Rheumatology International

, Volume 39, Issue 2, pp 255–263 | Cite as

Increased serum uric acid levels are associated with digital ulcers in patients with systemic sclerosis

  • Eunsung Kim
  • Han-Na Lee
  • Yun-Kyung Kim
  • Geun-Tae Kim
  • Min Wook So
  • Eunyoung Ahn
  • Dong Hyun Sohn
  • Seung-Geun LeeEmail author
Observational Research


Endothelial injury/dysfunction is thought to be one of the earliest events in the development of vascular diseases in systemic sclerosis (SSc). Although hyperuricemia is also known to induce endothelial dysfunction and vascular inflammation, the effect of uric acid on the microvascular involvement in SSc has not been well established. We investigated whether increased serum uric acid (SUA) levels are associated with digital ulcers (DUs) in SSc. In this cross-sectional study, we consecutively recruited 71 women with SSc and 349 age- and sex-matched healthy subjects, and SUA levels were measured in all study subjects. SSc patients had significantly higher mean SUA levels than healthy subjects (4.5 ± 1 mg/dL vs 4.2 ± 0.9 mg/dL, p = 0.017), although a significantly lower body mass index (BMI) was observed in SSc patients than in controls. Among 71 SSc patients, 22 (31%) had DUs ever (active DUs, 8; healed DUs, 14). SSc patients presenting with DUs ever showed significantly higher SUA levels than those without this feature (median, 5.2 mg/dL vs 4.1 mg/dL, p = 0.009). In multivariable logistic regression models adjusted for confounders such as BMI and estimated glomerular filtration rate, increased SUA levels were associated with a significantly higher risk for the presence of DUs ever (OR 2.3, 95% CI 1.16–4.57, p = 0.018). Our data revealed that elevated SUA levels are independently associated with the presence of DUs in SSc patients, thereby suggesting the potential role of hyperuricemia in the pathogenesis of SSc vasculopathy.


Systemic scleroderma Uric acid Ulcers Vascular endothelium 



We specially thank the late Professor Sung-Il Kim who devoted himself to education, research, and patient care in Division of Rheumatology, Department of Internal Medicine, Pusan National University School of Medicine (1963 to 2011).

Author contributions

EK: study design, data collection, analysis and interpretation and writing manuscript, HNL: data collection and analysis, YKK: data interpretation, GTK: data interpretation, MWS: data analysis and interpretation, EA: data analysis and interpretation, DHS: revision of manuscript, SGL: study design, data analysis and interpretation, writing manuscript and coordination of entire study.

Compliance with ethical standards

Conflict of interest

The authors have declared no conflicts of interest.

Ethical standards

The present study was approved by the Research and Ethical Review Board of Pusan National University Hospital (IRB no. H-1402-005-014). All study participants provided written informed consent in accordance with the principles of the Declaration of Helsinki.

Supplementary material

296_2019_4240_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 KB)


  1. 1.
    Moon KW, Lee SS, Lee YJ, Jun JB, Yoo SJ, Ju JH, Chang SH, Choi IA, Kang TY, Lee EB, Lee SG (2018) Clinical and laboratory characteristics and mortality in Korean patients with systemic sclerosis: a nationwide multicenter retrospective cohort study. J Rheumatol 45(9):1281–1288. CrossRefGoogle Scholar
  2. 2.
    Garrett SM, Frost DB, Feghali-Bostwick C (2017) The mighty fibroblast and its utility in scleroderma research. J Scler Rel Disord 2(2):69–134. CrossRefGoogle Scholar
  3. 3.
    Allanore Y, Distler O, Matucci-Cerinic M, Denton CP (2018) Review: defining a unified vascular phenotype in systemic sclerosis. Arthritis Rheumatol 70(2):162–170. CrossRefGoogle Scholar
  4. 4.
    Matucci-Cerinic M, Kahaleh B, Wigley FM (2013) Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum 65(8):1953–1962. CrossRefGoogle Scholar
  5. 5.
    Orlandi M, Barsotti S, Lepri G, Codullo V, Di Battista M, Guiducci S, Della Rossa A (2018) One year in review 2018: systemic sclerosis. Clin Exp Rheumatol 36(Suppl 113 (4):3–23Google Scholar
  6. 6.
    Abdulle AE, Diercks GFH, Feelisch M, Mulder DJ, van Goor H (2018) The role of oxidative stress in the development of systemic sclerosis related vasculopathy. Front Physiol 9:1177. CrossRefGoogle Scholar
  7. 7.
    Hughes M, Herrick AL (2017) Digital ulcers in systemic sclerosis. Rheumatology 56(1):14–25. CrossRefGoogle Scholar
  8. 8.
    Kawashiri SY, Nishino A, Igawa T, Takatani A, Shimizu T, Umeda M, Fukui S, Okada A, Suzuki T, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakashima M, Mizokami A, Matsuoka N, Migita K, Ogawa F, Ikeda S, Maemura K, Nakamura H, Origuchi T, Maeda T, Kawakami A (2018) Prediction of organ involvement in systemic sclerosis by serum biomarkers and peripheral endothelial function. Clin Exp RheumatolGoogle Scholar
  9. 9.
    Vassalle C, Mazzone A, Sabatino L, Carpeggiani C (2016) Uric acid for cardiovascular risk: Dr. Jekyll or Mr. Hide? Diseases 4 (1).
  10. 10.
    Din SE, Salem UAA, Abdulazim MM DO (2017) Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: a review. J Adv Res 8(5):537–548. CrossRefGoogle Scholar
  11. 11.
    Richette P, Perez-Ruiz F, Doherty M, Jansen TL, Nuki G, Pascual E, Punzi L, So AK, Bardin T (2014) Improving cardiovascular and renal outcomes in gout: what should we target? Nat Rev Rheumatol 10(11):654–661. CrossRefGoogle Scholar
  12. 12.
    Kim H, Kim SH, Choi AR, Kim S, Choi HY, Kim HJ, Park HC (2017) Asymptomatic hyperuricemia is independently associated with coronary artery calcification in the absence of overt coronary artery disease: a single-center cross-sectional study. Medicine 96(14):e6565. CrossRefGoogle Scholar
  13. 13.
    Ding XH, Wang X, Cao R, Yang X, Xiao W, Zhang Y, Bai Y, Wu H, Ye P (2017) A higher baseline plasma uric acid level is an independent predictor of arterial stiffness: a community-based prospective study. Medicine 96(6):e5957. CrossRefGoogle Scholar
  14. 14.
    Puddu P, Puddu GM, Cravero E, Vizioli L, Muscari A (2012) Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications. J Cardiol 59(3):235–242. CrossRefGoogle Scholar
  15. 15.
    Braga TT, Forni MF, Correa-Costa M, Ramos RN, Barbuto JA, Branco P, Castoldi A, Hiyane MI, Davanso MR, Latz E, Franklin BS, Kowaltowski AJ, Camara NO (2017) Soluble uric acid activates the NLRP3 inflammasome. Sci Rep 7:39884. CrossRefGoogle Scholar
  16. 16.
    Henderson J, Bhattacharyya S, Varga J, O’Reilly S (2018) Targeting TLRs and the inflammasome in systemic sclerosis. Pharmacol Ther 192:163–169. CrossRefGoogle Scholar
  17. 17.
    Coghlan JG, Denton CP, Grunig E, Bonderman D, Distler O, Khanna D, Muller-Ladner U, Pope JE, Vonk MC, Doelberg M, Chadha-Boreham H, Heinzl H, Rosenberg DM, McLaughlin VV, Seibold JR, group Ds (2014) Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis 73(7):1340–1349. CrossRefGoogle Scholar
  18. 18.
    Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee (1980). Arthritis Rheum 23 (5):581–590Google Scholar
  19. 19.
    LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 15(2):202–205Google Scholar
  20. 20.
    Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F (2007) Expressing the modification of diet in renal disease study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clinical chemistry 53(4):766–772. CrossRefGoogle Scholar
  21. 21.
    Khanna D, Furst DE, Clements PJ, Allanore Y, Baron M, Czirjak L, Distler O, Foeldvari I, Kuwana M, Matucci-Cerinic M, Mayes M, Medsger T Jr, Merkel PA, Pope JE, Seibold JR, Steen V, Stevens W, Denton CP (2017) Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J Scler Rel Disord 2(1):11–18. CrossRefGoogle Scholar
  22. 22.
    Khimdas S, Harding S, Bonner A, Zummer B, Baron M, Pope J (2011) Associations with digital ulcers in a large cohort of systemic sclerosis: results from the Canadian Scleroderma Research Group registry. Arthritis Care Res (Hoboken) 63(1):142–149. CrossRefGoogle Scholar
  23. 23.
    Park EK, Lee SG, Kim BH, Park JH, Lee S, Kim GT (2016) Insulin resistance is associated with digital ulcer in patients with systemic sclerosis. Clin Exp Rheumatol 34(Suppl 100 (5):85–91Google Scholar
  24. 24.
    Park EK, Park JH, Kweon SM, Kim GT, Lee SG (2017) Vitamin D deficiency is associated with digital ulcer but not with atherosclerosis or arterial stiffness in patients with systemic sclerosis: a pilot study. Clin Rheumatol 36(6):1325–1333. CrossRefGoogle Scholar
  25. 25.
    Hughes M, Tracey A, Bhushan M, Chakravarty K, Denton CP, Dubey S, Guiducci S, Muir L, Ong V, Parker L, Pauling JD, Prabu A, Rogers C, Roberts C, Herrick AL (2018) Reliability of digital ulcer definitions as proposed by the UK Scleroderma Study Group: a challenge for clinical trial design. J Scler Rel Disord 3(2):170–174. CrossRefGoogle Scholar
  26. 26.
    Amanzi L, Braschi F, Fiori G, Galluccio F, Miniati I, Guiducci S, Conforti ML, Kaloudi O, Nacci F, Sacu O, Candelieri A, Pignone A, Rasero L, Conforti D, Matucci-Cerinic M (2010) Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatology 49(7):1374–1382. CrossRefGoogle Scholar
  27. 27.
    Dimitroulas T, Giannakoulas G, Dimitroula H, Sfetsios T, Parcharidou D, Karvounis H, Settas L (2011) Significance of serum uric acid in pulmonary hypertension due to systemic sclerosis: a pilot study. Rheumatol Int 31(2):263–267. CrossRefGoogle Scholar
  28. 28.
    Gigante A, Barbano B, Barilaro G, Quarta S, Gasperini ML, Di Mario F, Romaniello A, Amoroso A, Cianci R, Rosato E (2016) Serum uric acid as a marker of microvascular damage in systemic sclerosis patients. Microvasc Res 106:39–43. CrossRefGoogle Scholar
  29. 29.
    Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ (2013) The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 99(11):759–766. CrossRefGoogle Scholar
  30. 30.
    Karasawa T, Takahashi M (2017) Role of NLRP3 Inflammasomes in Atherosclerosis. J Atheroscler Thromb 24(5):443–451. CrossRefGoogle Scholar
  31. 31.
    Rho YH, Zhu Y, Choi HK (2011) The epidemiology of uric acid and fructose. Semin Nephrol 31(5):410–419. CrossRefGoogle Scholar
  32. 32.
    Kim Y, Kang J, Kim GT (2018) Prevalence of hyperuricemia and its associated factors in the general Korean population: an analysis of a population-based nationally representative sample. Clin Rheumatol. Google Scholar
  33. 33.
    Lyngdoh T, Marques-Vidal P, Paccaud F, Preisig M, Waeber G, Bochud M, Vollenweider P (2011) Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study. PloS one 6(5):e19901. CrossRefGoogle Scholar
  34. 34.
    Krishnan E, Sokolove J (2011) Uric acid in heart disease: a new C-reactive protein? Curr Opin Rheumatol 23(2):174–177. CrossRefGoogle Scholar
  35. 35.
    Kim IY, Lee DW, Lee SB, Kwak IS (2014) The role of uric acid in kidney fibrosis: experimental evidences for the causal relationship. BioMed Res Int 2014:638732. Google Scholar
  36. 36.
    Romi MM, Arfian N, Tranggono U, Setyaningsih WAW, Sari DCR (2017) Uric acid causes kidney injury through inducing fibroblast expansion, Endothelin-1 expression, and inflammation. BMC Nephrol 18(1):326. CrossRefGoogle Scholar
  37. 37.
    Jaruvongvanich V, Ahuja W, Wijarnpreecha K, Ungprasert P (2017) Hyperuricemia is not associated with severity of liver fibrosis in patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 29(6):694–697. CrossRefGoogle Scholar
  38. 38.
    Gigante A, Rosato E, Massa R, Rossi C, Barbano B, Cianci R, Molinaro I, Amoroso A, Salsano F (2012) Evaluation of chronic kidney disease epidemiology collaboration equation to estimate glomerular filtration rate in scleroderma patients. Rheumatology 51(8):1426–1431. CrossRefGoogle Scholar
  39. 39.
    Caimmi C, Caramaschi P, Venturini A, Bertoldo E, Vantaggiato E, Viapiana O, Ferrari M, Lippi G, Frulloni L, Rossini M (2018) Malnutrition and sarcopenia in a large cohort of patients with systemic sclerosis. Clin Rheumatol 37(4):987–997. CrossRefGoogle Scholar
  40. 40.
    Li C, Hsieh MC, Chang SJ (2013) Metabolic syndrome, diabetes, and hyperuricemia. Curr Opin Rheumatol 25(2):210–216. CrossRefGoogle Scholar
  41. 41.
    Affandi AJ, Radstake TR, Marut W (2015) Update on biomarkers in systemic sclerosis: tools for diagnosis and treatment. Sem Immunopathol 37(5):475–487. CrossRefGoogle Scholar
  42. 42.
    Kim KJ, Baek IW, Park YJ, Yoon CH, Kim WU, Cho CS (2015) High levels of uric acid in systemic lupus erythematosus is associated with pulmonary hypertension. Int J Rheum Dis 18(5):524–532. CrossRefGoogle Scholar
  43. 43.
    Leberkuhne LJ, Ploegstra MJ, Douwes JM, Bartelds B, Roofthooft MT, Hillege HL, Berger RM (2017) Serially measured uric acid levels predict disease severity and outcome in pediatric pulmonary arterial hypertension. Am J Respir Crit Care Med 195(3):401–404. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of Internal MedicinePusan National University School of Medicine, Pusan National University HospitalBusanRepublic of Korea
  2. 2.Biomedical Research InstitutePusan National University HospitalBusanRepublic of Korea
  3. 3.Division of Rheumatology, Department of Internal MedicineKosin University College of MedicineBusanRepublic of Korea
  4. 4.Division of Rheumatology, Department of Internal MedicinePusan National University Yangsan HospitalYangsanRepublic of Korea
  5. 5.Department of Microbiology and ImmunologyPusan National University School of MedicineYangsanRepublic of Korea

Personalised recommendations