Between diffuse and limited: the unique identity of systemic sclerosis–overlap syndromes

Year 2025, Volume: 7 Issue: 6, 913 - 918, 26.10.2025

Hamit Küçük , İbrahim Vasi , İbrahim Karaduman , Abdulsamet Erden

https://doi.org/10.38053/acmj.1779330

Abstract

Aims: Systemic sclerosis–overlap syndrome (SSc-OS) constitutes a distinct clinical phenotype within the spectrum of systemic sclerosis, marked by unique immunological and clinical characteristics that differentiate it from the classical subsets. The present study aimed to characterise the demographic, serological, and organ involvement patterns of patients with SSc-OS, and to assess their disease manifestations and prognostic trajectories in comparison with diffuse cutaneous and limited cutaneous SSc.
Methods: This study included patients followed at the Gazi University Hospital Rheumatology Department between January 2010 and July 2025. SSc-OS was defined as patients fulfilling classification criteria for systemic sclerosis together with other autoimmune diseases as rheumatoid arthritis, polymyositis, and or Sjögren’s syndrome. Baseline and 1-year characteristics were compared between SSc and SSc-OS.
Results: A total of 160 patients were included: 68 diffuse cutaneous (dcSSc), 67 limited cutaneous (lcSSc), and 25 SSc-OS. Age at disease onset was lower in dcSSc (42.5±13.7 years) compared with lcSSc (50.6±13.7) and SSc-OS (47.2±13.9; p=0.003). Anti topoisomerase I positivity was highest in dcSSc (83.8%) versus lcSSc (43.3%) and SSc-OS (16%; p=0.001), whereas anti-centromere was most frequent in lcSSc (41.8%; p=0.001) and anti-SSa in SSc-OS (44%; p=0.002). Interstitial lung disease (ILD) occurred in 89.7% of dcSSc, 76% of SSc-OS, and 56.7% of lcSSc (p=0.001), with extensive disease more common in dcSSc (61.7%; p=0.001). Myopathy was higher in SSc-OS (44%) and dcSSc (35.3%) than lcSSc (12.1%; p=0.001). Immunosuppressive therapy was most frequent in dcSSc (88.2% vs. 35.8% lcSSc and 60% SSc-OS; p=0.001). At one year, SSc-OS patients showed greater improvements in force vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco), though not statistically significant. Mortality occurred in 25% of dcSSc, 14.9% of lcSSc, and 8% of SSc-OS (p=0.113); Kaplan–Meier analysis demonstrated numerically better survival in SSc-OS (mean 25.3 years) compared with lcSSc (19.8) and dcSSc (19.5; log-rank p=0.249).
Conclusion: This study identified SSc-OS in 15.6% of patients, most commonly SSc–Sjögren’s. Distinct autoantibody profiles and prominent musculoskeletal involvement differentiated SSc-OS from classical subsets. While dcSSc showed the highest ILD burden and lcSSc was linked to pulmonary arterial hypertension, SSc-OS demonstrated intermediate pulmonary disease and numerically better survival, supporting its recognition as a clinically distinct phenotype within the SSc spectrum.

Keywords

Mortality , overlap syndrome , prognosis , systemic sclerosis

Ethical Statement

Ethical approval for this study was obtained from the Ethics Committee of Gazi University on October 22, 2024.

Supporting Institution

No funding was received for this study.

Thanks

The authors declare that there is no acknowledgment.

Diffüz ve limitli arasında: sistemik skleroz–çakışma sendromlarının kendine özgü kimliği

Abstract

Amaç: Sistemik skleroz–Çakışma Sendromu (SSk-ÇS), sistemik skleroz spektrumu içinde, klasik alt tiplerden ayıran özgün immünolojik ve klinik özelliklerle karakterize ayrı bir klinik fenotip oluşturmaktadır. Bu çalışmanın amacı, SSk-ÇS hastalarının demografik, serolojik ve organ tutulum paternlerini tanımlamak ve bunların klinik yansımalarını ve prognostik seyirlerini diffüz kutanöz ve limitli kutanöz SSk ile karşılaştırmaktır.

Yöntem: Bu çalışmaya Ocak 2010–Temmuz 2025 tarihleri arasında Gazi Üniversitesi Tıp Fakültesi Romatoloji Anabilim Dalı’nda takip edilen hastalar dahil edildi. SSK-ÇS, sistemik skleroz sınıflama kriterleri ile birlikte romatoid artrit, polimiyozit veya Sjögren sendromu gibi diğer otoimmün hastalıkların kriterlerini de karşılayan hastalar olarak tanımlandı. Başlangıç ve 1. yıl özellikleri SSk ve SSk-ÇS grupları arasında karşılaştırıldı.

Bulgular: Çalışmaya toplam 160 hasta dahil edildi: 68 diffüz kutanöz (dkSSk), 67 limitli kutanöz (lkSSk) ve 25 SSk-ÇS. Hastalık başlangıç yaşı dkSSk’de (42,5 ± 13,7 yıl), lkSSk (50,6 ± 13,7) ve SSk-ÇS’e (47,2 ± 13,9) kıyasla daha düşüktü (p = 0,003). Anti-topoizomeraz I pozitifliği dkSSk’de (%83,8), lkSSk (%43,3) ve SSk-ÇS’e (%16) kıyasla daha yüksekti (p = 0,001); anti-sentromer en sık lkSSk’de (%41,8; p = 0,001) ve anti-SSa antikoru en sık SSk-ÇS’da (%44; p = 0,002) görüldü. İnterstisyel akciğer hastalığı (İAH), dkSSk’de %89,7, SSk-ÇS’da %76 ve lkSSk’de %56,7 oranında görüldü (p = 0,001); yaygın tutulum dkSSk’de (%61,7) daha sıktı (p = 0,001). Miyopati, SSk-ÇS (%44) ve dkSSk’de (%35,3) lkSSk’ye (%12,1) göre daha yüksekti (p = 0,001). İmmünsüpresif tedavi dkSSk’de (%88,2) lkSSk (%35,8) ve SSk-ÇS’a (%60) göre daha sık kullanıldı (p = 0,001). Birinci yılda, SSk-ÇS hastaları FVC ve DLco’da daha büyük iyileşme gösterdi ancak bu fark istatistiksel olarak anlamlı değildi. Mortalitenin dağılımı dkSSk’de %25, lkSSk’de %14,9 ve SSk-ÇS’da %8 idi (p = 0,113); Kaplan–Meier analizi SSk-ÇS’de (ortalama 25,3 yıl) lkSSk (19,8 yıl) ve dkSSk’ye (19,5 yıl) kıyasla daha iyi sağkalımı göstermesine rağmen fark istatistiksel olarak anlamlı değildi (log-rank p = 0,249).

Sonuç: Bu çalışmada hastaların %15,6’sında SSk-ÇS saptandı, en sık SSk–Sjögren’s alt tipi görüldü. Özgün otoantikor profilleri ve belirgin kas-iskelet tutulumları SSk-ÇS’u klasik alt tiplerden ayırdı. dkSSk en yüksek İAH yükü ile ilişkiliyken, lkSSk pulmoner arteriyel hipertansiyon ile ilişkili bulundu. SSk-ÇS ise orta düzeyde pulmoner tutulum ve sayısal olarak daha iyi sağkalım gösterdi; bu da SSk spektrumu içinde klinik olarak ayrı bir fenotip olarak tanınmasını desteklemektedir.

Keywords

çakışma sendromları , ölüm , prognoz , sistemik sklerozis

Ethical Statement

Bu çalışma için etik kurul onayı 22 Ekim 2024 tarihinde Gazi Üniversitesi Etik Komisyon' dan alınmıştır.

Supporting Institution

Bu çalışmayı destekleyen herhangi bir kurum bulunmamaktadır.

Thanks

Yazarların teşekkür beyanı yoktur.

References

• Denton CP, Khanna D. Systemic sclerosis. Lancet Lond Engl. 2017; 390(10103):1685-1699. doi:10.1016/S0140-6736(17)30933-9
• LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988; 15(2):202-205.
• Jantarat A, Muangchan C. Epidemiology and clinical characteristics of systemic sclerosis overlap syndrome (SSc-OS), and the factors significantly associated with SSc-OS in Thai patients with systemic sclerosis. Mod Rheumatol. 2022;32(5):899-907. doi:10.1093/mr/roab079
• Moinzadeh P, Bonella F, Oberste M, et al. Impact of systemic sclerosis-associated interstitial lung disease with and without pulmonary hypertension on survival: a large cohort study of the German network for systemic sclerosis. Chest. 2024;165(1):132-145. doi:10.1016/j.chest. 2023.08.013
• Hunzelmann N, Genth E, Krieg T, et al. The registry of the German network for systemic scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatol Oxf Engl. 2008;47(8):1185-1192. doi:10.1093/rheumatology/ken179
• Pakozdi A, Nihtyanova S, Moinzadeh P, Ong VH, Black CM, Denton CP. Clinical and serological hallmarks of systemic sclerosis overlap syndromes. J Rheumatol. 2011;38(11):2406-2409. doi:10.3899/jrheum. 101248
• Caramaschi P, Biasi D, Caimmi C, et al. Adherence to recommendations for cervical and breast cancer screening in systemic sclerosis. Reumatismo. 2015;66(4):264-269. doi:10.4081/reumatismo.2014.794
• Scherlinger M, Lutz J, Galli G, et al. Systemic sclerosis overlap and non-overlap syndromes share clinical characteristics but differ in prognosis and treatments. Semin Arthritis Rheum. 2021;51(1):36-42. doi:10.1016/j.semarthrit.2020.10.009
• Shenavandeh S, Azariyon Z, Nazarinia MA. Scleroderma-overlap syndromes: capillaroscopy, laboratory, and clinical manifestations and follow-up compared to scleroderma patients. Reumatologia. 2023;61(6): 448-459. doi:10.5114/reum/175508
• Balbir-Gurman A, Braun-Moscovici Y. Scleroderma overlap syndrome. Isr Med Assoc J IMAJ. 2011;13(1):14-20.
• Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980;23(5):581-590. doi:10.1002/art. 1780230510
• van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747-1755. doi:10.1136/annrheumdis-2013-204424
• Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. doi:10.1002/art.27584
• Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for primary sjögren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol Hoboken NJ. 2017;69(1):35-45. doi:10.1002/art.39859
• Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78(9):1151-1159. doi:10.1136/annrheumdis-2018-214819
• Lundberg IE, Tjärnlund A, Bottai M, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. 2017;76(12):1955-1964. doi:10. 1136/annrheumdis-2017-211468
• Goh NSL, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008;177(11):1248-1254. doi:10.1164/rccm.200706-877OC
• Foocharoen C, Pussadhamma B, Mahakkanukrauh A, Suwannaroj S, Nanagara R. Asymptomatic cardiac involvement in Thai systemic sclerosis: prevalence and clinical correlations with non-cardiac manifestations (preliminary report). Rheumatol Oxf Engl. 2015;54(9): 1616-1621. doi:10.1093/rheumatology/kev096