Skip to main content
Log in

Systemic sclerosis patients with negative antinuclear antibodies have distinctive clinical manifestations: a multicenter CRDC cohort in China

Patienten mit systemischer Sklerose und negativen antinukleären Antikörpern haben ausgeprägte klinische Symptome: eine multizentrische CRDC-Kohorte in China

  • Originalien
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Abstract

Background

The presence of circulating antinuclear antibodies (ANAs) is a hallmark of immune dysregulation in patients with systemic sclerosis (SSc).

Objective

A variety of ANAs are associated with unique sets of disease manifestations and are widely used in clinical practice in SSc. This study aimed to investigate the clinical features of SSc patients negative for ANAs in a Chinese Rheumatism Data Center (CRDC) multicenter cohort in China.

Methods

Patients were prospectively recruited between April 2008 and June 2019 from 154 clinical centers nationwide, and all cases fulfilled the 2013 ACR/EULAR classification criteria for systemic sclerosis. Results for antinuclear antibodies were intensively collected. Demographic, clinical, and laboratory data were compared between ANA-positive SSc patients and those negative for ANAs.

Results

Antinuclear antibodies were detected in 2129 of 2809 patients enrolled in the study; 4.2% of patients were negative. There were more males among ANA-negative SSc patients (29/60 vs. 294/1746, p < 0.001). The incidence of certain critical organ involvement, including gastroesophageal reflux (5.6% vs. 18.5%, p = 0.002), interstitial lung disease (65.2% vs. 77.9%, p = 0.015), and pulmonary arterial hypertension (11.5% vs. 29.0%, p = 0.006) was significantly lower in ANA-negative patients than in ANA-positive patients. The proportion of abnormal erythrocyte sedimentation rate (32.4% vs. 47.6%, p = 0.013) and IgG elevation (14.3% vs. 37.0%, p = 0.003), an indicator of disease activity, was significantly lower in ANA-negative patients than in ANA-positive patients.

Conclusion

Antinuclear antibodies are strongly associated with the clinical manifestations of systemic sclerosis, with ANA-negative SSc patients tending to exhibit relatively milder disease.

Zusammenfassung

Hintergrund

Das Vorhandensein von zirkulierenden antinukleären Antikörpern (ANA) ist ein Merkmal der Immundysregulation bei Patienten mit systemischer Sklerose (SSc).

Zielsetzung

Eine Vielzahl unterschiedlicher ANA wird mit einzigartigen Krankheitsmanifestationen in Verbindung gebracht und ist bei SSc in der klinischen Praxis weit verbreitet. Ziel dieser Studie war es, die klinischen Merkmale von SSc-Patienten zu untersuchen, die in einer multizentrischen Kohorte des Chinese Rheumatism Data Center (CRDC) in China negativ auf ANA reagieren.

Methoden

Die Patienten wurden zwischen April 2008 und Juni 2019 aus 154 klinischen Zentren im ganzen Land prospektiv rekrutiert, und alle Fälle erfüllten die ACR/EULAR-Klassifikationskriterien für systemische Sklerose von 2013. Die Ergebnisse für antinukleäre Antikörper wurden erfasst. Demografische, klinische und Labordaten von ANA-positiven und ANA-negativen Patienten wurden verglichen.

Ergebnisse

Antinukleäre Antikörper wurden bei 2129 von 2809 in die Studie aufgenommenen Patienten nachgewiesen; 4,2 % der Patienten waren negativ. Unter den ANA-negativen SSc-Patienten waren mehr Männer (29/60 vs. 294/1746; p < 0,001). Die Inzidenz bestimmter kritischer Organbeteiligungen, darunter gastroösophagealer Reflux (5,6 % vs. 18,5 %; p = 0,002), interstitielle Lungenerkrankung (65,2 % vs. 77,9 %, p = 0,015) und pulmonale arterielle Hypertonie (11,5 % vs. 29,0 %; p = 0,006), war bei ANA-negativen Patienten signifikant niedriger als bei ANA-positiven Patienten. Der Anteil der abnormalen Erythrozytensedimentationsrate (ESR; 32,4 % vs. 47,6 %; p = 0,013) und IgG-Erhöhung (14,3 % vs. 37,0 %, p = 0,003), ein Indikator für Krankheitsaktivität, war bei ANA-negativen Patienten signifikant niedriger als bei ANA-positiven Patienten.

Schlussfolgerung

Antinukleäre Antikörper stehen in engem Zusammenhang mit den klinischen Manifestationen der systemischen Sklerose, wobei ANA-negative SSc-Patienten in der Regel eine relativ mildere Erkrankung aufweisen.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Behmanesh F, Amin R, Khajedaluee M et al (2010) Autoantibody profile in systemic sclerosis. ACTA 48:12–20

    Google Scholar 

  2. Hudson M, Satoh M, Chan JY et al (2014) Prevalence and clinical profiles of “autoantibody-negative” systemic sclerosis subjects. Clin Exp Rheumatol 32:127–132

    Google Scholar 

  3. Pradhan V, Rajadhyaksha A, Nadkar M et al (2014) Clinical and autoimmune profile of scleroderma patients from Western India. Int J Rheumatol 2014:983781

    Article  PubMed  PubMed Central  Google Scholar 

  4. Savas N, Dagli U, Ertugrul E et al (2007) Autoantibody profile in systemic sclerosis as a marker for esophageal and other organ involvement in Turkish populations. Dig Dis Sci 52:3081–3086

    Article  PubMed  Google Scholar 

  5. Mierau R, Moinzadeh P, Riemekasten G et al (2011) Frequency of disease-associated and other nuclear autoantibodies in patients of the German Network for Systemic Scleroderma: correlation with characteristic clinical features. Arthritis Res Ther 13:R172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. van den Hoogen F, Khanna D, Fransen J et al (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 65:2737–2747

    Article  PubMed  PubMed Central  Google Scholar 

  7. Galiè N, Humbert M, Vachiery JL et al (2015) 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 46:903–975

    Article  PubMed  Google Scholar 

  8. Schneeberger D, Tyndall A, Kay J et al (2013) Systemic sclerosis without antinuclear antibodies or Raynaud’s phenomenon: a multicentre study in the prospective EULAR Scleroderma Trials and Research (EUSTAR) database. Rheumatology 52:560–567

    Article  CAS  PubMed  Google Scholar 

  9. Hamaguchi Y, Hasegawa M, Fujimoto M et al (2008) The clinical relevance of serum antinuclear antibodies in Japanese patients with systemic sclerosis. Br J Dermatol 158:487–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Salazar GA, Assassi S, Wigley F et al (2015) Antinuclear antibody-negative systemic sclerosis. Semin Arthritis Rheum 44:680–686

    Article  CAS  PubMed  Google Scholar 

  11. Kuwana M (2017) Circulating anti-nuclear antibodies in systemic sclerosis: utility in diagnosis and disease subsetting. J Nippon Med Sch 84:56–63

    Article  CAS  PubMed  Google Scholar 

  12. Mendes C, Viana VST, Pasoto SG et al (2020) Clinical and laboratory features of African-Brazilian patients with systemic sclerosis. Clin Rheumatol 39:9–17

    Article  PubMed  Google Scholar 

  13. Bardoni A, Rossi P, Salvini R et al (2003) Autoantibodies to RNA-polymerases in Italian patients with systemic sclerosis. Clin Exp Rheumatol 21:301–306

    CAS  PubMed  Google Scholar 

  14. Abd-Elmawla MA, Hassan M, Elsabagh YA et al (2020) Deregulation of long noncoding RNAs ANCR, TINCR, HOTTIP and SPRY4-IT1 in plasma of systemic sclerosis patients: SPRY4-IT1 as a novel biomarker of scleroderma and its subtypes. Cytokine 133:155124

    Article  CAS  PubMed  Google Scholar 

  15. Royle JG, Lanyon PC, Grainge MJ et al (2018) The incidence, prevalence, and survival of systemic sclerosis in the UK Clinical Practice Research Datalink. Clin Rheumatol 37:2601

    Article  PubMed  PubMed Central  Google Scholar 

  16. Legendre P (2017) Systemic sclerosis. Rev Prat 67:775–783

    PubMed  Google Scholar 

  17. Poormoghim H, Moghadam AS, Moradi-Lakeh M et al (2013) Systemic sclerosis: demographic, clinical and serological features in 100 Iranian patients. Rheumatol Int 33:1943–1950

    Article  CAS  PubMed  Google Scholar 

  18. Lescoat A, Yelnik CM, Coiffier G et al (2019) Ulnar artery occlusion and severity markers of vasculopathy in systemic sclerosis: a multicenter cross-sectional study. Arthritis Rheumatol 71:983–990

    Article  CAS  PubMed  Google Scholar 

  19. Caron M, Hoa S, Hudson M et al (2018) Pulmonary function tests as outcomes for systemic sclerosis interstitial lung disease. Eur Respir Rev 27:170102

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chwiesko A, Kowal-Bielecka O, Sierakowski S (2019) Perspectives on the interlinked nature of systemic sclerosis and reflux disease. Expert Rev Gastroenterol Hepatol 13:213–227

    Article  CAS  PubMed  Google Scholar 

  21. Gonzalez R, Storr M, Bloching H et al (2001) Autoantibody profile in progressive systemic sclerosis as markers for esophageal involvement. J Clin Gastroenterol 32:123–127

    Article  CAS  PubMed  Google Scholar 

  22. Bertolino J, Scafi M, Benyamine A et al (2019) Systemic sclerosis and macrovascular involvement: Status of the issue in 2019. J Med Vas 44:400–421

    CAS  Google Scholar 

  23. Shah AA, Wigley FM, LK H (2010) Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J Rheumatol 37:98–104

    Article  PubMed  Google Scholar 

  24. Sulli A, Paolino S, Pizzorni C et al (2020) Progression of nailfold capillaroscopic patterns and correlation with organ involvement in systemic sclerosis: a 12 year study. Rheumatology 59:1051–1058

    Article  CAS  PubMed  Google Scholar 

  25. Sundaram MS, Chung L (2018) An update on systemic sclerosis-associated pulmonary arterial hypertension: a review of the current literature. Curr Rheumatol Rep 20:10

    Article  PubMed  Google Scholar 

  26. Ulrich S, Taraseviciene-Stewart L, Huber LC et al (2008) Peripheral blood B lymphocytes derived from patients with idiopathic pulmonary arterial hypertension express a different RNA pattern compared with healthy controls: a cross sectional study. Respir Res 9:20

    Article  PubMed  PubMed Central  Google Scholar 

  27. Poudel DR, CT D (2018) Mortality and survival in systemic sclerosis: a review of recent literature. Curr Opin Rheumatol 30:588–593

    Article  PubMed  Google Scholar 

  28. Rubio-Rivas M, Royo C, Simeón CP et al (2014) Mortality and survival in systemic sclerosis: systematic review and meta-analysis. Semin Arthritis Rheum 44:208–219

    Article  PubMed  Google Scholar 

  29. Elhai M, Meune C, Boubaya M et al (2017) Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis 76:1897–1905

    Article  PubMed  Google Scholar 

  30. Hao Y, Hudson M, Baron M et al (2017) Early mortality in a multinational systemic sclerosis inception cohort. Arthritis Rheumatol 69:1067–1077

    Article  PubMed  Google Scholar 

  31. de Rezende RPV, Gismondi RA, Maleh HC et al (2019) Distinct mortality profile in systemic sclerosis: a death certificate study in Rio de Janeiro, Brazil (2006–2015) using a multiple causes of death analysis. Clin Rheumatol 38:189–194

    Article  PubMed  Google Scholar 

  32. Yamane K, Ihn H, Asano Y et al (2000) Clinical and laboratory features of scleroderma patients with pulmonary hypertension. Rheumatology 39:1269–1271

    Article  CAS  PubMed  Google Scholar 

  33. Pokeerbux MR, Giovannelli J, Dauchet L et al (2019) Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature. Arthritis Res Ther 21:86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Allanore Y, Simms R, Distler O et al (2015) Systemic sclerosis. Nat Rev Dis Primers 23:15002

    Article  Google Scholar 

  35. Bellando-Randone S, Matucci-Cerinic M (2019) Very early systemic sclerosis. Best Pract Res Clin Rheumatol 33(4):101428. https://doi.org/10.1016/j.berh.2019.101428

    Article  PubMed  Google Scholar 

  36. Janardana R, Nair AM, Surin AK et al (2019) Unique clinical and autoantibody profile of a large Asian Indian cohort of scleroderma-do South Asians have a more aggressive disease? Clin Rheumatol 38:3179–3187

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the CRDC multicenter coauthors as above for assistance with case collections.

Funding

This study was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS; 2019-I2M-2-008).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Dong Xu or Xiaofeng Zeng.

Ethics declarations

Conflict of interest

M. Hui, X. Wang, J. Zhou, L. Zhang, X. Duan, M. Li, Q. Wang, J. Zhao, Y. Hou, D. Xu, and X. Zeng declare that they have no competing interests.

This study was approved by Chinese Rheumatism Data Center (CRDC) with the number S‑478. Informed consent was obtained.

Additional information

Redaktion

Ulf Müller-Ladner, Bad Nauheim

Uwe Lange, Bad Nauheim

Min Hui and Xianbin Wang contributed equally to this work.

Availability of supporting data and materials

All data generated or analyzed during this study are included in the article.

figure qr

Scan QR code & read article online

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hui, M., Wang, X., Zhou, J. et al. Systemic sclerosis patients with negative antinuclear antibodies have distinctive clinical manifestations: a multicenter CRDC cohort in China. Z Rheumatol 83 (Suppl 1), 160–166 (2024). https://doi.org/10.1007/s00393-022-01242-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-022-01242-0

Keywords

Schlüsselwörter

Navigation