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Association of homocysteine with ankylosing spondylitis: a systematic review and meta-analysis

Association of homocysteine with ankylosing spondylitis: a systematic review and meta-analysis Background: Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. Methods: Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random- effect model, Stata16 software. Results: Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores (Bath AS disease activity index, BASDAI), and methylenetetrahydrofolate reductase (MTHFR) C677T genotype. Conclusion: This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. Trial registration: This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426. Keywords: Homocysteine, Meta-analysis, Ankylosing spondylitis, Controls * Correspondence: lzzlhx63@163.com; yzhaoqilu@sdu.edu.cn Hui-hui Li and Xue-quan Li contributed equally to this work. Department of Rheumatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53715, USA Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Li et al. Advances in Rheumatology (2021) 61:17 Page 2 of 9 Background HCY, at the range of physiologic concentrations, enhances Ankylosing spondylitis (AS) is an immune-associated monocyte proliferation in vitro [27]. HCY may also be in- systemic inflammatory rheumatic disease characterized volved in corona virus disease-19 (COVID-19) infection primarily by progressive inflammation of the spine, via transsulfuration pathway [32], which is catalyzed by sacroiliitis, and various extra-articular manifestations cystathionine β-synthase and cystathionine γ-lyase (CSE) such as anterior uveitis, inflammatory bowel disease, and serves as a modulator of inflammation [33]. Neverthe- subclinical inflammation of the gut, psoriasis, airway dis- less, HCY significantly ameliorates cholesterol-induced in- ease, and interstitial lung abnormalities [1–6]. Increasing flammation in an in vivo hypercholesterolemic rat model evidence indicates that AS increases cardiovascular mor- possibly by acting on the tissue plasminogen activator bidity and mortality as compared with the general popu- (tPA)-induced process [24]. lation [7]. Based on the facts that AS is associated with increased Homocysteine (HCY) is a sulfur-containing amino acid cardiovascular morbidity and mortality, the high level of formed during the metabolism of methionine to cysteine HCY is considered a well-known risk factor for cardio- [8]. HCY levels are elevated in many acquired disorders vascular disease [7, 8], it is necessary to define the asso- such as cardiovascular disease, cerebrovascular disease, ciation between HCY and AS. However, the conclusions dementia-type disorders, osteoporosis-associated frac- of HCY levels reported in AS patients are inconsistent. tures, chronic renal disease, autoimmune diseases, in- Several studies reported high levels of serum/plasma flammatory diseases, deficiency of vitamins B6, B12, or HCY levels in AS patients [34–38]. In contrast, others folic acid, as well as during anti-folate drug therapy [9– claimed that HCY levels in AS patients were similar or 19] Elevated HCY may trigger autoimmune reactions lower compared with control patients [16, 39–41]. through binding and structurally modifying specific pro- Therefore, in this meta-analysis, we aim to determine teins, resulting in the formation of neoantigens that are HCY levels in AS and investigate the correlation be- potentially relevant either in the onset of specific auto- tween HCY levels and disease activity and medical immune diseases or in the progression of the associated treatments. cardiovascular damage [20]. HCY could modify Human Leukocyte Antigens-B27 Methods (HLA-B27) through forming a disulfide bond with an Search strategy unpaired cysteine residue at position 67 (Cys67) of the We performed electronic literature searches in PubMed, HLA-B27 heavy chain [21], and subsequently, be Web of Science, Embase, ScienceDirect, China National destroyed by the abnormal autoimmunological reactions Knowledge Infrastructure (CNKI), and Wanfang data up [21]. An in vitro study has shown HCY could induce to May 7, 2020 with keywords including Homocysteine, specific cytotoxic T lymphocytes (CTLs), and HLA-B27- Hyperhomocysteinemia, Ankylosing, and Spondylitis. restricted HCY-specific CTLs are more often found in B27-positive patients [21]. HCY-treated B cells can be Inclusion criteria and exclusion criteria specifically lysed by CTLs in patients with AS and react- The article inclusion criteria were as follows: (1) a case- ive arthritis (ReA) [21]. Evidence also suggests that Sal- control or cross-sectional study; (2) based on adults; (3) monella infection could lead to the modification of HLA AS patients must conform to the American College of antigens and such modified HLA antigens can be recog- Rheumatology (ACR) criteria [42] or European Spondy- nized by HCY-specific CTLs [21]. Collectively, these loarthropathy Study Group (ESSG) criteria for classifica- findings support the notion that HCY may be involved tion of spondylarthropathies [43]; and (4) serum or in the mechanism underlying HLA-B27-associated AS. plasma HCY concentrations of both patients and con- Previous studies have shown both pro-inflammatory trols were available. Articles were not limited to geo- and anti-inflammatory properties of HCY [22–25]. An as- graphic location or language of publication. Articles sociation between hyperhomocysteinemia and inflamma- excluded in this meta-analysis were as follows: (1) re- tion has been identified in human and experimental views; (2) animal studies; and (3) lack of controls. A de- animal models [17, 26]. In vitro, HCY induces mRNA and tailed flow chart of article inclusion and exclusion protein expression of the inflammatory cytokines includ- process was presented in Fig. 1. All articles obtained ing tumor necrosis factor (TNF)-α, Interleukin (IL)-1β,IL- electronically were examined independently by two 6, IL-8, and IL-12 in human monocytes [27]. Correlations researchers. of HCY with soluble 75-kDa TNF-receptor (sTNF-R75) has also been found in RA patients [28]. HCY may activate Data extraction and quality assessment nuclear factor-kappaB (NF-κB) activation [29], which may Each of the enrolled articles was extracted by two re- lead to increased chemokine expression in vascular searchers independently for the following information: smooth muscle cells (VSMCs) and macrophages [30, 31]. first author’s name, year of publication, study design, the Li et al. Advances in Rheumatology (2021) 61:17 Page 3 of 9 Fig. 1 Flow chart of selected articles language of the article, region, participants’ characteris- the random-effects model was adopted to pool the SMD tics (age and gender), disease activity score (Bath AS dis- value; or else, the fixed-effect model was adopted. Sub- ease activity index, BASDAI) [44], disease duration, group analysis was performed to discover the sources of mean ± SD or mean ± SEM of the plasma/serum HCY heterogeneity. Sensitivity analysis was also executed to levels in AS and control groups, measurement method, detect studies that extremely contributed to the observed sample type, and any other relevant information. Meta- heterogeneity. This was done by omitting each study analysis was performed according to the Preferred one after the other to measure its impact on the sum- Reporting Items for Systematic Reviews and Meta- mary estimate. To evaluate the publication bias, Egger’s Analysis (PRISMA) guidelines [45]. Any disagreement and Begg’s tests were used. Stata 16 software was used on study inclusion or data extraction was discussed with in this meta-analysis to perform statistical analysis. a third reviewer to reach a consensus. The Newcastle- Ottawa quality assessment scale (NOS) was used to as- Results sess the methodological quality of eligible studies [46]. Publication search and study characteristics Out of a total of 15 relevant studies found, 9 original Statistical analysis studies met our inclusion criteria and were selected for The extracted results that were presented in median, this meta-analysis. These 9 studies were published be- standard error, range, and interquartile range were con- tween 2005 and 2020 and included 778 AS patients and verted to mean and standard deviation (SD) [47, 48]. 522 controls [16, 34–41]. Of the 9 studies, 4 were con- The mean and SD (mean ± SD) were extracted or esti- ducted in Asia, 3 in Asia-Europe (Turkey), 1 in Europe, mated in each study. For each study, the standardized and 1 in South America. As of the controls, 1 study in- mean difference (SMD) and 95% confidence intervals cluded non-inflammatory low back pain [39], 1 included (95% CI) were elaborately shown by the forest plot. osteoarthritis or soft tissue rheumatism [41], and the Cochrane Q statistics (chi-square test, χ2) were other 7 included healthy controls [16, 34–38, 40]. Our employed to evaluate statistical heterogeneity. The I- methodological quality assessment showed the NOS square (I ) statistics was used to further assess the extent scores of included studies ranged from 7 to 8. The char- of heterogeneity (I =([Q − df]) × 100%) [49]. Based on acteristics of the included studies are summarized in the Cochrane Handbook for Systematic Reviews’ recom- Table 1. Extracted data on circulating HCY levels were mendations, we interpreted I statistic between 0 and presented in Table 2. 40% as representing an insignificant amount of hetero- geneity; 30 to 60% as moderate heterogeneity; 50 to 90% Results of meta-analysis as substantial heterogeneity; and 75 to 100% as consider- Publication bias was assessed by Egger’s regression test able heterogeneity [50]. When P < 0.05 for the Q test or (t = − 0.74, P = 0.48) and Begg’s test (z = − 0.31, P = 1.25), I > 50, it indicated that heterogeneity was significant in suggesting no publication bias present. Among the en- the study. Assuming that the heterogeneity is significant, rolled studies, significant heterogeneity was observed Li et al. Advances in Rheumatology (2021) 61:17 Page 4 of 9 Table 1 Characteristics of individual studies included First Region AS Control author, Age BMI Sex BASDAI Duration Age BMI Sex Assay Study Criteria for NOS year (year) ratio (year) (year) ratio method, type the (mean ± (M/F) (mean ± sd) (mean ± (M/F) sample classification sd) sd) Shu JL, Mainland 41.6 ± 8.6 NA 30/5 NA NA 39.7 ± NA 36/5 NA CS ACR 7 2020 [16] China 14.4 Geçene M, Turkey 36.7 ± 4.8 24.9 ± 50/0 2.4 ± 1.7 NA 36.3 ± 4.7 25.0 ± 50/0 HPLC, CS ACR 7 2013 [39] 3.1 3.0 plasma Mao N, Mainland NA NA NA NA NA NA NA NA ELISA, CS ACR 7 2012 [34] China plasma Capkin E, Turkey 36.4 ± NA 88/20 3.7 ± 1.6 8.4 ± 5.6 38.2 ± NA 49/16 ELISA, CS ACR 7 2012 [40] 11.2 13.0 plasma Başkan BM, Turkey 40.1 ± NA NA 4.2 ± 1.7 10.0 ± 7.7 38.1 ± 0.6 NA NA NA CS ACR 7 2009 [35] 11.0 Gonzalez- Mexico 39.9 ± 8.4 26.0 ± 73/24 5.4 ± 2.1 7.8 ± 6.0 38.9 ± 7.8 25.8 ± 73/24 FPIA, CSS ACR 8 Lopez L, 2.8 4.2 Serum 2008 [36] Wei JC, Taiwan, NA NA NA NA NA NA NA NA ELISA, CSS ACR 7 2007 [37] China plasma Malesci D, Italy 47.6 ± 29.5 ± 21/3 2.7 ± 1.8 18.5 ± 10.8 49.6 ± 6.0 NA 16/3 NA CS ACR&ESSG 8 2007 [41] 11.8 4.4 Xu XY, 2005 Mainland 32.1 ± NA 44/16 NA NA 30.8 ± NA 30/32 FPIA, CS ACR 7 [38] China 13.7 19.7 plasma AS Ankylosing spondylitis, BMI Body mass index, BASDAI Bath AS disease activity index, NOS Newcastle-Ottawa Scale, NA Not available, HPLC High performance liquid chromatography, ELISA Enzyme-linked immunosorbent assays, FPIA Fluorescence polarization immunoassay, CS Case control, CSS Cross-sectional study, ACR American College of Rheumatology, ESSG European Spondyloarthropathy Study Group (I = 97.3%, P < 0.01). Sensitivity analysis by sequentially circulating HCY levels between AS patients and controls omitting individual studies did not significantly change (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23) the pooled results, suggesting that these results were (Fig. 3). Subgroup analysis stratified by region, sample stable (Fig. 2). size, disease activity, smoker or not, methylenetetrahy- drofolate reductase (MTHFR) C677T genotype, and HCY levels and subgroup analysis medication treatment were performed (Table 3). As of The random-effect model was used for the analysis of disease activity, 1 study defined that patients with BAS- results in this study based on the result that significant DAI values ≥4 were regarded as active AS group [40]. heterogeneity was observed among the enrolled studies Two studies defined that patients with BASDAI values > (P < 0.01). There were no significant differences in 3 and ESR > 20 mm/h were regarded as active AS group [35, 37]. To conduct medication treatment subgroup analysis, we analyzed four subgroups: nonsteroidal anti- inflammatory drugs (NSAIDs), sulfasalazine (SSZ), SSZ + Table 2 Extracted data on HCY levels of 9 studies included methotrexate (MTX), and anti-TNF-α. In SSZ + MTX First author, year AS (μmol/L) Control (μmol/L) treatment subgroup, HCY levels in AS patients were N Mean SD N Mean SD significantly higher than those in controls (pooled Shu JL, 2020 [16] 35 12.27 7.52 41 13.94 3.73 SMD = 0.915, 95% CI = 0.312 to 1.518, P = 0.003). In Geçene M, 2013 [39] 50 14.26 9.96 50 11.81 5.53 anti-TNF-α treatment subgroup, HCY levels in AS pa- Mao N, 2012 [34] 200 18.71 2.42 120 10.97 2.93 tients were significantly lower than in controls (pooled SMD = − 0.774, 95% CI = − 1.163 to − 0.385, P < 0.001). Capkin E, 2012 [40] 108 18.90 8.70 65 23.80 5.80 Meanwhile, no significant differences of HCY levels be- Başkan BM, 2009 [35] 92 17.18 12.47 58 13.16 4.09 tween AS patients and controls were detected in NSAI Gonzalez-Lopez L, 2008 [35] 97 11.35 5.39 97 9.61 2.33 Ds or SSZ treatment subgroup. In particular, no signifi- Wei JC, 2007 [37] 112 9.91 3.47 10 8.60 1.20 cant correlation between HCY levels and disease activity, Malesci D, 2007 [41] 24 8.70 2.00 19 9.10 1.20 and MTHFR C677T genotype, as well as in region, sam- Xu XY, 2005 [38] 60 16.47 6.50 62 12.24 3.58 ple size, and smoking subgroups was detected. HCY Homocysteine, N Number, SD Standard deviation Li et al. Advances in Rheumatology (2021) 61:17 Page 5 of 9 Fig. 2 Sensitivity analysis of the included studies. The two vertical axes, vertical middle axis, hollow circles, and two ends of the dotted lines respectively represent 95% confidence interval, overall odd ratio, pooled odd ratios, and 95% confidence interval Discussion of disease activity of systemic lupus erythematosus A positive relationship was reported between circulating (SLE), such as erythrocyte sedimentation rate, anti- HCY levels and certain clinical features of rheumatoid double-stranded DNA, complement levels in patients of arthritis (RA), such as higher disease activity [51] and SLE [15]. Intensive steroid therapy in RA patients results higher radiological damage [52]. A significant correlation in significant HCY reduction [53]. In contrast, Shu et al. also exists between HCY levels and the various indexes has reported that HCY levels are not associated with C- Fig. 3 Forest plot of 9 studies in HCY levels for AS patients versus controls, based on random effects model Li et al. Advances in Rheumatology (2021) 61:17 Page 6 of 9 Table 3 Subgroup analysis of HCY levels in AS Subgroups N SMD (95% CI) ZP Heterogeneity test PI (%) Region Asia 4 0.974 (−0.573, 2.521) 1.23 0.217 < 0.001 98.1% Asia + Europe (Turkey) 3 0.018 (− 0.661, 0.698) 0.05 0.958 < 0.001 91.4% Europe/America 2 0.148 (−0.484, 0.780) 0.46 0.646 0.055 73.0% Combined 9 0.463 (−0.300, 1.226) 1.19 0.234 < 0.001 97.3% Sample size ≥ 50 6 0.708 (−0.283, 1.700) 1.40 0.162 < 0.001 98.1% <50 2 −0.269 (− 0.632, 0.093) 1.46 0.145 0.891 0.0% Combined 8 0.471 (−0.355, 1.298) 1.12 0.264 < 0.001 97.6% Disease activity active 3 0.048 (−0.904, 1.000) 0.10 0.921 < 0.001 92.0% inactive 3 0.078 (−0.733, 0.889) 0.19 0.851 < 0.001 89.0% Combined 6 0.059 (−0.488, 0.606) 0.21 0.833 < 0.001 88.5% Smoking Smoker 1 0.497 (−0.066, 1.060) 1.73 0.084 NA NA Non-smoker 1 0.201 (−0.355, 0.757) 0.71 0.478 NA NA Combined 2 0.347 (−0.048, 0.743) 1.72 0.085 0.464 0.0% MTHFR C677T genotype CC 2 1.599 (−0.864, 4.062) 1.27 0.203 < 0.001 98.1% CT 2 1.693(−1.256, 4.642) 1.13 0.260 < 0.001 97.7% TT 2 2.771(−1.141, 6.682) 1.39 0.165 < 0.001 92.2% Combined 6 1.992 (0.663, 3.320) 2.94 0.003 < 0.001 95.7% Treatment NSAIDs 2 −0.365(− 1.020, 0.291) 1.09 0.275 0.092 64.8% SSZ 2 0.024 (−0.872, 0.920) 0.05 0.958 0.003 88.7% SSZ + MTX 1 0.915 (0.312, 1.518) 2.97 0.003 NA NA Anti-TNF-α 1 −0.774 (−1.163, − 0.385) 3.90 < 0.001 NA NA Combined 6 −0.094 (− 0.634, 0.445) 0.34 0.732 0.000 87.7% HCY Homocysteine, NA Not available, MTHFR Methylenetetrahydrofolate reductase, NSAIDs Non-steroidal anti-inflammatory drugs, SSZ Sulfasalazine, MTX Methotrexate, TNF Tumor necrosis factor reactive protein (CRP), erythrocyte sedimentation rate the other 5 studies, 3 didn’tuse MTX [38–40]and 2 (ESR), rheumatoid factor (RF), and anti-citrullinated didn’t mention any treatment method [16, 34]. protein antibody (ACPA) in RA [16]. Our study indi- SSZ has also been reported to have anti-folate proper- cates no significant correlation between HCY levels ties [56], implying SSZ may increase HCY levels in pa- and AS disease activity. However, subgroup analysis tients. This is supported by the observation that plasma suggests that elevated HCY levels are associated with HCY levels was increased significantly in AS patients the AS group treated with MTX. This association under SSZ, and SSZ/MTX combination treatment [37]. maybeattributedtothe inhibitory effect of MTXon However, our subgroup analysis showed no significant the levels of folate [19, 40]. Specifically, MTX treat- differences in HCY levels in AS patients treated with ment influences folate metabolism in RA patients, SSZ compared with controls. In addition, HCY levels leading to a decrease in serum folate levels and a rise were significantly lower in AS group treated with anti- in HCY levels [54]. However, while MTX increases TNF-α regimen. These findings support the note that plasma HCY levels, folate supplementation decreases different medical treatments may influence HCY levels. HCY concentrations, protecting against potential car- However, the reasons attributed to the above results re- diovascular risks in RA patients [55]. In clinical prac- main unknown. In this meta-analysis, two studies con- tice, folate supplement is used to reduce side-effect tain HCY levels and treatment methods in AS patients incidence of MTX in RA patients, suggesting that fol- (n =198) [35, 40]. The above findings might be a result ate supplement should be considered for AS patients of the small sample size employed in the individual stud- treated with MTX. Of the 9 studies included in this ies. Further studies are needed to confirm these findings. analysis, 4 recruited AS patients on MTX [35–37, 41], HCY levels are known to be controlled by methylene- 2 of which used folate supplementation [35, 36]. Of tetrahydrofolate reductase (MTHFR), which is a key Li et al. Advances in Rheumatology (2021) 61:17 Page 7 of 9 enzyme in HCY metabolism [57]. MTHFR C677T poly- the significant heterogeneity in our meta-analysis may morphism causes a thermolability of MTHFR, reducing restrict the generalization of the pooled result. Second, its enzymatic activity [57]. Such a reduction inhibits the due to the lack of sufficient data to perform more ex- formation of 5-methyltetrahydrofolate, which serves as a haustive subgroup analysis and meta-regression, the ori- methyl donor during the remethylation of HCY to me- gin of heterogeneity could not be fully revealed. thionine [57]. Studies indicated that the TT genotype of the MTHFR C677T polymorphism exhibits higher Conclusions plasma HCY concentrations than CT heterozygotes and This meta-analysis suggests that HCY may partially par- CC homozygotes [58, 59]. Besides, Mao et al. reported ticipate in the pathogenesis of AS, although it is not a that high plasma HCY levels are associated with MTHF major contributing factor. Further and larger studies are R 677TT polymorphism as compared with the CC or needed to confirm these findings. CT genotype in AS patients [34]. In this meta-analysis, Acknowledgements subgroup analysis showed no significant correlation be- Not applicable. tween all 3 genotypes of the MTHFR C677T polymorph- ism and HCY levels in AS. This result agrees with the Authors’ contributions HHL performed literature search and prepared the draft of the paper. XQL previous report which showed no association between performed literature search and prepared the draft of the paper. LTS MTHFR 677TT polymorphism and plasma HCY levels participated in manuscript preparation. YC draw the figures. JHX participated in obese children and adolescents [60] and no statisti- in manuscript preparation and designed the Table. CZ read the manuscript critically. JZ developed the main idea and read the manuscript critically. XFL cally significant differences according to the frequency of developed the main idea and read the manuscript critically. HXL developed MTHFR C677T polymorphism between AS patients and the main idea, designed the work, and read the manuscript critically. YJZ controls [39]. developed the main idea, designed the work, and read the manuscript critically. All authors read and approved the final manuscript. As a well-known risk factor for cardiovascular disease, HCY can mediate the development of the cardiovascular Funding disease by acting adversely on vascular endothelium and This work was supported by Key Technology Research and Development Program of Shandong (CN) (2018GSF118071 to YJZ, and 2018GSF118025 to smooth muscle cells [61]. Elevated HCY levels may also HHL). enhance oxidative stress and inflammation of vascular endothelial cells and reduce the production and bioavail- Availability of data and materials ability of nitric oxide (a strong relaxing factor) by endo- The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. thelium [62]. HCY stimulates the proliferation of vascular smooth muscle cells, synthesis of collagen, and Declaration deterioration of arterial wall elastic material [61]. AS also Ethics approval and consent to participate significantly increases risks of myocardial infarction and Not applicable. stroke [63]. Multiple factors contribute to such increased cardiovascular risk. In this regard, systemic inflammation Consent for publication and high disease activity play pivotal roles in the process Not applicable. [64]. Another possible factor is the proatherogenic pro- Competing interests file of AS patients who were smokers and/or hyperten- The authors declare that they have no competing interests. sive with a poor atherogenic lipid profile [64]. Author details Recommendations from EULAR pointed out that disease Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College activity should be controlled optimally to lower CVD of Medicine, Shandong University, Jinan 250012, Shandong, China. risk in all patients with AS, RA or psoriatic arthritis Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Gastroenterology, Shouguang (PsA) [65]. In addition, MTX treatment decreases the People’s Hospital, Shouguang 262700, Shandong, China. Department of acute myocardial infarction (AMI) among RA patients Infectious Diseases, Qilu Hospital, Cheeloo College of Medicine, Shandong [66], suggesting that MTX plays a role in protecting pa- University, Jinan 250012, Shandong, China. Department of Intensive Care Unit, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan tients from CVD risk, possibly via controlling the inflam- 250012, Shandong, China. Shandong First Medical University & Shandong matory process although MTX elevates HCY levels. Academic of Medical Sciences, Jinan 250000, Shandong, China. School of To our knowledge, this is the first meta-analysis that Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA. Department of Rheumatology, Qilu Hospital, Cheeloo College of provides evidence of HCY levels in AS patients com- Medicine, Shandong University, Jinan 250012, Shandong, China. pared with controls. 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Antirheumatic drug use and the risk of acute myocardial infarction. Arthritis Rheum. 2006;55(4):531–6. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

Association of homocysteine with ankylosing spondylitis: a systematic review and meta-analysis

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Abstract

Background: Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. Methods: Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random- effect model, Stata16 software. Results: Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores (Bath AS disease activity index, BASDAI), and methylenetetrahydrofolate reductase (MTHFR) C677T genotype. Conclusion: This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. Trial registration: This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426. Keywords: Homocysteine, Meta-analysis, Ankylosing spondylitis, Controls * Correspondence: lzzlhx63@163.com; yzhaoqilu@sdu.edu.cn Hui-hui Li and Xue-quan Li contributed equally to this work. Department of Rheumatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53715, USA Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Li et al. Advances in Rheumatology (2021) 61:17 Page 2 of 9 Background HCY, at the range of physiologic concentrations, enhances Ankylosing spondylitis (AS) is an immune-associated monocyte proliferation in vitro [27]. HCY may also be in- systemic inflammatory rheumatic disease characterized volved in corona virus disease-19 (COVID-19) infection primarily by progressive inflammation of the spine, via transsulfuration pathway [32], which is catalyzed by sacroiliitis, and various extra-articular manifestations cystathionine β-synthase and cystathionine γ-lyase (CSE) such as anterior uveitis, inflammatory bowel disease, and serves as a modulator of inflammation [33]. Neverthe- subclinical inflammation of the gut, psoriasis, airway dis- less, HCY significantly ameliorates cholesterol-induced in- ease, and interstitial lung abnormalities [1–6]. Increasing flammation in an in vivo hypercholesterolemic rat model evidence indicates that AS increases cardiovascular mor- possibly by acting on the tissue plasminogen activator bidity and mortality as compared with the general popu- (tPA)-induced process [24]. lation [7]. Based on the facts that AS is associated with increased Homocysteine (HCY) is a sulfur-containing amino acid cardiovascular morbidity and mortality, the high level of formed during the metabolism of methionine to cysteine HCY is considered a well-known risk factor for cardio- [8]. HCY levels are elevated in many acquired disorders vascular disease [7, 8], it is necessary to define the asso- such as cardiovascular disease, cerebrovascular disease, ciation between HCY and AS. However, the conclusions dementia-type disorders, osteoporosis-associated frac- of HCY levels reported in AS patients are inconsistent. tures, chronic renal disease, autoimmune diseases, in- Several studies reported high levels of serum/plasma flammatory diseases, deficiency of vitamins B6, B12, or HCY levels in AS patients [34–38]. In contrast, others folic acid, as well as during anti-folate drug therapy [9– claimed that HCY levels in AS patients were similar or 19] Elevated HCY may trigger autoimmune reactions lower compared with control patients [16, 39–41]. through binding and structurally modifying specific pro- Therefore, in this meta-analysis, we aim to determine teins, resulting in the formation of neoantigens that are HCY levels in AS and investigate the correlation be- potentially relevant either in the onset of specific auto- tween HCY levels and disease activity and medical immune diseases or in the progression of the associated treatments. cardiovascular damage [20]. HCY could modify Human Leukocyte Antigens-B27 Methods (HLA-B27) through forming a disulfide bond with an Search strategy unpaired cysteine residue at position 67 (Cys67) of the We performed electronic literature searches in PubMed, HLA-B27 heavy chain [21], and subsequently, be Web of Science, Embase, ScienceDirect, China National destroyed by the abnormal autoimmunological reactions Knowledge Infrastructure (CNKI), and Wanfang data up [21]. An in vitro study has shown HCY could induce to May 7, 2020 with keywords including Homocysteine, specific cytotoxic T lymphocytes (CTLs), and HLA-B27- Hyperhomocysteinemia, Ankylosing, and Spondylitis. restricted HCY-specific CTLs are more often found in B27-positive patients [21]. HCY-treated B cells can be Inclusion criteria and exclusion criteria specifically lysed by CTLs in patients with AS and react- The article inclusion criteria were as follows: (1) a case- ive arthritis (ReA) [21]. Evidence also suggests that Sal- control or cross-sectional study; (2) based on adults; (3) monella infection could lead to the modification of HLA AS patients must conform to the American College of antigens and such modified HLA antigens can be recog- Rheumatology (ACR) criteria [42] or European Spondy- nized by HCY-specific CTLs [21]. Collectively, these loarthropathy Study Group (ESSG) criteria for classifica- findings support the notion that HCY may be involved tion of spondylarthropathies [43]; and (4) serum or in the mechanism underlying HLA-B27-associated AS. plasma HCY concentrations of both patients and con- Previous studies have shown both pro-inflammatory trols were available. Articles were not limited to geo- and anti-inflammatory properties of HCY [22–25]. An as- graphic location or language of publication. Articles sociation between hyperhomocysteinemia and inflamma- excluded in this meta-analysis were as follows: (1) re- tion has been identified in human and experimental views; (2) animal studies; and (3) lack of controls. A de- animal models [17, 26]. In vitro, HCY induces mRNA and tailed flow chart of article inclusion and exclusion protein expression of the inflammatory cytokines includ- process was presented in Fig. 1. All articles obtained ing tumor necrosis factor (TNF)-α, Interleukin (IL)-1β,IL- electronically were examined independently by two 6, IL-8, and IL-12 in human monocytes [27]. Correlations researchers. of HCY with soluble 75-kDa TNF-receptor (sTNF-R75) has also been found in RA patients [28]. HCY may activate Data extraction and quality assessment nuclear factor-kappaB (NF-κB) activation [29], which may Each of the enrolled articles was extracted by two re- lead to increased chemokine expression in vascular searchers independently for the following information: smooth muscle cells (VSMCs) and macrophages [30, 31]. first author’s name, year of publication, study design, the Li et al. Advances in Rheumatology (2021) 61:17 Page 3 of 9 Fig. 1 Flow chart of selected articles language of the article, region, participants’ characteris- the random-effects model was adopted to pool the SMD tics (age and gender), disease activity score (Bath AS dis- value; or else, the fixed-effect model was adopted. Sub- ease activity index, BASDAI) [44], disease duration, group analysis was performed to discover the sources of mean ± SD or mean ± SEM of the plasma/serum HCY heterogeneity. Sensitivity analysis was also executed to levels in AS and control groups, measurement method, detect studies that extremely contributed to the observed sample type, and any other relevant information. Meta- heterogeneity. This was done by omitting each study analysis was performed according to the Preferred one after the other to measure its impact on the sum- Reporting Items for Systematic Reviews and Meta- mary estimate. To evaluate the publication bias, Egger’s Analysis (PRISMA) guidelines [45]. Any disagreement and Begg’s tests were used. Stata 16 software was used on study inclusion or data extraction was discussed with in this meta-analysis to perform statistical analysis. a third reviewer to reach a consensus. The Newcastle- Ottawa quality assessment scale (NOS) was used to as- Results sess the methodological quality of eligible studies [46]. Publication search and study characteristics Out of a total of 15 relevant studies found, 9 original Statistical analysis studies met our inclusion criteria and were selected for The extracted results that were presented in median, this meta-analysis. These 9 studies were published be- standard error, range, and interquartile range were con- tween 2005 and 2020 and included 778 AS patients and verted to mean and standard deviation (SD) [47, 48]. 522 controls [16, 34–41]. Of the 9 studies, 4 were con- The mean and SD (mean ± SD) were extracted or esti- ducted in Asia, 3 in Asia-Europe (Turkey), 1 in Europe, mated in each study. For each study, the standardized and 1 in South America. As of the controls, 1 study in- mean difference (SMD) and 95% confidence intervals cluded non-inflammatory low back pain [39], 1 included (95% CI) were elaborately shown by the forest plot. osteoarthritis or soft tissue rheumatism [41], and the Cochrane Q statistics (chi-square test, χ2) were other 7 included healthy controls [16, 34–38, 40]. Our employed to evaluate statistical heterogeneity. The I- methodological quality assessment showed the NOS square (I ) statistics was used to further assess the extent scores of included studies ranged from 7 to 8. The char- of heterogeneity (I =([Q − df]) × 100%) [49]. Based on acteristics of the included studies are summarized in the Cochrane Handbook for Systematic Reviews’ recom- Table 1. Extracted data on circulating HCY levels were mendations, we interpreted I statistic between 0 and presented in Table 2. 40% as representing an insignificant amount of hetero- geneity; 30 to 60% as moderate heterogeneity; 50 to 90% Results of meta-analysis as substantial heterogeneity; and 75 to 100% as consider- Publication bias was assessed by Egger’s regression test able heterogeneity [50]. When P < 0.05 for the Q test or (t = − 0.74, P = 0.48) and Begg’s test (z = − 0.31, P = 1.25), I > 50, it indicated that heterogeneity was significant in suggesting no publication bias present. Among the en- the study. Assuming that the heterogeneity is significant, rolled studies, significant heterogeneity was observed Li et al. Advances in Rheumatology (2021) 61:17 Page 4 of 9 Table 1 Characteristics of individual studies included First Region AS Control author, Age BMI Sex BASDAI Duration Age BMI Sex Assay Study Criteria for NOS year (year) ratio (year) (year) ratio method, type the (mean ± (M/F) (mean ± sd) (mean ± (M/F) sample classification sd) sd) Shu JL, Mainland 41.6 ± 8.6 NA 30/5 NA NA 39.7 ± NA 36/5 NA CS ACR 7 2020 [16] China 14.4 Geçene M, Turkey 36.7 ± 4.8 24.9 ± 50/0 2.4 ± 1.7 NA 36.3 ± 4.7 25.0 ± 50/0 HPLC, CS ACR 7 2013 [39] 3.1 3.0 plasma Mao N, Mainland NA NA NA NA NA NA NA NA ELISA, CS ACR 7 2012 [34] China plasma Capkin E, Turkey 36.4 ± NA 88/20 3.7 ± 1.6 8.4 ± 5.6 38.2 ± NA 49/16 ELISA, CS ACR 7 2012 [40] 11.2 13.0 plasma Başkan BM, Turkey 40.1 ± NA NA 4.2 ± 1.7 10.0 ± 7.7 38.1 ± 0.6 NA NA NA CS ACR 7 2009 [35] 11.0 Gonzalez- Mexico 39.9 ± 8.4 26.0 ± 73/24 5.4 ± 2.1 7.8 ± 6.0 38.9 ± 7.8 25.8 ± 73/24 FPIA, CSS ACR 8 Lopez L, 2.8 4.2 Serum 2008 [36] Wei JC, Taiwan, NA NA NA NA NA NA NA NA ELISA, CSS ACR 7 2007 [37] China plasma Malesci D, Italy 47.6 ± 29.5 ± 21/3 2.7 ± 1.8 18.5 ± 10.8 49.6 ± 6.0 NA 16/3 NA CS ACR&ESSG 8 2007 [41] 11.8 4.4 Xu XY, 2005 Mainland 32.1 ± NA 44/16 NA NA 30.8 ± NA 30/32 FPIA, CS ACR 7 [38] China 13.7 19.7 plasma AS Ankylosing spondylitis, BMI Body mass index, BASDAI Bath AS disease activity index, NOS Newcastle-Ottawa Scale, NA Not available, HPLC High performance liquid chromatography, ELISA Enzyme-linked immunosorbent assays, FPIA Fluorescence polarization immunoassay, CS Case control, CSS Cross-sectional study, ACR American College of Rheumatology, ESSG European Spondyloarthropathy Study Group (I = 97.3%, P < 0.01). Sensitivity analysis by sequentially circulating HCY levels between AS patients and controls omitting individual studies did not significantly change (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23) the pooled results, suggesting that these results were (Fig. 3). Subgroup analysis stratified by region, sample stable (Fig. 2). size, disease activity, smoker or not, methylenetetrahy- drofolate reductase (MTHFR) C677T genotype, and HCY levels and subgroup analysis medication treatment were performed (Table 3). As of The random-effect model was used for the analysis of disease activity, 1 study defined that patients with BAS- results in this study based on the result that significant DAI values ≥4 were regarded as active AS group [40]. heterogeneity was observed among the enrolled studies Two studies defined that patients with BASDAI values > (P < 0.01). There were no significant differences in 3 and ESR > 20 mm/h were regarded as active AS group [35, 37]. To conduct medication treatment subgroup analysis, we analyzed four subgroups: nonsteroidal anti- inflammatory drugs (NSAIDs), sulfasalazine (SSZ), SSZ + Table 2 Extracted data on HCY levels of 9 studies included methotrexate (MTX), and anti-TNF-α. In SSZ + MTX First author, year AS (μmol/L) Control (μmol/L) treatment subgroup, HCY levels in AS patients were N Mean SD N Mean SD significantly higher than those in controls (pooled Shu JL, 2020 [16] 35 12.27 7.52 41 13.94 3.73 SMD = 0.915, 95% CI = 0.312 to 1.518, P = 0.003). In Geçene M, 2013 [39] 50 14.26 9.96 50 11.81 5.53 anti-TNF-α treatment subgroup, HCY levels in AS pa- Mao N, 2012 [34] 200 18.71 2.42 120 10.97 2.93 tients were significantly lower than in controls (pooled SMD = − 0.774, 95% CI = − 1.163 to − 0.385, P < 0.001). Capkin E, 2012 [40] 108 18.90 8.70 65 23.80 5.80 Meanwhile, no significant differences of HCY levels be- Başkan BM, 2009 [35] 92 17.18 12.47 58 13.16 4.09 tween AS patients and controls were detected in NSAI Gonzalez-Lopez L, 2008 [35] 97 11.35 5.39 97 9.61 2.33 Ds or SSZ treatment subgroup. In particular, no signifi- Wei JC, 2007 [37] 112 9.91 3.47 10 8.60 1.20 cant correlation between HCY levels and disease activity, Malesci D, 2007 [41] 24 8.70 2.00 19 9.10 1.20 and MTHFR C677T genotype, as well as in region, sam- Xu XY, 2005 [38] 60 16.47 6.50 62 12.24 3.58 ple size, and smoking subgroups was detected. HCY Homocysteine, N Number, SD Standard deviation Li et al. Advances in Rheumatology (2021) 61:17 Page 5 of 9 Fig. 2 Sensitivity analysis of the included studies. The two vertical axes, vertical middle axis, hollow circles, and two ends of the dotted lines respectively represent 95% confidence interval, overall odd ratio, pooled odd ratios, and 95% confidence interval Discussion of disease activity of systemic lupus erythematosus A positive relationship was reported between circulating (SLE), such as erythrocyte sedimentation rate, anti- HCY levels and certain clinical features of rheumatoid double-stranded DNA, complement levels in patients of arthritis (RA), such as higher disease activity [51] and SLE [15]. Intensive steroid therapy in RA patients results higher radiological damage [52]. A significant correlation in significant HCY reduction [53]. In contrast, Shu et al. also exists between HCY levels and the various indexes has reported that HCY levels are not associated with C- Fig. 3 Forest plot of 9 studies in HCY levels for AS patients versus controls, based on random effects model Li et al. Advances in Rheumatology (2021) 61:17 Page 6 of 9 Table 3 Subgroup analysis of HCY levels in AS Subgroups N SMD (95% CI) ZP Heterogeneity test PI (%) Region Asia 4 0.974 (−0.573, 2.521) 1.23 0.217 < 0.001 98.1% Asia + Europe (Turkey) 3 0.018 (− 0.661, 0.698) 0.05 0.958 < 0.001 91.4% Europe/America 2 0.148 (−0.484, 0.780) 0.46 0.646 0.055 73.0% Combined 9 0.463 (−0.300, 1.226) 1.19 0.234 < 0.001 97.3% Sample size ≥ 50 6 0.708 (−0.283, 1.700) 1.40 0.162 < 0.001 98.1% <50 2 −0.269 (− 0.632, 0.093) 1.46 0.145 0.891 0.0% Combined 8 0.471 (−0.355, 1.298) 1.12 0.264 < 0.001 97.6% Disease activity active 3 0.048 (−0.904, 1.000) 0.10 0.921 < 0.001 92.0% inactive 3 0.078 (−0.733, 0.889) 0.19 0.851 < 0.001 89.0% Combined 6 0.059 (−0.488, 0.606) 0.21 0.833 < 0.001 88.5% Smoking Smoker 1 0.497 (−0.066, 1.060) 1.73 0.084 NA NA Non-smoker 1 0.201 (−0.355, 0.757) 0.71 0.478 NA NA Combined 2 0.347 (−0.048, 0.743) 1.72 0.085 0.464 0.0% MTHFR C677T genotype CC 2 1.599 (−0.864, 4.062) 1.27 0.203 < 0.001 98.1% CT 2 1.693(−1.256, 4.642) 1.13 0.260 < 0.001 97.7% TT 2 2.771(−1.141, 6.682) 1.39 0.165 < 0.001 92.2% Combined 6 1.992 (0.663, 3.320) 2.94 0.003 < 0.001 95.7% Treatment NSAIDs 2 −0.365(− 1.020, 0.291) 1.09 0.275 0.092 64.8% SSZ 2 0.024 (−0.872, 0.920) 0.05 0.958 0.003 88.7% SSZ + MTX 1 0.915 (0.312, 1.518) 2.97 0.003 NA NA Anti-TNF-α 1 −0.774 (−1.163, − 0.385) 3.90 < 0.001 NA NA Combined 6 −0.094 (− 0.634, 0.445) 0.34 0.732 0.000 87.7% HCY Homocysteine, NA Not available, MTHFR Methylenetetrahydrofolate reductase, NSAIDs Non-steroidal anti-inflammatory drugs, SSZ Sulfasalazine, MTX Methotrexate, TNF Tumor necrosis factor reactive protein (CRP), erythrocyte sedimentation rate the other 5 studies, 3 didn’tuse MTX [38–40]and 2 (ESR), rheumatoid factor (RF), and anti-citrullinated didn’t mention any treatment method [16, 34]. protein antibody (ACPA) in RA [16]. Our study indi- SSZ has also been reported to have anti-folate proper- cates no significant correlation between HCY levels ties [56], implying SSZ may increase HCY levels in pa- and AS disease activity. However, subgroup analysis tients. This is supported by the observation that plasma suggests that elevated HCY levels are associated with HCY levels was increased significantly in AS patients the AS group treated with MTX. This association under SSZ, and SSZ/MTX combination treatment [37]. maybeattributedtothe inhibitory effect of MTXon However, our subgroup analysis showed no significant the levels of folate [19, 40]. Specifically, MTX treat- differences in HCY levels in AS patients treated with ment influences folate metabolism in RA patients, SSZ compared with controls. In addition, HCY levels leading to a decrease in serum folate levels and a rise were significantly lower in AS group treated with anti- in HCY levels [54]. However, while MTX increases TNF-α regimen. These findings support the note that plasma HCY levels, folate supplementation decreases different medical treatments may influence HCY levels. HCY concentrations, protecting against potential car- However, the reasons attributed to the above results re- diovascular risks in RA patients [55]. In clinical prac- main unknown. In this meta-analysis, two studies con- tice, folate supplement is used to reduce side-effect tain HCY levels and treatment methods in AS patients incidence of MTX in RA patients, suggesting that fol- (n =198) [35, 40]. The above findings might be a result ate supplement should be considered for AS patients of the small sample size employed in the individual stud- treated with MTX. Of the 9 studies included in this ies. Further studies are needed to confirm these findings. analysis, 4 recruited AS patients on MTX [35–37, 41], HCY levels are known to be controlled by methylene- 2 of which used folate supplementation [35, 36]. Of tetrahydrofolate reductase (MTHFR), which is a key Li et al. Advances in Rheumatology (2021) 61:17 Page 7 of 9 enzyme in HCY metabolism [57]. MTHFR C677T poly- the significant heterogeneity in our meta-analysis may morphism causes a thermolability of MTHFR, reducing restrict the generalization of the pooled result. Second, its enzymatic activity [57]. Such a reduction inhibits the due to the lack of sufficient data to perform more ex- formation of 5-methyltetrahydrofolate, which serves as a haustive subgroup analysis and meta-regression, the ori- methyl donor during the remethylation of HCY to me- gin of heterogeneity could not be fully revealed. thionine [57]. Studies indicated that the TT genotype of the MTHFR C677T polymorphism exhibits higher Conclusions plasma HCY concentrations than CT heterozygotes and This meta-analysis suggests that HCY may partially par- CC homozygotes [58, 59]. Besides, Mao et al. reported ticipate in the pathogenesis of AS, although it is not a that high plasma HCY levels are associated with MTHF major contributing factor. Further and larger studies are R 677TT polymorphism as compared with the CC or needed to confirm these findings. CT genotype in AS patients [34]. In this meta-analysis, Acknowledgements subgroup analysis showed no significant correlation be- Not applicable. tween all 3 genotypes of the MTHFR C677T polymorph- ism and HCY levels in AS. This result agrees with the Authors’ contributions HHL performed literature search and prepared the draft of the paper. XQL previous report which showed no association between performed literature search and prepared the draft of the paper. LTS MTHFR 677TT polymorphism and plasma HCY levels participated in manuscript preparation. YC draw the figures. JHX participated in obese children and adolescents [60] and no statisti- in manuscript preparation and designed the Table. CZ read the manuscript critically. JZ developed the main idea and read the manuscript critically. XFL cally significant differences according to the frequency of developed the main idea and read the manuscript critically. HXL developed MTHFR C677T polymorphism between AS patients and the main idea, designed the work, and read the manuscript critically. YJZ controls [39]. developed the main idea, designed the work, and read the manuscript critically. All authors read and approved the final manuscript. As a well-known risk factor for cardiovascular disease, HCY can mediate the development of the cardiovascular Funding disease by acting adversely on vascular endothelium and This work was supported by Key Technology Research and Development Program of Shandong (CN) (2018GSF118071 to YJZ, and 2018GSF118025 to smooth muscle cells [61]. Elevated HCY levels may also HHL). enhance oxidative stress and inflammation of vascular endothelial cells and reduce the production and bioavail- Availability of data and materials ability of nitric oxide (a strong relaxing factor) by endo- The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. thelium [62]. HCY stimulates the proliferation of vascular smooth muscle cells, synthesis of collagen, and Declaration deterioration of arterial wall elastic material [61]. AS also Ethics approval and consent to participate significantly increases risks of myocardial infarction and Not applicable. stroke [63]. Multiple factors contribute to such increased cardiovascular risk. In this regard, systemic inflammation Consent for publication and high disease activity play pivotal roles in the process Not applicable. [64]. Another possible factor is the proatherogenic pro- Competing interests file of AS patients who were smokers and/or hyperten- The authors declare that they have no competing interests. sive with a poor atherogenic lipid profile [64]. Author details Recommendations from EULAR pointed out that disease Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College activity should be controlled optimally to lower CVD of Medicine, Shandong University, Jinan 250012, Shandong, China. risk in all patients with AS, RA or psoriatic arthritis Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Gastroenterology, Shouguang (PsA) [65]. In addition, MTX treatment decreases the People’s Hospital, Shouguang 262700, Shandong, China. Department of acute myocardial infarction (AMI) among RA patients Infectious Diseases, Qilu Hospital, Cheeloo College of Medicine, Shandong [66], suggesting that MTX plays a role in protecting pa- University, Jinan 250012, Shandong, China. Department of Intensive Care Unit, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan tients from CVD risk, possibly via controlling the inflam- 250012, Shandong, China. Shandong First Medical University & Shandong matory process although MTX elevates HCY levels. Academic of Medical Sciences, Jinan 250000, Shandong, China. School of To our knowledge, this is the first meta-analysis that Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA. Department of Rheumatology, Qilu Hospital, Cheeloo College of provides evidence of HCY levels in AS patients com- Medicine, Shandong University, Jinan 250012, Shandong, China. pared with controls. 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