Top

Clinical Rheumatology

Published in:

02-02-2024 | Systemic Sclerosis | ORIGINAL ARTICLE

Digital gangrene in systemic sclerosis patients: not only due to the microvascular disease

Authors: Min Hui, Jiaxin Zhou, Mengtao Li, Qian Wang, Jiuliang Zhao, Yong Hou, Dong Xu, Xiaofeng Zeng

Published in: Clinical Rheumatology | Issue 3/2024

Abstract

Objective

This study aims to investigate the characteristics, risk factors, and outcomes of digital gangrenes in SSc patients, and to identify whether vasculitis is one of the causes for digital gangrene.

Methods

A retrospective case–control study was performed from February 2003 to April 2021. Forty-three SSc patients with digital gangrene admitted to Peking Union Medical College Hospital were included. One-hundred forty-six age- and sex-matched SSc patients without gangrene were selected as controls during the same period. Univariate and multivariate logistic regression analysis was used to determine risk factors.

Results

Among 43 SSc patients with gangrene, 93.0% had Raynaud’s phenomenon (RP) and 32.6% had current or previous digital ulcers (DU). SSc patients with digital gangrene had more ESR elevation (54.8% vs. 34.9%, p = 0.020) and higher level of high-sensitive C reactive protein (median 7.2 mg/L vs. 1.8 mg/L, p = 0.045) compared with controls. In the multivariable logistic regression analysis, smoking history (OR 4.119, p = 0.037), anti-centromere antibody positivity (OR 3.542, p = 0.016), anti-neutrophil cytoplasmic antibody positivity (OR 22.605, p = 0.037), and anti-phospholipid antibody positivity (OR 16.563, p = 0.001), as well as elevated ESR (OR 2.524, p = 0.038) were identified as independent risk factors for gangrenes. Most (79.1%) cases were treated with combination of immunosuppressive and vasodilating therapy, and four cases also got remised after treatment of only glucocorticoid and immunosuppressive agent.

Conclusion

Smoking history; positive-ACA, ANCA, and anti-phospholipid antibodies; and increased ESR were independent risk factors for digital gangrenes in SSc. Vasculitis and macrovascular disease may contribute to the progression of digital gangrenes.

Key Points

•18.6% of SSc patients with digital gangrene had macrovascular stenosis.

•Smoking, positive-ACA, ANCA, aPL, and increased ESR were indicators for digital gangrenes in SSc.

•Vasculitis and macrovascular disease may involve in the pathogenesis.

Available only for authorised users

Hughes M, Herrick AL (2019) Systemic sclerosis. Br J Hosp Med (London) 80(9):530–536. https://doi.org/10.12968/hmed.2019.80.9.530CrossRef

Cutolo M, Soldano S, Smith V (2019) Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol 15(7):753–764. https://doi.org/10.1080/1744666X.2019.1614915CrossRefPubMed

Amanzi LBF, 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 (Oxford) 49(7):1374–1382. https://doi.org/10.1093/rheumatology/keq097CrossRefPubMed

Mihai C, Distler O, Gheorghiu AM, Constantin PI, Dobrota R, Jordan S, Smith V, Hachulla E, Henes J, Siegert E, Vettori S, Müller-Ladner U, Matucci Cerinic M, Allanore Y (2020) Incidence and risk factors for gangrene in patients with systemic sclerosis from the EUSTAR cohort. Rheumatology (Oxford) 59(8):2016–2023. https://doi.org/10.1093/rheumatology/kez558CrossRefPubMed

Liu AZW, Tian X, Zhang X, Zhang F, Zeng X (2009) Prevalence, risk factors and outcome of digital gangrene in 2684 lupus patients. Lupus 18(12):1112–1118. https://doi.org/10.1177/0961203309106643CrossRefPubMed

van den Hoogen FKD, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthr Rheumatol 65(11):2737–2747. https://doi.org/10.1002/art.38098CrossRef

Buttolph A, Sapra A (2021) Gangrene. BTI - StatPearls

LeRoy ECMTJ (2001) Criteria for the classification of early systemic sclerosis. J Rheumatol 28(7):1573–1576PubMed

Galiè NHM, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, VonkNoordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, ESC Scientific Document Group (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119. https://doi.org/10.1093/eurheartj/ehv317CrossRefPubMed

10.

Allanore Y, Denton CP, Krieg T, Cornelisse P, Rosenberg D, Schwierin B, Matucci-Cerinic M (2016) Clinical characteristics and predictors of gangrene in patients with systemic sclerosis and digital ulcers in the Digital Ulcer Outcome Registry: a prospective, observational cohort. Ann Rheum Dis 75(9):1736–1740. https://doi.org/10.1136/annrheumdis-2016-209481CrossRefPubMed

11.

Hachulla ECP, Launay D, Lambert M, Morell-Dubois S, Queyrel V, Hatron PY (2007) Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J Rheumatol 34(12):2423–2430PubMed

12.

Herrick A (2008) Diagnosis and management of scleroderma peripheral vascular disease. Rheum Dis Clin North Am 34(1):89–114. https://doi.org/10.1016/j.rdc.2007.11.006CrossRefPubMed

13.

Nussinovitch U, Shoenfeld Y (2011) Atherosclerosis and macrovascular involvement in systemic sclerosis: myth or reality. Autoimmun Rev 10(5):259–266. https://doi.org/10.1016/j.autrev.2010.09.014CrossRefPubMed

14.

Nordin AJ-UK, Björnådal L, Pettersson S, Larsson A, Svenungsson E (2013) Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study. Arthritis Res Ther 15(4):R87. https://doi.org/10.1186/ar4267CrossRefPubMedPubMedCentral

15.

Mostmans Y, Cutolo M, Giddelo C, Decuman S, Melsens K, Declercq H, Vandecasteele E, De Keyser F, Distler O, Gutermuth J, Smith V (2017) The role of endothelial cells in the vasculopathy of systemic sclerosis: a systematic review. Autoimmun Rev 16(8):774–786. https://doi.org/10.1016/j.autrev.2017.05.024CrossRefPubMed

16.

Hashimoto TST, Yokozeki H (2018) Toe gangrene associated with macroangiopathy in systemic sclerosis: a case series on the unreliability of the ankle-brachial pressure index. Acta Derm Venereol 98(5):532–533. https://doi.org/10.2340/00015555-2897CrossRefPubMed

17.

Bohelay GBS, Levy P, Claeys A, Baudot N, Cuny JF, Maillard H, Granel-Brocard F, Boyé T, Lok C, Bénéton N, Francès C, Senet P (2018) Lower-limb ulcers in systemic sclerosis: a multicentre retrospective case-control study. Acta Derm Venereol 98(7):677–682. https://doi.org/10.2340/00015555-2939CrossRefPubMed

18.

Rosato EGA, Barbano B, Cianci R, Molinaro I, Pisarri S, Salsano F (2011) In systemic sclerosis macrovascular damage of hands digital arteries correlates with microvascular damage. Microvasc Res 82(3):410–415. https://doi.org/10.1016/j.mvr.2011.07.009CrossRefPubMed

19.

Amanzi L BF, 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 (Oxford) 49 (7). https://doi.org/10.1093/rheumatology/keq097

20.

Harrison BJSA, Hider SL, Herrick AL (2002) Cigarette smoking as a significant risk factor for digital vascular disease in patients with systemic sclerosis. Arthritis Rheum 46(12):3312–3316. https://doi.org/10.1002/art.10685CrossRefPubMed

21.

Elneihoum AMFP, Hedblad B, Lindgärde F, Ohlsson K (1997) Leukocyte activation in atherosclerosis: correlation with risk factors. Atherosclerosis 131(1):79–84. https://doi.org/10.1016/s0021-9150(96)06077-7CrossRefPubMed

22.

Powell JT (1998) Vascular damage from smoking: disease mechanisms at the arterial wall. Vasc Med 3(1):21–28. https://doi.org/10.1177/1358836X9800300105CrossRefPubMed

23.

Herrick ALMCM (2001) The emerging problem of oxidative stress and the role of antioxidants in systemic sclerosis. Clin Exp Rheumatol 19(1):4–8PubMed

24.

Caramaschi PBD, Caimmi C, Barausse G, Sabbagh D, Tinazzi I, LA Verde V, Tonetta S, Adami S (2012) Digital amputation in systemic sclerosis: prevalence and clinical associations. A retrospective longitudinal study. J Rheumatol 39(8):1648–1653. https://doi.org/10.3899/jrheum.111506CrossRefPubMed

25.

Wigley FMWR, Miller R, Needleman BW, Spence RJ (1992) Anticentromere antibody as a predictor of digital ischemic loss in patients with systemic sclerosis. Arthritis Rheum 35(6):688–693. https://doi.org/10.1002/art.1780350614CrossRefPubMed

26.

Herrick ALHM, Hollis S, Jayson MI (1994) Anticardiolipin, anticentromere and anti-Scl-70 antibodies in patients with systemic sclerosis and severe digital ischaemia. Ann Rheum Dis 53(8):540–542. https://doi.org/10.1136/ard.53.8.540CrossRefPubMedPubMedCentral

27.

Wig S, Wilkinson J, Moore T, Manning J, Chevance A, Vail A, Herrick AL (2014) A longitudinal study of ankle brachial pressure indices in a cohort of patients with systemic sclerosis. Rheumatology (Oxford) 53(11):2009–2013. https://doi.org/10.1093/rheumatology/keu227CrossRefPubMed

28.

Ahmed SSTF, Arnett FC, Jin L, Geng YJ (2006) Induction of apoptosis and fibrillin 1 expression in human dermal endothelial cells by scleroderma sera containing anti-endothelial cell antibodies. Arthritis Rheum 54(7):2250–2262. https://doi.org/10.1002/art.21952CrossRefPubMed

29.

Merashli M, Alves J, Ames PRJ (2017) Clinical relevance of antiphospholipid antibodies in systemic sclerosis: a systematic review and meta-analysis. Semin Arthritis Rheum 46(5):615–624. https://doi.org/10.1016/j.semarthrit.2016.10.004CrossRefPubMed

30.

Altorok NWY, Kahaleh B (2014) Endothelial dysfunction in systemic sclerosis. Curr Opin Rheumatol 26(6):615–620. https://doi.org/10.1097/BOR.0000000000000112CrossRefPubMed

31.

Marie IJF, Hellot MF, Levesque H (2008) Anticardiolipin and anti-beta2 glycoprotein I antibodies and lupus-like anticoagulant: prevalence and significance in systemic sclerosis. Br J Dermatol 158(1):141–144. https://doi.org/10.1111/j.1365-2133.2007.08309.xCrossRefPubMed

32.

Ames PR (2009) Antiphospholipid antibodies in systemic sclerosis: a double oxidative hit? Clin Rheumatol 28(8):881–882. https://doi.org/10.1007/s10067-009-1210-3CrossRefPubMed

33.

Rampling MW, Meiselman HJ, Fau-Neu B, Neu B, Fau-Baskurt OK, Baskurt OK (2011) Influence of cell-specific factors on red blood cell aggregation. Biorheology 41(2):91–112

34.

Picart C CP, Galliard H, Piau JM (1999) Blood yield stress in systemic sclerosis. Am J Physiol 276(2):H771–777

35.

Korsten PA-O, Niewold TA-O, Zeisberg M, Utset TO, Cho D, Zachary LS, Sweiss NJ, Volkov S (2017) Increased whole blood viscosity is associated with the presence of digital ulcers in systemic sclerosis: results from a cross-sectional pilot study. Autoimmune Dis 2017:3529214PubMedPubMedCentral

36.

de Simone GDR, Chien S, Alderman MH, Atlas SA, Laragh JH (1990) Relation of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 81(1):107–117CrossRefPubMed

37.

Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, Distler O, Clements P, Cutolo M, Czirjak L, Damjanov N, Del Galdo F, Denton CP, Distler JHW, Foeldvari I, Figelstone K, Frerix M, Furst DE, Guiducci S, Hunzelmann N, Khanna D, Matucci-Cerinic M, Herrick AL, van den Hoogen F, van Laar JM, Riemekasten G, Silver R, Smith V, Sulli A, Tarner I, Tyndall A, Welling J, Wigley F, Valentini G, Walker UA, Zulian F, Müller-Ladner U (2017) Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 76(8):1327–1339. https://doi.org/10.1136/annrheumdis-2016-209909CrossRefPubMed

38.

Abraham S, Steen V (2015) Optimal management of digital ulcers in systemic sclerosis. Ther Clin Risk Manag 15(11):939–947. https://doi.org/10.2147/TCRM.S82561CrossRef

39.

Starnoni M, Pappalardo M, Spinella A, Testoni S, Lattanzi M, Feminò R, De Santis G, Salvarani C, Giuggioli D (2021) Systemic sclerosis cutaneous expression: management of skin fibrosis and digital ulcers. Ann Med Surg (Lond) 2(71):102984. https://doi.org/10.1016/j.amsu.2021.102984CrossRef

40.

García de la Peña-Lefebvre PRRS, Valero Expósito M, Carmona L, Gámir Gámir ML, Beltrán Gutiérrez J, Díaz-Miguel C, Orte Martínez J, Zea Mendoza AC (2008) Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis patients. Rheumatology (Oxford) 47(4):464–466. https://doi.org/10.1093/rheumatology/ken001CrossRefPubMed

41.

Steen VDC, Pope JE, Matucci-Cerinic M (2009) Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology (Oxford) 48(Suppl 3):19–24. https://doi.org/10.1093/rheumatology/kep105CrossRef

42.

Youssef PBT, Englert H, Bertouch J (1995) Limited scleroderma is associated with increased prevalence of macrovascular disease. J Rheumatol 22(3):469–472PubMed

43.

Herrick ALOP, Freemont AJ, Marcuson R, Haeney M, Jayson MI (1994) Vasculitis in patients with systemic sclerosis and severe digital ischaemia requiring amputation. Ann Rheum Dis 53(5):323–326. https://doi.org/10.1136/ard.53.5.323CrossRefPubMedPubMedCentral

Title: Digital gangrene in systemic sclerosis patients: not only due to the microvascular disease
Authors: Min Hui
Jiaxin Zhou
Mengtao Li
Qian Wang
Jiuliang Zhao
Yong Hou
Dong Xu
Xiaofeng Zeng
Publication date: 02-02-2024
Publisher: Springer International Publishing
Keywords: Systemic Sclerosis
Vasculitis
Vasculitis
Published in: Clinical Rheumatology / Issue 3/2024
Print ISSN: 0770-3198
Electronic ISSN: 1434-9949
DOI: https://doi.org/10.1007/s10067-024-06886-8

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2024

Risk of gout flare after medication: prescription symmetry sequence analysis

Impact of subcutaneous belimumab on disease activity, patient satisfaction, and metabolic profile in long-lasting systemic lupus erythematosus

Effects of disease-modifying anti-rheumatic drugs on sacroiliac MRI score in axial spondyloarthritis: a systematic review and meta-analysis

Association between anthropometric indices and hyperuricemia: a nationwide study in China

Correction to: What is the association of depression with clinical response to therapy in patients with psoriatic arthritis treated with biologic disease-modifying antirheumatic drugs?

Why is polymyalgia rheumatica a disease of older adults? Explanations through etiology and pathogenesis: a narrative review

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials