Cardiovascular disease has become the first cause of death for patients with ankylosing spondylitis (AS). However, the relevant data is limited and the relationship between AS and subclinical atherosclerosis remains questionable. Therefore, we assessed the relationship between subclinical atherosclerosis and AS in this meta-analysis. We synthesized the primary data on flow-mediated vasodilation (FMD), carotid intima media thickness (cIMT), or pulse wave velocity (PWV)-related studies involving AS and using searched electronic databases. Not only were heterogeneity tests, publication bias, and sensitivity analysis performed overall, but also subgroup analysis and meta-regression grouped by measuring site, region, age, sex, and sample size were also carried out. A total of 35 articles involving 1535 patients with AS and 1347 normal controls were included. Significantly increased cIMT (weighted mean difference [WMD]; 95% confidence interval [CI]) = 0.071 [0.048-0.094]), PWV (WMD [95%CI] = 0.910 [0.464-1.356]), and decreased FMD (WMD [95%CI] = −4.459 [−8.389 to −0.529]) were observed in patients with AS compared to controls. The funnel plots or Egger test or Begg test showed no significant publication bias (all P > .05). Sensitivity analysis did not show statistical significance. We conclude that patients with AS have a higher risk of subclinical atherosclerosis. Early screening and intervention deserves consideration.
RomanMJSalmonJE. Cardiovascular manifestations of rheumatologic diseases. Circulation. 2007;116:2346–55.
2.
YiYS. Role of inflammasomes in inflammatory autoimmune rheumatic diseases. Korean J Physiol Pharmacol. 2018;22:1–15.
3.
ShenJShangQTamLS. Targeting inflammation in the prevention of cardiovascular disease in patients with inflammatory arthritis. Transl Res. 2016;167:138–51.
4.
CastanedaSNurmohamedMTGonzalez-GayMA. Cardiovascular disease in inflammatory rheumatic diseases. Best Pract Res Clin Rheumatol. 2016;30:851–69.
5.
BodnarNKerekesGSeresI. Assessment of subclinical vascular disease associated with ankylosing spondylitis. J Rheumatol. 2011;38:723–9.
6.
VermaISyngleAKrishanPGargN. Endothelial progenitor cells as a marker of endothelial dysfunction and atherosclerosis in ankylosing spondylitis: a cross-sectional study. Int J Angiol. 2017;26:36–42.
7.
CapkinEKirisAKarkucakM. Investigation of effects of different treatment modalities on structural and functional vessel wall properties in patients with ankylosing spondylitis. Joint Bone Spine. 2011;78:378–82.
8.
AvramCDragoiRGPopoviciuHDragoiMAvramAAmaricaiE. Association between arterial stiffness, disease activity and functional impairment in ankylosing spondylitis patients: a cross-sectional study. Clin Rheumatol. 2016;35:2017–22.
9.
Kucukali TurkyilmazADevrimselGSerdaroglu BeyazalM. The relationship between serum YKL-40 levels and arterial stiffness in patients with ankylosing spondylitis. Acta Reumatol Port. 2017;42:183–90.
10.
Dzieza-GrudnikASulickaJStrachM. Arterial stiffness is not increased in patients with short duration rheumatoid arthritis and ankylosing spondylitis. Blood Press. 2017;26:115–21.
11.
PerrottaFMScarnoACarboniA. Assessment of subclinical atherosclerosis in ankylosing spondylitis: correlations with disease activity indices. Reumatismo. 2013;65:105–12.
12.
ErreGLSannaPZinelluA. Plasma asymmetric dimethylarginine (ADMA) levels and atherosclerotic disease in ankylosing spondylitis: a cross-sectional study. Clin Rheumatol. 2011;30:21–7.
13.
DeiserothAMarcinTBergerC. Retinal vessel diameters and physical activity in patients with mild to moderate rheumatic disease without cardiovascular comorbidities. Front Physiol. 2018;9:176.
14.
CureEIcliAUsluAU. Atherogenic index of plasma: a useful marker for subclinical atherosclerosis in ankylosing spondylitis: AIP associate with cIMT in AS. Clin Rheumatol. 2018;37:1273–80.
15.
AksenovaTIvashhenkoNTsarenokSGorbunovVGromovP. The data of central aortic pressure and pulse wave velocity in patients with ankylosing spondylitis. Ann Rheum Dis. 2017;76:1311–12.
16.
TurkonHGokmenFUysalS. Evaluation of serum endothelial cell-specific molecule-1 levels and carotid intima-media thickness in patients with ankylosing spondylitis. Turk J Biochem. 2016;41:19–25.
17.
Serdaroglu BeyazalMErdoganTTurkyilmazAK. Relationship of serum osteoprotegerin with arterial stiffness, preclinical atherosclerosis, and disease activity in patients with ankylosing spondylitis. Clin Rheumatol. 2016;35:2235–41.
18.
CaglarSOBoyrazIErdemF. Evaluation of atrial conduction times, epicardial fat thickness and carotid intima-media thickness in patients with ankylosing spondylitis. Arch Rheumatol. 2016;31:353–8.
19.
VermaIKrishanPSyngleA. Predictors of atherosclerosis in ankylosing spondylitis. Rheumatol Ther. 2015;2:173–82.
20.
ResorluHAkbalAResorluM. Epicardial adipose tissue thickness in patients with ankylosing spondylitis. Clin Rheumatol. 2015;34:295–9.
21.
UstunNKurtMAtciNYagizEGulerHTurhanogluA. Increased epicardial fat tissue is a marker of subclinic atherosclerosis in ankylosing spondylitis. Arch Rheumatol. 2014;29:267–72.
22.
GuptaNSaigalRGoyalLAgrawalABhargavaRAgrawalA. Carotid intima media thickness as a marker of atherosclerosis in ankylosing spondylitis. Int J Rheumatol. 2014;2014:839135.
23.
ValenteRLMValenteJMde CastroGRWZimmermannAFFialhoSCDSPereiraIA. Subclinical atherosclerosis in ankylosing spondylitis: is there a role for inflammation?Rev Bras Reumatol. 2013;53:377–81.
OzsahinMBuyukkayaRBesirFH. Assessment of carotid intima-media thickness in ankylosing spondylitis patients. Acta Medica Mediterr. 2013;29:687–91.
26.
GeceneMTuncayFBormanPYucelDSenesMYilmazBK. Atherosclerosis in male patients with ankylosing spondylitis: the relation with methylenetetrahydrofolate reductase (C677 T) gene polymorphism and plasma homocysteine levels. Rheumatol Int. 2013;33:1519–24.
27.
ErcanSGoktepeFKisacikB. Subclinical cardiovascular target organ damage manifestations of ankylosing spondylitis in young adult patients. Mod Rheumatol. 2013;23:1063–68.
28.
CecconFTAzevedoVFEngelhornCA. Evaluation of sub-clinical atherosclerosis and plasma levels of minimally modified LDL in patients with ankylosing spondylitis and its correlation with disease activity. Rev Bras Reumatol. 2013;53:470–5.
29.
HamdiWChelli BouazizMZouchI. Assessment of preclinical atherosclerosis in patients with ankylosing spondylitis. J Rheumatol. 2012;39:322–6.
30.
CeceHYazganPKarakasE. Carotid intima-media thickness and paraoxonase activity in patients with ankylosing spondylitis. Clin Invest Med. 2011;34:E225.
31.
PetersMJLvan EijkICSmuldersYM. Signs of accelerated preclinical atherosclerosis in patients with ankylosing spondylitis. J Rheumatol. 2010;37:161–6.
32.
KarkucakMCapkinEAlverA. The effect of anti-TNF agent on oxidation status in patients with ankylosing spondylitis. Clin Rheumatol. 2010;29:303–7.
33.
Gonzalez-JuanateyCVazquez-RodriguezTRMiranda-FilloyJA. The high prevalence of subclinical atherosclerosis in patients with ankylosing spondylitis without clinically evident cardiovascular disease. Medicine (Baltimore). 2009;88:358–65.
34.
SeyahiEUgurluSCumaliR. Atherosclerosis in Behcet’s syndrome. Semin Arthritis Rheum. 2008;38:1–12.
35.
MathieuSJolyHBaronG. Trend towards increased arterial stiffness or intima-media thickness in ankylosing spondylitis patients without clinically evident cardiovascular disease. Rheumatology (Oxford). 2008;47:1203–7.
36.
ChoeJYLeeMYRheemIRheeMYParkSHKimSK. No differences of carotid intima-media thickness between young patients with ankylosing spondylitis and healthy controls. Joint Bone Spine. 2008;75:548–53.
37.
MalesciDNiglioAMennilloGABuonoRValentiniGLa MontagnaG. High prevalence of metabolic syndrome in patients with ankylosing spondylitis. Clin Rheumatol. 2007;26:710–4.
38.
SariIOkanTAkarS. Impaired endothelial function in patients with ankylosing spondylitis. Rheumatology (Oxford). 2006;45:283–6.
39.
KucukAUsluAUIcliA. The LDL/HDL ratio and atherosclerosis in ankylosing spondylitis. Z Rheumatol. 2017;76:58–63.
40.
WuYSunDWangBLiYMaY. The relationship of depressive symptoms and functional and structural markers of subclinical atherosclerosis: a systematic review and meta-analysis. Eur J Prev Cardiol. 2018;25:706–16.
41.
BuschiazzoEASchneebergerEESommerfleckFALedesmaCCiteraG. Mortality in patients with ankylosing spondylitis in Argentina. Clin Rheumatol. 2016;35:2229–33.
42.
CastanedaSMartin-MartinezMAGonzalez-JuanateyC. Cardiovascular morbidity and associated risk factors in Spanish patients with chronic inflammatory rheumatic diseases attending rheumatology clinics: baseline data of the CARMA Project. Semin Arthritis Rheum. 2015;44:618–26.
43.
SzaboSMLevyARRaoSR. Increased risk of cardiovascular and cerebrovascular diseases in individuals with ankylosing spondylitis: a population-based study. Arthritis Rheum. 2011;63:3294–304.
44.
MathieuSGossecLDougadosMSoubrierM. Cardiovascular profile in ankylosing spondylitis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2011;63:557–63.
45.
AridaAProtogerouADKonstantonisG. Subclinical atherosclerosis is not accelerated in patients with ankylosing spondylitis with low disease activity: new data and metaanalysis of published studies. J Rheumatol. 2015;42:2098–105.
46.
YuanYYangJZhangX. Carotid intima-media thickness in patients with ankylosing spondylitis: a systematic review and updated meta-analysis. J Atheroscler Thromb. 2019;26(3):260–71. doi:10.5551/jat.45294
47.
HahnBHGrossmanJChenWMcMahonM. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun. 2007;28:69–75.
48.
GiolloADalbeniACioffiG. Factors associated with accelerated subclinical atherosclerosis in patients with spondyloarthritis without overt cardiovascular disease. Clin Rheumatol. 2017;36:2487–95.
49.
GenreFRueda-GotorJRemuzgo-MartinezS. Implication of osteoprotegerin and sclerostin in axial spondyloarthritis cardiovascular disease: a study of 163 Spanish patients. Clin Exp Rheumatol. 2018;36:302–9.
50.
Rueda-GotorJCorralesABlancoR. Atherosclerotic disease in axial spondyloarthritis: increased frequency of carotid plaques. Clin Exp Rheumatol. 2015;33:315–20.
51.
KaraderiTKeidelSMPointonJJ. Ankylosing spondylitis is associated with the anthrax toxin receptor 2 gene (ANTXR2). Ann Rheum Dis. 2014;73:2054–58.
52.
TangYYangPWangFXuHZongSY. Association of polymorphisms in ERAP1 and risk of ankylosing spondylitis in a Chinese population. Gene. 2018;646:8–11.
53.
CaiGZhangXXinL. Associations between vitamin D receptor gene polymorphisms and ankylosing spondylitis in Chinese Han population: a case–control study. Osteoporos Int. 2016;27:2327–33.
54.
YangTDuanZWuS. Association of HLA-B27 genetic polymorphisms with ankylosing spondylitis susceptibility worldwide: a meta-analysis. Mod Rheumatol. 2014;24:150–61.
55.
TamLSGuJYuD. Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol. 2010;6:399–405.
56.
WrightPBMcEntegartAMcCareyDMcInnesIBSiebertSMillingSWF. Ankylosing spondylitis patients display altered dendritic cell and T cell populations that implicate pathogenic roles for the IL-23 cytokine axis and intestinal inflammation. Rheumatology (Oxford). 2016;55:120–32.
57.
SuttonCELalorSJSweeneyCMBreretonCFLavelleECMillsKH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31:331–41.
58.
ChenWSChangYSLinKC. Association of serum interleukin-17 and interleukin-23 levels with disease activity in Chinese patients with ankylosing spondylitis. J Chinese Med Assoc. 2012;75:303–8.
59.
WangXLinZWeiQJiangYGuJ. Expression of IL-23 and IL-17 and effect of IL-23 on IL-17 production in ankylosing spondylitis. Rheumatol Int. 2009;29:1343–47.
60.
RezaiemaneshAMahmoudiMAmirzargarAAVojdanianMJamshidiARNicknamMH. Ankylosing spondylitis M-CSF-derived macrophages are undergoing unfolded protein response (UPR) and express higher levels of interleukin-23. Mod Rheumatol. 2017;27:862–7.
61.
JoSWangSELeeYL. IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis. Arthritis Res Ther. 2018;20:115.
62.
SchuettHOestreichRWaetzigGH. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2012;32:281–90.
63.
HoshiTKitagawaKYamagamiHFurukadoSHougakuHHoriM. Relation between interleukin-6 level and subclinical intracranial large-artery atherosclerosis. Atherosclerosis. 2008;197:326–2.
64.
HsuDCMaYFHurS. Plasma IL-6 levels are independently associated with atherosclerosis and mortality in HIV-infected individuals on suppressive antiretroviral therapy. AIDS. 2016;30:2065–74.
65.
LinJKakkarVLuX. Impact of matrix metalloproteinases on atherosclerosis. Curr Drug Targets. 2014;15:442–53.
66.
HreggvidsdottirHSNoordenbosTBaetenDL. Inflammatory pathways in spondyloarthritis. Mol Immunol. 2014;57:28–37.
67.
LibbyPRidkerPMMaseriA. Inflammation and atherosclerosis. Circulation. 2002;105:1135–43.
68.
PopaCDArtsEFransenJvan RielPL. Atherogenic index and high-density lipoprotein cholesterol as cardiovascular risk determinants in rheumatoid arthritis: the impact of therapy with biologicals. Mediators Inflamm. 2012;2012:785946.
69.
ChoyEGaneshalingamKSembAGSzekaneczZNurmohamedM. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology (Oxford). 2014;53:2143–54.
70.
BandealiSFarmerJ. High-density lipoprotein and atherosclerosis: the role of antioxidant activity. Curr Atheroscler Rep. 2012;14:101–7.
71.
MonnetDKadiAIzacB. Association between the IL-1 family gene cluster and spondyloarthritis. Ann Rheum Dis. 2012;71:885–90.
72.
KimTJKimTHLeeHJ. Interleukin 1 polymorphisms in patients with ankylosing spondylitis in Korea. J Rheumatol. 2008;35:1603–8.
73.
MaksymowychWPRahmanPReeveJPGladmanDDPeddleLInmanRD. Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: an analysis of three Canadian populations. Arthritis Rheum. 2006;54:974–85.
74.
LiLShiBZhengW. Association of IL-1A and IL-1B polymorphisms with ankylosing spondylitis among the Chinese Han population: a case–control study. Oncotarget. 2017;8:28278–84.
75.
ChatzikyriakidouAVoulgariPVDrososAA. Non-HLA genes in ankylosing spondylitis: what meta-analyses have shown?Clin Exp Rheumatol. 2014;32:735–9.
76.
SimsAMTimmsAEBruges-ArmasJ. Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis. Ann Rheum Dis. 2008;67:1305–9.
77.
LeaWILeeYH. The associations between interleukin-1 polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis. Joint Bone Spine. 2012;79:370–4.
78.
RiosDLCerqueiraCCBonfim-SilvaR. Interleukin-1 beta and interleukin-6 gene polymorphism associations with angiographically assessed coronary artery disease in Brazilians. Cytokine. 2010;50:292–6.
79.
OdaKTanakaNAraiT. Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: a pathological study of 1503 consecutive autopsy cases. Hum Mol Genet. 2007;16:592–9.
80.
ManolovaIIvanovaMStoilovRRashkovRStanilovaS. Association of single nucleotide polymorphism at position −308 of the tumor necrosis factor-alpha gene with ankylosing spondylitis and rheumatoid arthritis. Biotechnol Biotechnol Equip. 2014;28:1108–14.
81.
RoitenbergGESharkhunOOUshakovaTISerebriakovaOE. Impact of TNF-alpha gene polymorphism, development of atherogenic dyslipidemia and risk of atherosclerosis[in Russian]. Vestn Ross Akad Med Nauk. 2010;(3):3–6.
82.
ChenJGuoYGuiYXuD. Physical exercise, gut, gut microbiota, and atherosclerotic cardiovascular diseases. Lipids Health Dis. 2018;17:17.
83.
ParsonsCAgasthiPMookadamFArsanjaniR. Reversal of coronary atherosclerosis: role of life style and medical management. Trends Cardiovasc Med. 2018;28:524–31.
84.
HalvorsenSVollestadNKFongenC. Physical fitness in patients with ankylosing spondylitis: comparison with population controls. Phys Ther. 2012;92:298–309.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
