Open Access
Review
The Role of Biomarkers in the the Pathogenesis, Clinical Manifestations, and Therapeutic Outcome of Systemic Sclerosis
Anna Bazsó1, *
, Péter Szodoray2
, Yehuda Shoenfeld3, 4
, Emese Virág Kiss Med Dsci1, 5
Author Information
Submitted: 12 Jan 2025 | Revised: 20 Mar 2025 | Accepted: 28 Mar 2025 | Published: 3 Apr 2025
Abstract
Systemic sclerosis (SSc) is a complex autoimmune disorder characterized by progressive fibrosis and obliterative vasculopathy affecting the skin and various internal organs, including the kidneys, lungs, cardiovascular system, and gastrointestinal tract. The disease manifests in two major clinical subtypes: limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc), distinguished primarily by the extent of skin involvement and the pattern of internal organ involvement. Biomarkers, serving as quantifiable indicators of biological processes in SSc, hold significant potential for refining disease classification, predicting progression, assessing therapeutic responses, and evaluating clinical outcomes. Unlike other autoimmune diseases, SSc lacks highly specific biomarkers. Given its heterogeneity and multifactorial pathogenesis, the development of a composite biomarker panel may represent the most effective approach for future diagnostic and longitudinal monitoring strategies in SSc.
Keywords
References
1.
Denton, C.P.; Kanna, D. Systemic sclerosis. Lancet 2017, 390, 1685–1699. https://doi.org/10.1016/S0140-6736(17)30933-9.
2.
Ingegnoli, F.; Ughi, N.; Mihai, C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract. Res. Clin. Rheumatol. 2018, 32, 223–240. https://doi.org/10.1016/j.berh.2018.08.005.
3.
van den Hoogen, F.; Khanna, D.; Fransen, J.; et al. Classification Criteria for Systemic Sclerosis: An ACR-EULAR Collaborative Initiative. Arthritis Rheum. 2013, 65, 2737–2747. https://doi.org/10.1002/art.38098.
4.
Guillén-Del-Castillo, A.; Meseguer, M.L.; Fonollosa-Pla, V.; et al. Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension. Sci. Rep. 2022, 12, 5289. https://doi.org/10.1038/s41598-022-09353-z.
5.
Ko, J.; Noviani, M.; Chellamuthu, V.R.; et al. The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity. Int. J. Mol. Sci. 2023, 19, 14287.https://doi.org/10.3390/ijms241814287.
6.
Raschi, E.; Privitera, D.; Bodio, C.; et al. Scleroderma-Specific Auto-antibodies Embedded in Immune Complexes Mediate Endothelial Damage: An Early Event in the Pathogenesis of Systemic Sclerosis. Arthritis Res. Ther. 2020, 22, 265. https://doi.org/10.1186/s13075-020-02360.
7.
Jiang, Y.; Turk, M.A.; Pope, J.E. Factors Associated with Pulmonary Arterial Hypertension (PAH) in Systemic Sclerosis (SSc). Autoimmun. Rev. 2020, 19, 102602. https://doi.org/10.1016/j.autrev.2020.102602.
8.
Young, C.; Lau, A.W.Y.; Burnett, D.L. B Cells in the Balance: Offsetting Self-Reactivity Avoidance with Protection against Foreign. Front. Immunol. 2022, 13, 951385.https://doi.org/10.3389/fimmu.2022.951385.
9.
Rosa, I.; Romano, E.; Fioretto, B.S.; et al. Autoantibodies as putative biomarkers and triggers of cell dysfunctions in systemic sclerosis. Curr. Opin. Rheumatol. 2025, 37, 51–63. https://doi.org/10.1097/BOR.0000000000001035.
10.
Al Dulaijan, B.; Huang, S.; Lin, C.J.F.; et al. Impact of Scleroderma-Associated Autoantibodies on Clinical Outcome Assessments: Post Hoc Analysis from a Randomised, Double-blind, Placebo-controlled, Phase 3 Trial of Tocilizumab in Scleroderma. ACR Open Rheumatol. 2025, 7, 11782. https://doi.org/10.1002/acr2.11782.
11.
Bazsó, A.; Szodoray, P.; Shoenfeld, Y.; et al. Biomarkers reflecting the pathogenesis, clinical manifestations, and guide therapeutic approach in systemic sclerosis: A narrative review. Clin. Rheumatol. 2024, 43, 3055–3072. https://doi.org/10.1007/s10067-024-07123-y.
12.
Brown, M.; O’Reilly, S. The Immunopathogenesis of Fibrosis in Systemic Sclerosis. Clin. Exp. Immunol. 2019, 195, 310–321.https://doi.org/10.1111/cei.13238.
13.
Al-Adwi, Y.; Westra, J.; van Goor, H.; et al. Macrophages as Determinants and Regulators of Fibrosis in Systemic Sclerosis. Rheumatology 2023, 62, 535–545.https://doi.org/10.1093/rheumatology/keac410.
14.
Kulshrestha, R.; Singh, H.; Pandey, A.; et al. Caveolin-1 as a critical component in the pathogenesis of lung fibrosis of different etiology: Evidences and mechanisms. Exp. Mol. Pathol. 2019, 111, 104315. https://doi.org/10.1016/j.yexmp.2019.104315.
15.
Pattanaik, D.; Brown, M.; Postlethwaite, B.C.; et al. Pathogenesis of Systemic Sclerosis. Front. Immunol. 2015, 6, 272. https://doi.org/10.3389/fimmu.2015.00272.
16.
Lafyatis, R. Transforming Growth Factor β—At the Centre of Systemic Sclerosis. Nat. Rev. Rheumatol. 2014, 10, 706–719. https://doi.org/10.3389/fimmu.2015.00272.
17.
Yang, M.M.; Boin, F.; Wolters, P.J. Molecular underpinnings of aging contributing to systemic sclerosis pathogenesis. Curr. Opin. Rheumatol. 2025, 1, 86–92. https://doi.org/10.1097/BOR.0000000000001061.
18.
Blackburn, E.H.; Epel, E.S.; Lin, J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science 2015, 350, 1193–1198. https://doi.org/10.1126/science.aab3389.
19.
Miller, K.N.; Victorelli, S.G.; Salmonowicz, H.; et al. Cytoplasmic DNA: Sources, sensing, and role in aging and disease. Cell 2021, 184, 5506–5526. https://doi.org/10.1016/j.cell.2021.09.034.
20.
Di Micco, R.; Krizhanowsky, V.; Baker, D.; et al. Cellular senescence in aging: From mechanisms to therapeutic oppurtunitites. Nat. Rev. Mol. Cell Biol. 2021, 22, 75–95. https://doi.org/10.1038/s41580-020-00314-w.
21.
Ledda, R.E.; Campochiaro, C. High resolution computed tomography in systemic sclerosis: From diagnosis to follow-up. Rheumatol. Immunol. Res. 2024, 5, 166–174. https://doi.org/10.2478/rir-2024-0023.
22.
Di Maggio, G.; Confalonieri, P.; Salton, F.; et al. Biomarkers in systemic sclerosis. An overview. Curr. Issues Mol. Biol. 2023, 45, 7775–7802. https://doi.org/10.3390/cimb45100490.
23.
Hoffmann-Vold, A.-M.; Allanore, Y.; Alves, M.; et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann. Rheum. Dis. 2021, 80, 219–227. https://doi.org/10.1136/annrheumdis-2020-217455.
24.
Perelas, A.; Silver, R.M.; Arrossi, A.V.; et al. Systemic sclerosis-associated interstitial lung disease. Lancet Respir. Med. 2020, 8, 304–320. https://doi.org/10.1016/S2213-2600(19)30480-1.
25.
Volkmann, E.R.; Wilhalme, H.; Assassi, S.; et al. Combining Clinical and Biological Data to Predict. Progressive Pulmonary Fibrosis in Patients with Systemic Sclerosis Despite Immunomodulatory Therapy. ACR Open Rheumatol. 2023, online ahead of print. https://doi.org/10.1002/acr2.11598.
26.
Bruni, C.; De Luca, G.; Lazzaroni, M.-G.; et al. Screening for pulmonary arterial hypertension in systemic sclerosis: A systematic literature review. Eur. J. Intern. Med. 2020, 78, 17–25. https://doi.org/10.1016/j.ejim.2020.05.042.
27.
Yaqub, A.; Chung, L. Epidemiology and risk factors for pulmonary hypertension in systemic sclerosis. Curr. Rheumatol. Rep. 2013, 15, 302. https://doi.org/10.1007/s11926-012-0302-2.
28.
Sanges, S.; Rice, L.; Tu, L.; et al. Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis. Ann. Rheum. Dis. 2023, 82, 365–373. https://doi.org/10.1136/ard-2022-223237.
29.
Kiely, D.G.; Lawrie, A.; Humbert, M. Screening strategies for pulmonary arterial hypertension. Eur. Heart. J. Suppl. 2019, 21, K9–K20. https://doi.org/10.1093/eurheartj/suz204.
30.
Hojda, S.E.; Chis, I.C.; Clichici, S. Biomarkers in Pulmonary Arterial Hypertension. Diagnostics 2022, 12, 3033. https://doi.org/10.3390/diagnostics12123033.
31.
Vasile, M.; Avouac, J.; Sciarra, I.; et al. From VEDOSS to established systemic sclerosis diagnosis according to ACR/EULAR 2013 classification criteria: A French-Italian capillaroscopic survey. Clin. Exp. Rheumatol. 2018, 113, 82–87.
32.
Romano, E.; Rosa, I.; Fioretto, B.S.; et al. Circulating neurovascular guidance molecules and their relationship with peripherial microvacular impairment in sytsemic sclerosis. Life 2022, 12, 1056. https://doi.org/10.3390/life12071056.
33.
Adams, R.H.; Eichmann, A. Axon guidance molecules in vascular patterning. Cold Spring Harb. Perspect. Biol. 2010, 2, a001875. https://doi.org/10.1101/cshperspect.a001875.
34.
Romano, E.; Rosa, I.; Fioretto, B.S.; et al. A new avenue in the pathogenesis of systemic sclerosis: The molecular interface between the endothelial and the nervous systems. Clin. Exp. Rheumatol. 2019, 37 (Suppl. 1), 133–140.
35.
Chora, I.; Romano, E.; Manetti, M.; et al. Evidence for a derangement of the microvascular system in patients with a very early diagnosis of systemic sclerosis. J. Rheumatol. 2017, 44, 1190–1197. https://doi.org/10.3899/jrheum.160791.
36.
Mazzotta, C.; Romano, E.; Bruni, C.; et al. Plexin-D1/Semaphorin 3E pathway may contribute to dysregulation of vascular tone control and defective angiogenesis in systemic sclerosis. Arthritis Res. Ther. 2015, 17, 221. https://doi.org/10.1186/s13075-015-0749-4.
37.
Romano, E.; Chora, I.; Manetti, M.; et al. Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis. Ann. Rheum. Dis. 2016, 75, 1541–1549. https://doi.org/10.1136/annrheumdis-2015-207483.
38.
Cole, A.; Ong, V.H.; Denton, C.P. Renal Disease and Systemic Sclerosis: An Update on Scleroderma Renal Crisis. Clin. Rev. Allergy Immunol. 2022, 64, 378–391. https://doi.org/10.1007/s12016-022-08945-x.
39.
Shah, R.C.; Morrisroe, K.; Stevens, W.; et al. Scleroder, a renal crisis, an increasingly rare but persistently challenging condition: A retrospective cohort study. Rheumatol. Adv. Pract. 2024, 8, rkae131. https://doi.org/10.1093/rap/rkae131.
40.
Trang, G.; Steele, R.; Baron, M.; et al. Coricosteroids and the risk of scleroderma renal crisis: A systematic review. Rheumatol. Int. 2012, 32, 645–653. https://doi.org/10.1007/s00296-010-1697-6.
41.
Nassar, M.; Ghernautan, V.; Nso, N.; et al. Gastrointestinal involvement in systemic sclerosis: An updated review. Medicine 2022, 101, e31780. https://doi.org/10.1097/MD.0000000000031780.
42.
Bandini, G.; Alunno, A.; Ruaro, B.; et al. Significant gastrointestinal unmet needs in patients with systemic sclerosis: Insights from a large international patient survey. Rheumatology 2024, 63, e92–e93. https://doi.org/10.1093/rheumatology/kead486.
43.
Hu, S.; Zuo, X.; Li, Y. Coexistence of systemic sclerosis and ankylosing spondylitis: A case report and literature review. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018, 43, 1263–1265. https://doi.org/10.11817/j.issn.1672-7347.2018.11.016.
44.
Hamberg, V.; Wallman, J.K.; Mogard, E.; et al. Elevated fecal levels of the inflammatory biomarker calprotectin in early systemic sclerosis. Rheumatol. Int. 2023, 5, 961–967. https://doi.org/10.1007/s00296-022-05264-4.
45.
Maria, A.T.J.; Partouche, L.; Goulabchand, R.; et al. Intriguing relationships between cancer and systemic sclerosis: Role of the immune system and other contributiors. Front. Immunol. 2019, 9, 3112. https://doi.org/10.3389/fimmu.2018.03112.
46.
Lepri, G.; Catalano, M.; Bellando-Randone, S.; et al. Systemic Sclerosis Association with Malignancy. Clin. Rev. Allergy Immunol. 2022, 63, 398–416. https://doi.org/10.1007/s12016-022-08930-4.
47.
Dolcino, M.; Pelosi, A.; Fiore, P.F.; et al. Gene Profiling in Patients with Systemic Sclerosis Reveals the Presence of Oncogenic Gene Signatures. Front. Immunol. 2018, 9, 449. https://doi.org/10.3389/fimmu.2018.00449.
48.
Artlett, C.M.; Black, C.M.; Briggs, D.C.; et al. Telomer reduction in scleroderma patients: A possible cause for chromosomal instability. Br. J. Rheumatol. 1996, 35, 732–737. https://doi.org/10.1007/s00296-007-0472-9.
49.
Ciechomska, M.; van Laar, J.M.; O’Reilly, S. Emerging role of epigenetics in systemic sclerosis pathogenesis. Genes. Immun. 2014, 15, 433–439. https://doi.org/10.1038/gene.2014.44.
50.
Peng, Y.; Wang, Y.; Zhou, C.; et al. PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? Front. Oncol. 2022, 12, 819128. https://doi.org/10.3389/fonc.2022.819128.
51.
Galluzzi, L.; Spranger, S.; Fuchs, E.; et al. WNT signaling in cancer immunsurveillance. Trends Cell Biol. 2018, 29, 4–65. https://doi.org/10.1016/j.tcb.2018.08.005.
52.
Marie, I.; Gehanno, J.F. Enviromental risk factors of systemic sclerosis. Semin. Immunpathol. 2015, 37, 463–473. https://doi.org/10.1007/s00281-015-0507-3.
53.
Tashkin, D.P.; Roth, M.D.; Clements, P.J.; et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A randomised controlled, double-blind, parallel group trial. Lancet Respir. Med. 2016, 4, 708–719. https://doi.org/10.1016/S2213-2600(16)30152-7.
54.
Park, B.; Vemulapalli, R.C.; Gupta, A.; et al. Docetaxel-induced systemic sclerosis with internal organ involvement masquerading as congestive heart failure. Case Rep. Immunol. 2017, 2017, 4249157. https://doi.org/10.1155/2017/4249157.
55.
Peng, H.; Wu, X.; Wen, Y.; et al. Association between systemic sclerosis and risk of lung cancer: Results from a pool of cohort studies and Mendelian randomization analysis. Autoimmun. Rev. 2020, 19, 102633. https://doi.org/10.1016/j.autrev.2020.102633.
56.
Duffau, P.; Dimicoli, S.; Gensous, N.; et al. Anti-NOR90 antibody associated with paraneoplastic systemic sclerosis. Clin. Exp. Rheumatol. 2022, 40, 2002–2003. https://doi.org/10.55563/clinexprheumatol/r6fqel.
57.
Didier, K.; Sobanski, V.; Robbins, A.; et al. Impact of autoantibody status on stratifying the risk of organ involvement and mortality in SSc: Experience from a multicentre French cohort of 1605 French patients. RMD Open 2024, 10, e004580. https://doi.org/10.1136/rmdopen-2024-004580.
58.
Hochhegger, B.; Marchiori, E.; Sedlaczek, O.; et al. MRI in lung cancer: A pictorial essay. Br. J. Radiol. 2011, 84, 661–668. https://doi.org/10.1259/bjr/24661484.
59.
Derk, C.T. Association of breast cancer development in patients with systemic sclerosis: An explorating study. Clin. Rheumatol. 2004, 26, 1615–1619. https://doi.org/10.1007/s10067-007-0546-9.
60.
Anilkumar, M.; Alkhayyat, M.; Grewal, U.S.; et al. Higher risk of neoplastic progression of Barrett’s esophagus in patients with systemic sclerosis. Gastroenterol. Rep. 2021, 9, 595–596. https://doi.org/10.1093/gastro/goaa096.
61.
Colaci, M.; Giuggioli, D.; Vacchi, C.; et al. Haematological Malignancies in Systemic Sclerosis Patients: Case Reports and Review of the World Literature. Case Rep. Rheumatol. 2017, 2017, 6230138. https://doi.org/10.1155/2017/6230138.
Issue
Volume 1, Issue 1How to Cite
Bazsó, A., Szodoray, P., Shoenfeld, Y., & Dsci, E. V. K. M. (2025). The Role of Biomarkers in the the Pathogenesis, Clinical Manifestations, and Therapeutic Outcome of Systemic Sclerosis. Journal of Mosaic of Autoimmunity, 1(1), 5. https://doi.org/10.53941/jmai.2025.100005
RIS
BibTex
Copyright & License
Copyright (c) 2025 by the authors.
This work is licensed under a This work is licensed under a Creative Commons Attribution 4.0 International License.