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. The random-effect method was used for analyses and results were expressed as mean difference (MD).

      Results

      A total of 20 studies (852 RA patients, 836 controls) were included in the final analysis. In detail, 20 studies with data on FMD (852 cases, 836 controls) and 5 studies with data on NMD (207 cases, 147 controls) were analyzed. Compared to controls, RA patients showed a significantly lower FMD (MD: −2.16%; 95% CI: −3.33, −0.98; P = 0.0003), with no differences in NMD (MD: −0.41%; 95% CI: −2.89, 2.06; P = 0.74). Interestingly, a lower FMD (MD: −2.00%; 95% CI: −3.20, −0.80; P = 0.001) and no differences in NMD (P = 0.49) were confirmed when excluding data on patients with early-RA. Meta-regression models showed that a more severe inflammatory status was associated with a more significant impairment in FMD.

      Conclusions

      RA patients show impaired FMD, which is currently considered an independent predictor of CV events. The presence of endothelial dysfunction in RA should be taken into account to plan adequate prevention strategies and therapeutic approaches.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Scarno A.
        • Perrotta F.M.
        • Cardini F.
        • Carboni A.
        • Annibali G.
        • Lubrano E.
        • et al.
        Beyond the joint: subclinical atherosclerosis in rheumatoid arthritis.
        World J Orthop. 2014; 5: 328-335
        • Alamanos Y.
        • Drosos A.A.
        Epidemiology of adult rheumatoid arthritis.
        Autoimmun Rev. 2005; 4: 130-136
        • Gibofsky A.
        Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis.
        Am J Manag Care. 2012; 18: S295-S302
        • Mitchell D.M.
        • Spitz P.W.
        • Young D.Y.
        • Bloch D.A.
        • McShane D.J.
        • Fries J.F.
        Survival, prognosis, and causes of death in rheumatoid arthritis.
        Arthritis Rheum. 1986; 29: 706-714
        • Vandenbroucke J.P.
        • Hazevoet H.M.
        • Cats A.
        Survival and cause of death in rheumatoid arthritis: a 25-year prospective follow up.
        J Rheumatol. 1984; 11: 158-161
        • Monson R.R.
        • Hall A.P.
        Mortality among arthritics.
        J Chronic Dis. 1976; 29: 459-467
        • Prior P.
        • Symmons D.P.M.
        • Scott D.L.
        • Brown R.
        • Hawkins C.F.
        Cause of death in rheumatoid arthritis.
        Br J Rheumatol. 1984; 23: 92-99
        • Mutru O.
        • Laakso M.
        • Isomaki H.
        • Koota K.
        Ten year mortality and causes of death in patients with rheumatoid arthritis.
        Br Med J (Clin Res Ed). 1985; 290: 1797-1799
        • Di Minno M.N.
        • Iervolino S.
        • Lupoli R.
        • Russolillo A.
        • Coppola A.
        • Peluso R.
        • et al.
        Cardiovascular risk in rheumatic patients: the link between inflammation and atherothrombosis.
        Semin Thromb Hemost. 2012; 38: 497-505
        • Minaur N.J.
        • Jacoby R.K.
        • Cosh J.A.
        • Taylor G.
        • Rasker J.J.
        Outcome after 40 years with rheumatoid arthritis: a prospective study of function, disease activity, and mortality.
        J Rheumatol Suppl. 2004; 69: 3-8
        • Aviña-Zubieta J.A.
        • Choi H.K.
        • Sadatsafavi M.
        • Etminan M.
        • Esdaile J.M.
        • Lacaille D.
        Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies.
        Arthritis Rheum. 2008; 59: 1690-1697
        • La Montagna G.
        • Cacciapuoti F.
        • Buono R.
        • Manzella D.
        • Mennillo G.A.
        • Arciello A.
        • et al.
        Insulin resistance is an independent risk factor for atherosclerosis in rheumatoid arthritis.
        Diab Vasc Dis Res. 2007; 4: 130-135
        • Salmon J.E.
        • Roman M.J.
        Subclinical atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus.
        Am J Med. 2008; 121: S3-S8
        • Simon A.
        • Chironi G.
        • Levenson J.
        The performance of subclinical arterial disease detection as screening test for coronary heart disease.
        Hypertension. 2006; 48: 392-396
        • Vaudo G.
        • Marchesi S.
        • Gerli R.
        • Allegrucci R.
        • Giordano A.
        • Siepi D.
        • et al.
        Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity.
        Ann Rheum Dis. 2004; 63: 31-35
        • Corretti M.C.
        • Anderson T.J.
        • Benjamin E.J.
        • Celermajer D.
        • Charbonneau F.
        • Creager M.A.
        • et al.
        Guidelines for the ultrasound assessment of endothelial dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
        J Am Coll Cardiol. 2002; 39: 257-265
        • Khan F.
        • Galarraga B.
        • Belch J.J.
        The role of endothelial function and its assessment in rheumatoid arthritis.
        Nat Rev Rheumatol. 2010; 6: 253-261
        • Ras R.T.
        • Streppel M.T.
        • Draijer R.
        • Zock P.L.
        Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis.
        Int J Cardiol. 2013; 168: 344-351
        • Bosello S.
        • Santoliquido A.
        • Zoli A.
        • Di Campli C.
        • Flore R.
        • Tondi P.
        • et al.
        TNF-alpha blockade induces a reversible but transient effect on endothelial dysfunction in patients with long-standing severe rheumatoid arthritis.
        Clin Rheumatol. 2008; 27: 833-839
        • Spinelli F.R.
        • Metere A.
        • Barbati C.
        • Pierdominici M.
        • Iannuccelli C.
        • Lucchino B.
        • et al.
        Effect of therapeutic inhibition of TNF on circulating endothelial progenitor cells in patients with rheumatoid arthritis.
        Mediators Inflamm. 2013; 2013: 537539
        • Södergren A.
        • Karp K.
        • Boman K.
        • Eriksson C.
        • Lundström E.
        • Smedby T.
        • et al.
        Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness.
        Arthritis Res Ther. 2010; 12: R158
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        PLoS Med. 2009; 6: e1000097
      1. Wells GA, Shea B, O'Connell D, J Peterson, V Welch, M Losos, et al. Ottawa Hospital Research Institute. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.

        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Sterne J.A.
        • Egger M.
        • Smith G.D.
        Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis.
        BMJ. 2001; 323: 101-105
        • Duval S.
        • Tweedie R.
        Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
        Biometrics. 2000; 56: 455-463
        • Arosio E.
        • De Marchi S.
        • Rigoni A.
        • Prior M.
        • Delva P.
        • Lechi A.
        Forearm haemodynamics, arterial stiffness and microcirculatory reactivity in rheumatoid arthritis.
        J Hypertens. 2007; 25: 1273-1278
        • Cypienė A.
        • Dadonienė J.
        • Rugienė R.
        • Ryliškytė L.
        • Kovaitė M.
        • Petrulionienė Z.
        • et al.
        The influence of mean blood pressure on arterial stiffening and endothelial dysfunction in women with rheumatoid arthritis and systemic lupus erythematosus.
        Medicina (Kaunas). 2010; 46: 522-530
        • Fan C.Y.
        • Zhang Z.Y.
        • Mei Y.F.
        • Wu C.J.
        • Shen B.Z.
        Impaired brachial artery flow-mediated dilation and increased carotid intima-media thickness in rheumatoid arthritis patients.
        Chin Med J (Engl). 2012; 125: 832-837
        • Gonzalez-Juanatey C.
        • Llorca J.
        • Sanchez-Andrade A.
        • Garcia-Porrua C.
        • Martin J.
        • Gonzalez-Gay M.A.
        Short-term adalimumab therapy improves endothelial function in patients with rheumatoid arthritis refractory to infliximab.
        Clin Exp Rheumatol. 2006; 24: 309-312
        • Hannawi S.
        • Marwick T.H.
        • Thomas R.
        Inflammation predicts accelerated brachial arterial wall changes in patients with recent-onset rheumatoid arthritis.
        Arthritis Res Ther. 2009; 11: R51
        • Holmes M.V.
        • Jiang B.
        • McNeill K.
        • Wong M.
        • Oakley S.P.
        • Kirkham B.
        • et al.
        Paradoxical association of C-reactive protein with endothelial function in rheumatoid arthritis.
        PLoS ONE. 2010; 5: e10242
        • Hürlimann D.
        • Forster A.
        • Noll G.
        • Enseleit F.
        • Chenevard R.
        • Distler O.
        • et al.
        Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis.
        Circulation. 2002; 106: 2184-2187
        • Irace C.
        • Mancuso G.
        • Fiaschi E.
        • Madia A.
        • Sesti G.
        • Gnasso A.
        Effect of anti TNFalpha therapy on arterial diameter and wall shear stress and HDL cholesterol.
        Atherosclerosis. 2004; 177: 113-118
        • Kerekes G.
        • Szekanecz Z.
        • Dér H.
        • Sándor Z.
        • Lakos G.
        • Muszbek L.
        • et al.
        Endothelial dysfunction and atherosclerosis in rheumatoid arthritis: a multiparametric analysis using imaging techniques and laboratory markers of inflammation and autoimmunity.
        J Rheumatol. 2008; 35: 398-406
        • Mäki-Petäjä K.M.
        • Hall F.C.
        • Booth A.D.
        • Wallace S.M.
        • Yasmin
        • Bearcroft P.W.
        • et al.
        Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy.
        Circulation. 2006; 114: 1185-1192
        • Mäki-Petäjä K.M.
        • Booth A.D.
        • Hall F.C.
        • Wallace S.M.
        • Brown J.
        • McEniery C.M.
        • et al.
        Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis.
        J Am Coll Cardiol. 2007; 50: 852-858
        • Protogerou A.D.
        • Zampeli E.
        • Fragiadaki K.
        • Stamatelopoulos K.
        • Papamichael C.
        • Sfikakis P.P.
        A pilot study of endothelial dysfunction and aortic stiffness after interleukin-6 receptor inhibition in rheumatoid arthritis.
        Atherosclerosis. 2011; 219: 734-736
        • Sarli B.
        • Baktir A.O.
        • Cebicci M.
        • Dogan Y.
        • Demirbas M.
        • Kurtul S.
        • et al.
        Predictors of endothelial dysfunction in patients with rheumatoid arthritis.
        Angiology. 2014; 9: 778-782
        • Stamatelopoulos K.S.
        • Kitas G.D.
        • Papamichael C.M.
        • Chryssohoou E.
        • Kyrkou K.
        • Georgiopoulos G.
        • et al.
        Atherosclerosis in rheumatoid arthritis versus diabetes: a comparative study.
        Arterioscler Thromb Vasc Biol. 2009; 29: 1702-1708
        • Van Doornum S.
        • McColl G.
        • Jenkins A.
        • Green D.J.
        • Wicks I.P.
        Screening for atherosclerosis in patients with rheumatoid arthritis: comparison of two in vivo tests of vascular function.
        Arthritis Rheum. 2003; 48: 72-80
        • Veselinovic M.V.
        • Zivkovic V.I.
        • Toncev S.
        • Tasic N.
        • Bogdanovic V.
        • Djuric D.M.
        • et al.
        Carotid artery intima-media thickness and brachial artery flow-mediated vasodilatation in patients with rheumatoid arthritis.
        Vasa. 2012; 41: 343-351
        • Ambrosino P.
        • Lupoli R.
        • Di Minno A.
        • Tasso M.
        • Peluso R.
        • Di Minno M.N.
        Subclinical atherosclerosis in patients with rheumatoid arthritis: a meta-analysis of literature studies.
        Thromb Haemost. 2015; 113: 916-930
        • Di Minno M.N.
        • Ambrosino P.
        • Lupoli R.
        • Di Minno A.
        • Tasso M.
        • Peluso R.
        • et al.
        Cardiovascular risk markers in patients with psoriatic arthritis: a meta-analysis of literature studies.
        Ann Med. 2015 Jun; 47: 346-353
        • Ambrosino P.
        • Lupoli R.
        • Di Minno A.
        • Iervolino S.
        • Peluso R.
        • Di Minno M.N.
        Markers of cardiovascular risk in patients with antiphospholipid syndrome: a meta-analysis of literature studies.
        Ann Med. 2014; 46: 693-702
        • Ambrosino P.
        • Tasso M.
        • Lupoli R.
        • Di Minno A.
        • Baldassarre D.
        • Tremoli E.
        • et al.
        Non-invasive assessment of arterial stiffness in patients with rheumatoid arthritis: a systematic review and meta-analysis of literature studies.
        Ann Med. 2015; 6: 457-467
        • Martín-Timón I.
        • Sevillano-Collantes C.
        • Segura-Galindo A.
        • Del Cañizo-Gómez F.J.
        Type 2 diabetes and cardiovascular disease: have all risk factors the same strength?.
        World J Diabetes. 2014; 5: 444-470
        • Flammer A.J.
        • Anderson T.
        • Celermajer D.S.
        • Creager M.A.
        • Deanfield J.
        • Ganz P.
        • et al.
        The assessment of endothelial function: from research into clinical practice.
        Circulation. 2012; 126: 753-767
        • van den Oever I.A.
        • van Sijl A.M.
        • Nurmohamed M.T.
        Management of cardiovascular risk in patients with rheumatoid arthritis: evidence and expert opinion.
        Ther Adv Musculoskelet Disord. 2013; 5: 166-181
        • Bacon P.A.
        • Stevens R.J.
        • Carruthers D.M.
        • Young S.P.
        • Kitas G.D.
        Accelerated atherogenesis in autoimmune rheumatic diseases.
        Autoimmun Rev. 2002; 1: 338-347
        • Bilsborough W.
        • Keen H.
        • Taylor A.
        • O'Driscoll G.J.
        • Arnolda L.
        • Green D.J.
        Anti-tumour necrosis factor-alpha therapy over conventional therapy improves endothelial function in adults with rheumatoid arthritis.
        Rheumatol Int. 2006; 26: 1125-1131
        • Barnabe C.
        • Martin B.J.
        • Ghali W.A.
        Systematic review and meta-analysis: anti-tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis.
        Arthritis Care Res (Hoboken). 2011; 63: 522-529
        • Boyer J.F.
        • Gourraud P.A.
        • Cantagrel A.
        • Davignon J.L.
        • Constantin A.
        Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis.
        Joint Bone Spine. 2011; 78: 179-183
        • Peters M.J.
        • Symmons D.P.
        • McCarey D.
        • Dijkmans B.A.
        • Nicola P.
        • Kvien T.K.
        • et al.
        EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.
        Ann Rheum Dis. 2010; 69: 325-331
        • van Sijl A.M.
        • Peters M.J.
        • Knol D.K.
        • de Vet H.C.
        • Gonzalez-Gay M.A.
        • Smulders Y.M.
        • et al.
        Carotid intima media thickness in rheumatoid arthritis as compared to control subjects: a meta-analysis.
        Semin Arthritis Rheum. 2011; 40: 389-397
        • Gonzalez-Juanatey C.
        • Llorca J.
        • Testa A.
        • Revuelta J.
        • Garcia-Porrua C.
        • Gonzalez-Gay M.A.
        Increased prevalence of severe subclinical atherosclerotic findings in long term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease.
        Medicine. 2003; 82: 407-413
        • Green D.J.
        • Jones H.
        • Thijssen D.
        • Cable N.T.
        • Atkinson G.
        Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter?.
        Hypertension. 2011; 57: 363-369
        • Cooke J.P.
        • Tsao P.S.
        Is no an endogenous antiatherogenic molecule?.
        Arterioscler Thromb. 1994; 14: 653-655
        • Shimbo D.
        • Grahame-Clarke C.
        • Miyake Rodriguez C.
        • Sciacca R.
        • Di Tullio M.
        • et al.
        The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort.
        Atherosclerosis. 2007; 192: 197-203
        • Raitakari O.T.
        • Seale J.P.
        • Celermajer D.S.
        Impaired vascular responses to nitroglycerin in subjects with coronary atherosclerosis.
        Am J Cardiol. 2001; 87: 217-219
        • Soltész P.
        • Kerekes G.
        • Dér H.
        • Szücs G.
        • Szántó S.
        • Kiss E.
        • et al.
        Comparative assessment of vascular function in autoimmune rheumatic diseases: considerations of prevention and treatment.
        Autoimmun Rev. 2011; 10: 416-425
        • Doshi S.N.
        • Naka K.K.
        • Payne N.
        • Jones C.J.
        • Ashton M.
        • Lewis M.J.
        • et al.
        Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide.
        Clin Sci. 2001; 101: 629-635
        • Mullen M.J.
        • Kharbanda R.K.
        • Cross J.
        • Donald A.E.
        • Taylor M.
        • Vallance P.
        • et al.
        Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo.
        Circ Res. 2001; 88: 145-151