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  • Review Article
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Raynaud phenomenon and digital ulcers in systemic sclerosis

Nature Reviews Rheumatology volume 16, pages 208–221 (2020)Cite this article

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An Author Correction to this article was published on 09 March 2021

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Abstract

Raynaud phenomenon is a symptom complex caused by impaired digital perfusion and can occur as a primary phenomenon or secondary to a wide range of underlying causes. Raynaud phenomenon occurs in virtually all patients with systemic sclerosis (SSc) and is often the earliest clinical manifestation to occur. Careful assessment is required in patients with Raynaud phenomenon to avoid missing secondary causes such as SSc. Digital ulcers are a painful and disabling visible manifestation of digital vascular injury in patients with SSc. Progress has been made in the classification and assessment of digital ulcers and in understanding ulcer pathogenesis, and there are a wide range of treatments available to both prevent and heal digital ulcers, some of which are also used in Raynaud phenomenon management. In this Review, the assessment of patients with Raynaud phenomenon is discussed, including ‘red flags’ that are suggestive of SSc. The pathogenesis, classification and assessment of SSc-associated digital ulcers are also covered, alongside an overview of management approaches for SSc-associated Raynaud phenomenon and digital ulcers. Finally, unmet needs are discussed and the concept of a unified vascular phenotype in which therapies that affect the vasculature to support disease modification strategies is introduced.

Key points

  • Vascular injury and Raynaud phenomenon are the earliest manifestations of systemic sclerosis (SSc).

  • Patients with Raynaud phenomenon need careful assessment to identify secondary causes such as SSc using investigations including nailfold capillaroscopy and autoantibody detection.

  • Raynaud phenomenon and ischaemic complications such as digital ulcers are the main causes of disease-related morbidity in patients with SSc.

  • The classification and assessment of digital ulcers can be challenging, although progress has been made in understanding the pathogenesis of ulcers, in improving patient experiences and in ulcer definition.

  • A number of treatments are available to both prevent and heal digital ulcers, including vasoactive drug therapies and ulcer debridement.

  • The concept of a unified vascular diagnosis could herald the onset of a potential disease-modifying effect in SSc of therapies that affect the vasculature.

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Fig. 1: Clinical presentation of Raynaud phenomenon.
Fig. 2: Clinical presentation of digital ulcers in systemic sclerosis.
Fig. 3: The pathogenesis of systemic sclerosis-associated digital ulcers.
Fig. 4: The heterogeneity of lower-limb cutaneous ulcer disease in SSc.
Fig. 5: Non-invasive imaging in the assessment of digital vasculopathy.
Fig. 6: Management of Raynaud phenomenon and digital ulcers in systemic sclerosis.

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References

  1. Katsumoto, T. R. & Whitfield, M. L. The pathogenesis of systemic sclerosis. Annu. Rev. Pathol. 6, 509–537 (2011).

    CAS  PubMed  Google Scholar 

  2. Denton, C. P. & Khanna, D. K. Systemic sclerosis. Lancet 390, 1685–1699 (2017).

    PubMed  Google Scholar 

  3. Meier, F. M. P. et al. Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database. Ann. Rheum. Dis. 71, 1355–1360 (2012).

    PubMed  Google Scholar 

  4. Merkel, P. A. et al. Measuring disease activity and functional status in patients with scleroderma and Raynaud’s phenomenon. Arthritis Rheum. 46, 2410–2420 (2002).

    PubMed  Google Scholar 

  5. LeRoy, E. C. et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J. Rheumatol. 15, 202–205 (1988).

    CAS  PubMed  Google Scholar 

  6. Hughes, M. & Herrick, A. L. Digital ulcers in systemic sclerosis. Rheumatology 56, 14–25 (2017).

    CAS  PubMed  Google Scholar 

  7. Hachulla, E. et al. Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J. Rheumatol. 34, 2423–2430 (2007).

    PubMed  Google Scholar 

  8. Steen, V., Denton, C. P., Pope, J. E. & Matucci-Cerinic, M. Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology 48 (Suppl. 3), iii19–iii24 (2009).

    PubMed  Google Scholar 

  9. Tiev, K. P. et al. Clinical features of scleroderma patients with or without prior or current ischemic digital ulcers: post-hoc analysis of a nationwide multicenter cohort (ItinérAIR-Sclérodermie). J. Rheumatol. 36, 1470–1476 (2009).

    PubMed  Google Scholar 

  10. Khimdas, S. et al. Associations with digital ulcers in a large cohort of systemic sclerosis: results from the Canadian Scleroderma Research Group registry. Arthritis Care Res. 63, 142–149 (2011).

    Google Scholar 

  11. Ennis, H. et al. A prospective study of systemic sclerosis-related digital ulcers: prevalence, location, and functional impact. Scand. J. Rheumatol. 42, 483–486 (2013).

    CAS  PubMed  Google Scholar 

  12. Wirz, E. G. et al. Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database. Ann. Rheum. Dis. 75, 1285–1292 (2015).

    PubMed  Google Scholar 

  13. Lambova, S., Batalov, A., Sapundzhiev, L. & Müller-Ladner, U. Digital ulcers in systemic sclerosis - frequency, subtype distribution and clinical outcome. Curr. Rheumatol. Rev. 9, 268–273 (2013).

    PubMed  Google Scholar 

  14. Caramaschi, P. et al. A score of risk factors associated with ischemic digital ulcers in patients affected by systemic sclerosis treated with iloprost. Clin. Rheumatol. 28, 807–813 (2009).

    PubMed  Google Scholar 

  15. Amanzi, L. et al. Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatology 49, 1374–1382 (2010).

    PubMed  Google Scholar 

  16. Matucci-Cerinic, M. et al. Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO registry. Ann. Rheum. Dis. 75, 1770–1776 (2016).

    CAS  PubMed  Google Scholar 

  17. Pauling, J. D., Hughes, M. & Pope, J. E. Raynaud’s phenomenon - an update on diagnosis, classification and management. Clin. Rheumatol. 38, 3317–3330 (2019).

    PubMed  Google Scholar 

  18. Pauling, J. D., Reilly, E., Smith, T. & Frech, T. M. Evolving symptoms of Raynaud’s phenomenon in systemic sclerosis are associated with physician and patient-reported assessments of disease severity. Arthritis Care Res. 71, 1119–1126 (2019).

    Google Scholar 

  19. Pauling, J. D., Reilly, E., Smith, T. & Frech, T. M. Factors influencing Raynaud’s condition score diary outcomes in systemic sclerosis. J. Rheumatol. 46, 1326–1334 (2019).

    PubMed  Google Scholar 

  20. LeRoy, E. C. & Medsger, T. A. Raynaud’s phenomenon: a proposal for classification. Clin. Exp. Rheumatol. 10, 485–488 (1992).

    CAS  PubMed  Google Scholar 

  21. Brennan, P. et al. Validity and reliability of three methods used in the diagnosis of Raynaud’s phenomenon. The UK Scleroderma Study Group. Br. J. Rheumatol. 32, 357–361 (1993).

    CAS  PubMed  Google Scholar 

  22. Maricq, H. R. & Weinrich, M. C. Diagnosis of Raynaud’s phenomenon assisted by color charts. J. Rheumatol. 15, 454–459 (1988).

    CAS  PubMed  Google Scholar 

  23. Wigley, F. M. Raynaud’s phenomenon. N. Engl. J. Med. 347, 1001–1008 (2002).

    PubMed  Google Scholar 

  24. Maverakis, E. et al. International consensus criteria for the diagnosis of Raynaud’s phenomenon. J. Autoimmun. 48–49, 60–65 (2014).

    PubMed  Google Scholar 

  25. Nihtyanova, S. I., Brough, G. M., Black, C. M. & Denton, C. P. Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann. Rheum. Dis. 67, 120–123 (2008).

    CAS  PubMed  Google Scholar 

  26. Mihai, C. et al. Incidence and risk factors for gangrene in patients with systemic sclerosis from the EUSTAR cohort. Rheumatology https://doi.org/10.1093/rheumatology/kez558 (2019).

    Article  Google Scholar 

  27. Mouthon, L. et al. Ischemic digital ulcers affect hand disability and pain in systemic sclerosis. J. Rheumatol. 41, 1317–1323 (2014).

    PubMed  Google Scholar 

  28. Guillevin, L. et al. Functional impairment of systemic scleroderma patients with digital ulcerations: results from the DUO registry. Clin. Exp. Rheumatol. 31, 71–80 (2013).

    PubMed  Google Scholar 

  29. Mouthon, L. et al. Impact of digital ulcers on disability and health-related quality of life in systemic sclerosis. Ann. Rheum. Dis. 69, 214–217 (2010).

    CAS  PubMed  Google Scholar 

  30. Bérezné, A. et al. Impact of systemic sclerosis on occupational and professional activity with attention to patients with digital ulcers. Arthritis Care Res. 63, 277–285 (2011).

    Google Scholar 

  31. Brand, M. et al. An observational cohort study of patients with newly diagnosed digital ulcer disease secondary to systemic sclerosis registered in the EUSTAR database. Clin. Exp. Rheumatol. 33, S47–S54 (2015).

    PubMed  Google Scholar 

  32. Cozzi, F. et al. The social costs of digital ulcer management in sclerodema patients: an observational Italian pilot study. Joint Bone Spine 77, 83–84 (2010).

    PubMed  Google Scholar 

  33. Giuggioli, D., Manfredi, A., Colaci, M., Lumetti, F. & Ferri, C. Scleroderma digital ulcers complicated by infection with fecal pathogens. Arthritis Care Res. 64, 295–297 (2012).

    Google Scholar 

  34. Giuggioli, D., Manfredi, A., Colaci, M., Lumetti, F. & Ferri, C. Osteomyelitis complicating scleroderma digital ulcers. Clin. Rheumatol. 32, 623–627 (2013).

    PubMed  Google Scholar 

  35. Barsotti, S. et al. Is there a role for laser speckle contrast analysis (LASCA) in predicting the outcome of digital ulcers in patients with systemic sclerosis? Clin. Rheumatol. 39, 69–75 (2020).

    PubMed  Google Scholar 

  36. Herrick, A. L. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat. Rev. Rheumatol. 8, 469–479 (2012).

    CAS  PubMed  Google Scholar 

  37. Hughes, M., Murray, A., Denton, C. P. & Herrick, A. L. Should all digital ulcers be included in future clinical trials of systemic sclerosis-related digital vasculopathy? Med. Hypotheses 116, 101–104 (2018).

    PubMed  Google Scholar 

  38. Sebastiani, M. et al. Capillaroscopic skin ulcer risk index: a new prognostic tool for digital skin ulcer development in systemic sclerosis patients. Arthritis Rheum. 61, 688–694 (2009).

    CAS  PubMed  Google Scholar 

  39. Sebastiani, M. et al. Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study. Ann. Rheum. Dis. 71, 67–70 (2012).

    CAS  PubMed  Google Scholar 

  40. Smith, V. et al. Do worsening scleroderma capillaroscopic patterns predict future severe organ involvement? A pilot study. Ann. Rheum. Dis. 71, 1636–1639 (2012).

    PubMed  Google Scholar 

  41. Paxton, D. & Pauling, J. D. Does nailfold capillaroscopy help predict future outcomes in systemic sclerosis? A systematic literature review. Semin. Arthritis Rheum. 48, 482–494 (2018).

    PubMed  Google Scholar 

  42. Wan, M. C., Moore, T., Hollis, S. & Herrick, A. L. Ankle brachial pressure index in systemic sclerosis: influence of disease subtype and anticentromere antibody. Rheumatology 40, 1102–1105 (2001).

    CAS  PubMed  Google Scholar 

  43. Wig, S. et al. A longitudinal study of ankle brachial pressure indices in a cohort of patients with systemic sclerosis. Rheumatology 53, 2009–2013 (2014).

    PubMed  Google Scholar 

  44. Manetti, M. et al. Progressive loss of lymphatic vessels in skin of patients with systemic sclerosis. J. Rheumatol. 38, 297–301 (2011).

    PubMed  Google Scholar 

  45. Blagojevic, J. et al. Assessment, definition, and classification of lower limb ulcers in systemic sclerosis: a challenge for the rheumatologist. J. Rheumatol. 43, 592–598 (2016).

    PubMed  Google Scholar 

  46. Avouac, J. et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann. Rheum. Dis. 70, 476–481 (2011).

    CAS  PubMed  Google Scholar 

  47. Koenig, M. et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 58, 3902–3912 (2008).

    PubMed  Google Scholar 

  48. Hughes, M. et al. Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis. Rheumatology 54, 2015–2024 (2015).

    CAS  PubMed  Google Scholar 

  49. Flower, V., Pauling, J. D. & McHugh, N. in Raynaud’s Phenomenon: A Guide to Pathogenesis and Treatment (eds. Wigley, F. M., Herrick, A. L. & Flavahan, N. A.) 253–266 (Springer, 2015).

  50. Pauling, J. D. et al. Presence of anti-eukaryotic initiation factor-2B, anti-RuvBL1/2 and anti-synthetase antibodies in patients with anti-nuclear antibody negative systemic sclerosis. Rheumatology 57, 712–717 (2017).

    Google Scholar 

  51. Ho, K. T. & Reveille, J. D. The clinical relevance of autoantibodies in scleroderma. Arthritis Res. Ther. 5, 80 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ho, M., Veale, D., Eastmond, C., Nuki, G. & Belch, J. Macrovascular disease and systemic sclerosis. Ann. Rheum. Dis. 59, 39–43 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Au, K. et al. Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis. Arthritis Rheum. 63, 2078–2090 (2011).

    PubMed  PubMed Central  Google Scholar 

  54. Park, J. H. et al. Ulnar artery vasculopathy in systemic sclerosis. Rheumatol. Int. 29, 1081–1086 (2009).

    PubMed  Google Scholar 

  55. Frerix, M., Stegbauer, J., Dragun, D., Kreuter, A. & Weiner, S. M. Ulnar artery occlusion is predictive of digital ulcers in SSc: a duplex sonography study. Rheumatology 51, 735–742 (2012).

    PubMed  Google Scholar 

  56. van den Hoogen, F. et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann. Rheum. Dis. 72, 1747–1755 (2013).

    PubMed  Google Scholar 

  57. Cutolo, M. et al. Nailfold videocapillaroscopic features and other clinical risk factors for digital ulcers in systemic sclerosis: a multicenter, prospective cohort study. Arthritis Rheumatol. 68, 2527–2539 (2016).

    PubMed  PubMed Central  Google Scholar 

  58. Baron, M. et al. Office capillaroscopy in systemic sclerosis. Clin. Rheumatol. 26, 1268–1274 (2007).

    PubMed  Google Scholar 

  59. Hughes, M. et al. A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis-spectrum disorders. Rheumatology 54, 1435–1442 (2015).

    PubMed  Google Scholar 

  60. Mihai, C. et al. The emerging application of semi-quantitative and quantitative capillaroscopy in systemic sclerosis. Microvasc. Res. 118, 113–120 (2018).

    PubMed  Google Scholar 

  61. Bernadino, V., Rodrigues, A., Lladó, A. & Panarra, A. Nailfold capillaroscopy and autoimmune connective tissue diseases in patients from a Portuguese nailfold capillaroscopy clinic. Rheumatol. Int. 40, 295–301 (2020).

    Google Scholar 

  62. Cutolo, M., Sulli, A., Pizzorni, C. & Accardo, S. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J. Rheumatol. 27, 155–160 (2000).

    CAS  PubMed  Google Scholar 

  63. Smith, V. et al. Fast track algorithm: how to differentiate a “scleroderma pattern” from a “non-scleroderma pattern”. Autoimmun. Rev. 18, 102394 (2019).

    PubMed  Google Scholar 

  64. Cutolo, M. et al. Peripheral blood perfusion correlates with microvascular abnormalities in systemic sclerosis: a laser-Doppler and nailfold videocapillaroscopy study. J. Rheumatol. 37, 1174–1180 (2010).

    PubMed  Google Scholar 

  65. Ruaro, B. et al. Correlations between skin blood perfusion values and nailfold capillaroscopy scores in systemic sclerosis patients. Microvasc. Res. 105, 119–124 (2016).

    CAS  PubMed  Google Scholar 

  66. Pauling, J. D., Shipley, J. A., Hart, D. J., McGrogan, A. & McHugh, N. J. Use of laser speckle contrast imaging to assess digital microvascular function in primary Raynaud phenomenon and systemic sclerosis: a comparison using the Raynaud Condition Score Diary. J. Rheumatol. 42, 1163–1168 (2015).

    CAS  PubMed  Google Scholar 

  67. Anderson, M. E., Moore, T. L., Lunt, M. & Herrick, A. L. Digital iontophoresis of vasoactive substances as measured by laser Doppler imaging–a non-invasive technique by which to measure microvascular dysfunction in Raynaud’s phenomenon. Rheumatology 43, 986–991 (2004).

    CAS  PubMed  Google Scholar 

  68. Gunawardena, H., Harris, N. D., Carmichael, C. & McHugh, N. J. Maximum blood flow and microvascular regulatory responses in systemic sclerosis. Rheumatology 46, 1079–1082 (2007).

    CAS  PubMed  Google Scholar 

  69. Herrick, A. L. et al. A double-blind, randomized, placebo-controlled crossover trial of the α2C-adrenoceptor antagonist ORM-12741 for prevention of cold-induced vasospasm in patients with systemic sclerosis. Rheumatology 53, 948–952 (2014).

    CAS  PubMed  Google Scholar 

  70. Hummers, L. K. et al. A multi-centre, blinded, randomised, placebo-controlled, laboratory-based study of MQX-503, a novel topical gel formulation of nitroglycerine, in patients with Raynaud phenomenon. Ann. Rheum. Dis. 72, 1962–1967 (2013).

    CAS  PubMed  Google Scholar 

  71. Cutolo, M. et al. Is laser speckle contrast analysis (LASCA) the new kid on the block in systemic sclerosis? A systematic literature review and pilot study to evaluate reliability of LASCA to measure peripheral blood perfusion in scleroderma patients. Autoimmun. Rev. 17, 775–780 (2018).

    PubMed  Google Scholar 

  72. Wilkinson, J. D. et al. A multicenter study of the validity and reliability of responses to hand cold challenge as measured by laser speckle contrast imaging and thermography: outcome measures for systemic sclerosis-related Raynaud’s phenomenon. Arthritis Rheumatol. 70, 903–911 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. Melsens, K. et al. The preliminary validation of laser Doppler flowmetry in systemic sclerosis in accordance with the OMERACT filter: a systematic review. Semin. Arthritis Rheum. https://doi.org/10.1016/j.semarthrit.2019.08.007 (2019).

    Article  PubMed  Google Scholar 

  74. Dinsdale, G. & Herrick, A. L. Vascular diagnostics for Raynaud’s phenomenon. J. Vasc. Diagn. 2, 127–139 (2014).

    Google Scholar 

  75. Pauling, J. D., Flower, V., Shipley, J. A., Harris, N. D. & McHugh, N. J. Influence of the cold challenge on the discriminatory capacity of the digital distal-dorsal difference in the thermographic assessment of Raynaud’s phenomenon. Microvasc. Res. 82, 364–368 (2011).

    CAS  PubMed  Google Scholar 

  76. Anderson, M. E., Moore, T. L., Lunt, M. & Herrick, A. L. The ‘distal-dorsal difference’: a thermographic parameter by which to differentiate between primary and secondary Raynaud’s phenomenon. Rheumatology 46, 533–538 (2007).

    CAS  PubMed  Google Scholar 

  77. Pauling, J. & Murray, A. in Raynaud’s Phenomenon: A Guide to Pathogenesis and Treatment (eds. Wigley, F. M., Herrick, A. L. & Flavahan, N. A.) 199–242 (Springer, 2015).

  78. Lüders, S. et al. Detection of severe digital vasculopathy in systemic sclerosis by colour Doppler sonography is associated with digital ulcers. Rheumatology 56, 1865–1873 (2017).

    PubMed  Google Scholar 

  79. Lescoat, A. et al. Vascular evaluation of the hand by power doppler ultrasonography and new predictive markers of ischemic digital ulcers in systemic sclerosis: results of a prospective pilot study. Arthritis Care Res. 69, 543–551 (2017).

    Google Scholar 

  80. Allanore, Y., Drappe, J.-L. & Reifsnyder, T. in Raynaud’s Phenomenon: A Guide to Pathogenesis and Treatment (eds. Wigley, F. M., Herrick, A. L. & Flavahan, N. A.) 243–252 (Springer, 2015).

  81. Bruni, C. et al. Preliminary validation of the digital ulcer clinical assessment score in systemic sclerosis. J. Rheumatol. 46, 603–608 (2019).

    PubMed  Google Scholar 

  82. Blagojevic, J. et al. Classification, categorization and essential items for digital ulcer evaluation in systemic sclerosis: a DeSScipher/European Scleroderma Trials and Research group (EUSTAR) survey. Arthritis Res. Ther. 21, 35 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Dinsdale, G. et al. Tracking digital ulcers in systemic sclerosis: a feasibility study assessing lesion area in patient-recorded smartphone photographs. Ann. Rheum. Dis. 77, 1382–1384 (2018).

    PubMed  Google Scholar 

  84. Simpson, V., Hughes, M., Wilkinson, J., Herrick, A. L. & Dinsdale, G. Quantifying digital ulcers in systemic sclerosis: reliability of digital planimetry in measuring lesion size. Arthritis Care Res. 70, 486–490 (2018).

    CAS  Google Scholar 

  85. Hughes, M. et al. A pilot study using high-frequency ultrasound to measure digital ulcers: a possible outcome measure in systemic sclerosis clinical trials? Clin. Exp. Rheumatol. 35, 218–219 (2017).

    PubMed  Google Scholar 

  86. Suliman, Y. A. et al. Ultrasound characterization of cutaneous ulcers in systemic sclerosis. Clin. Rheumatol. 37, 1555–1561 (2018).

    PubMed  Google Scholar 

  87. Hughes, M. Response to ‘Ultrasound characterization of cutaneous ulcers in systemic sclerosis’. Clin. Rheumatol. 37, 2013 (2018).

    PubMed  Google Scholar 

  88. Li, W. & Frech, T. M. The critical need for accurately defining digital ulcers in scleroderma. J. Scleroderma Relat. Disord. 2, 69–71 (2017).

    PubMed  Google Scholar 

  89. Herrick, A. L. et al. Lack of agreement between rheumatologists in defining digital ulceration in systemic sclerosis. Arthritis Rheum. 60, 878–882 (2009).

    PubMed  Google Scholar 

  90. Hughes, M. et al. Does the clinical context improve the reliability of rheumatologists grading digital ulcers in systemic sclerosis? Arthritis Care Res. 68, 1340–1345 (2016).

    CAS  Google Scholar 

  91. Hughes, M. et al. Reliability of digital ulcer definitions as proposed by the UK Scleroderma Study Group: a challenge for clinical trial design. J. Scleroderma Relat. Disord. 3, 170–174 (2018).

    PubMed  PubMed Central  Google Scholar 

  92. Matucci-Cerinic, M. et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 70, 32–38 (2011).

    CAS  PubMed  Google Scholar 

  93. Gliddon, A. E. et al. Prevention of vascular damage in scleroderma and autoimmune Raynaud’s phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum. 56, 3837–3846 (2007).

    CAS  PubMed  Google Scholar 

  94. Hachulla, E. et al. Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study. Ann. Rheum. Dis. 75, 1009–1015 (2016).

    CAS  PubMed  Google Scholar 

  95. Khanna, D. et al. Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: DUAL-1 and DUAL-2 randomized clinical trials. JAMA 315, 1975–1988 (2016).

    CAS  PubMed  Google Scholar 

  96. Seibold, J. R. et al. Digital ulcers in SSc treated with oral treprostinil: a randomized, double-blind, placebo-controlled study with open-label follow-up. J. Scleroderma Relat. Disord. 2, 42–49 (2017).

    Google Scholar 

  97. Suliman, Y. A. et al. Defining skin ulcers in systemic sclerosis: systematic literature review and proposed World Scleroderma Foundation (WSF) definition. J. Scleroderma Relat. Disord. 2, 115–120 (2017).

    CAS  PubMed  Google Scholar 

  98. Harrison, B. J., Silman, A. J., Hider, S. L. & Herrick, A. L. Cigarette smoking as a significant risk factor for digital vascular disease in patients with systemic sclerosis. Arthritis Rheum. 46, 3312–3316 (2002).

    PubMed  Google Scholar 

  99. Jaeger, V. K. et al. Brief report: smoking in systemic sclerosis: a longitudinal European Scleroderma Trials and Research group study. Arthritis Rheumatol. 70, 1829–1834 (2018).

    CAS  PubMed  Google Scholar 

  100. Sharp, C. A., Akram, Q., Hughes, M., Muir, L. & Herrick, A. L. Differential diagnosis of critical digital ischemia in systemic sclerosis: report of five cases and review of the literature. Semin. Arthritis Rheum. 46, 209–216 (2016).

    PubMed  Google Scholar 

  101. Allanore, Y. et al. 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, 1736–1740 (2016).

    PubMed  Google Scholar 

  102. Murphy, S. L. et al. Occupational therapy treatment to improve upper extremity function in individuals with early systemic sclerosis: a pilot study. Arthritis Care Res. 70, 1653–1660 (2018).

    Google Scholar 

  103. Becetti, K. et al. Physical or occupational therapy use in systemic sclerosis: a scleroderma patient-centered intervention network cohort study. J. Rheumatol. 46, 1605–1613 (2019).

    PubMed  Google Scholar 

  104. Lebedoff, N. et al. Review of local wound management for scleroderma-associated digital ulcers. J. Scleroderma Relat. Disord. 3, 66–70 (2017).

    PubMed  PubMed Central  Google Scholar 

  105. Hughes, M. et al. Digital ulcer debridement in systemic sclerosis: a systematic literature review. Clin. Rheumatol. https://doi.org/10.1007/s10067-019-04924-4 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ozgocmen, S., Kaya, A. & Coskun, B. K. Topical lidocaine helps reduce pain of digital ulcers in systemic sclerosis (scleroderma). Clin. Rheumatol. 25, 378–379 (2006).

    PubMed  Google Scholar 

  107. Baron, M., Chung, L., Gyger, G., Hummers, L. & Khanna, D. Consensus opinion of a North American Working Group regarding the classification of digital ulcers in systemic sclerosis. Clin. Rheumatol. 33, 207–214 (2014).

    PubMed  Google Scholar 

  108. Markus, Y. M., Bell, M. J. & Evans, A. W. Ischemic scleroderma wounds successfully treated with hyperbaric oxygen therapy. J. Rheumatol. 33, 1694–1696 (2006).

    PubMed  Google Scholar 

  109. Mirasoglu, B., Bagli, B. S. & Aktas, S. Hyperbaric oxygen therapy for chronic ulcers in systemic sclerosis – case series. Int. J. Dermatol. 56, 636–640 (2017).

    CAS  PubMed  Google Scholar 

  110. Beckett, V. L. et al. Trial of platelet-inhibiting drug in scleroderma. Double-blind study with dipyridamole and aspirin. Arthritis Rheum. 27, 1137–1143 (1984).

    CAS  PubMed  Google Scholar 

  111. Denton, C. P., Howell, K., Stratton, R. J. & Black, C. M. Long-term low molecular weight heparin therapy for severe Raynaud’s phenomenon: a pilot study. Clin. Exp. Rheumatol. 18, 499–502 (2000).

    CAS  PubMed  Google Scholar 

  112. Abou-Raya, A., Abou-Raya, S. & Helmii, M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J. Rheumatol. 35, 1801–1808 (2008).

    CAS  PubMed  Google Scholar 

  113. Rosato, E., Borghese, F., Pisarri, S. & Salsano, F. The treatment with N-acetylcysteine of Raynaud’s phenomenon and ischemic ulcers therapy in sclerodermic patients: a prospective observational study of 50 patients. Clin. Rheumatol. 28, 1379–1384 (2009).

    PubMed  Google Scholar 

  114. Ladak, K. & Pope, J. E. A review of the effects of statins in systemic sclerosis. Semin. Arthritis Rheum. 45, 698–705 (2016).

    CAS  PubMed  Google Scholar 

  115. Hughes, M., Khanna, D. & Pauling, J. D. Drug initiation and escalation strategies of vasodilator therapies for Raynaud’s phenomenon: can we treat to target? Rheumatology https://doi.org/10.1093/rheumatology/kez522 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Tingey, T., Shu, J., Smuczek, J. & Pope, J. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res. 65, 1460–1471 (2013).

    CAS  Google Scholar 

  117. Hughes, M. & Herrick, A. in Novel Insights into Systemic Sclerosis Management. (eds M. Cutolo & V. Smith) 232–241 (Future Medicine, 2013).

  118. Korn, J. H. et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 50, 3985–3993 (2004).

    CAS  PubMed  Google Scholar 

  119. Pauling, J. D., Nagaraja, V. & Khanna, D. Insight into the contrasting findings of therapeutic trials of digital ischaemic manifestations of systemic sclerosis. Curr. Treat. Options Rheumatol. 5, 85–103 (2019).

    Google Scholar 

  120. Wigley, F. M., Seibold, J. R., Wise, R. A., McCloskey, D. A. & Dole, W. P. Intravenous iloprost treatment of Raynaud’s phenomenon and ischemic ulcers secondary to systemic sclerosis. J. Rheumatol. 19, 1407–1414 (1992).

    CAS  PubMed  Google Scholar 

  121. Wigley, F. M. et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann. Intern. Med. 120, 199–206 (1994).

    CAS  PubMed  Google Scholar 

  122. Badesch, D. B. et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann. Intern. Med. 132, 425–434 (2000).

    CAS  PubMed  Google Scholar 

  123. Ambach, A., Seo, W., Bonnekoh, B. & Gollnick, H. Low-dose combination therapy of severe digital ulcers in diffuse progressive systemic sclerosis with the endothelin-1 receptor antagonist bosentan and the phosphodiesterase V inhibitor sildenafil. J. Dtsch. Dermatol. Ges. 7, 888–891 (2009).

    PubMed  Google Scholar 

  124. Moinzadeh, P., Hunzelmann, N. & Krieg, T. Combination therapy with an endothelin-1 receptor antagonist (bosentan) and a phosphodiesterase V inhibitor (sildenafil) for the management of severe digital ulcerations in systemic sclerosis. J. Am. Acad. Dermatol. 65, e102–e104 (2011).

    PubMed  Google Scholar 

  125. Muir, L. in Raynaud’s Phenomenon: A Guide to Pathogenesis and Treatment (eds. Wigley, F. M., Herrick, A. L. & Flavahan, N. A.) 361–372 (Springer, 2015).

  126. Momeni, A. et al. Surgical treatment of systemic sclerosis — is it justified to offer peripheral sympathectomy earlier in the disease process? Microsurgery 35, 441–446 (2015).

    PubMed  Google Scholar 

  127. Chiou, G. et al. Digital sympathectomy in patients with scleroderma: an overview of the practice and referral patterns and perceptions of rheumatologists. Ann. Plast. Surg. 75, 637–643 (2015).

    CAS  PubMed  Google Scholar 

  128. Leyden, J. et al. Upper extremity angiographic patterns in systemic sclerosis: implications for surgical treatment. J. Hand Surg. Am. 44, 990.e1–990.e7 (2019).

    Google Scholar 

  129. Satteson, E. S., Chung, M. P., Chung, L. S. & Chang, J. Microvascular hand surgery for digital ischemia in scleroderma. J. Scleroderma Relat. Disord. https://doi.org/10.1177/2397198319863565 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Iorio, M. L., Masden, D. L. & Higgins, J. P. Botulinum toxin A treatment of Raynaud’s phenomenon: a review. Semin. Arthritis Rheum. 41, 599–603 (2012).

    CAS  PubMed  Google Scholar 

  131. Żebryk, P. & Puszczewicz, M. J. Botulinum toxin A in the treatment of Raynaud’s phenomenon: a systematic review. Arch. Med. Sci. 12, 864–870 (2016).

    PubMed  Google Scholar 

  132. Bello, R. J. et al. The therapeutic efficacy of botulinum toxin in treating scleroderma-associated Raynaud’s phenomenon: a randomized, double-blind, placebo-controlled clinical trial. Arthritis Rheumatol. 69, 1661–1669 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Bene, M. D. et al. Autologous fat grafting for scleroderma-induced digital ulcers. An effective technique in patients with systemic sclerosis. Handchir. Mikrochir. Plast. Chir. 46, 242–247 (2014).

    PubMed  Google Scholar 

  134. Bank, J., Fuller, S. M., Henry, G. I. & Zachary, L. S. Fat grafting to the hand in patients with Raynaud phenomenon: a novel therapeutic modality. Plast. Reconstr. Surg. 133, 1109–1118 (2014).

    CAS  PubMed  Google Scholar 

  135. Takagi, G. et al. Therapeutic vascular angiogenesis for intractable macroangiopathy-related digital ulcer in patients with systemic sclerosis: a pilot study. Rheumatology 53, 854–859 (2014).

    CAS  PubMed  Google Scholar 

  136. Del Papa, N. et al. Regional grafting of autologous adipose tissue is effective in inducing prompt healing of indolent digital ulcers in patients with systemic sclerosis: results of a monocentric randomized controlled study. Arthritis Res. Ther. 21, 7 (2019).

    PubMed  PubMed Central  Google Scholar 

  137. Hughes, M. et al. Prediction and impact of attacks of Raynaud’s phenomenon, as judged by patient perception. Rheumatology 54, 1443–1447 (2015).

    PubMed  Google Scholar 

  138. Pauling, J. D. et al. Patient-reported outcome instruments for assessing Raynaud’s phenomenon in systemic sclerosis: a SCTC Vascular Working Group report. J. Scleroderma Relat. Disord. 3, 249–252 (2018).

    PubMed  PubMed Central  Google Scholar 

  139. Pauling, J. D., Saketkoo, L. A., Matucci-Cerinic, M., Ingegnoli, F. & Khanna, D. The patient experience of Raynaud’s phenomenon in systemic sclerosis. Rheumatology 58, 18–26 (2019).

    PubMed  Google Scholar 

  140. Hughes, M. & Pauling, J. D. Exploring the patient experience of digital ulcers in systemic sclerosis. Semin. Arthritis Rheum. 48, 888–894 (2019).

    PubMed  Google Scholar 

  141. Pauling, J. D. et al. Multinational qualitative research study exploring the patient experience of Raynaud’s phenomenon in systemic sclerosis. Arthritis Care Res. 70, 1373–1384 (2018).

    Google Scholar 

  142. Hughes, M. et al. A multi-centre qualitative study exploring the patient experience of digital ulcers in systemic sclerosis. Arthritis Care Res. https://doi.org/10.1002/acr.24127 (2019).

    Article  Google Scholar 

  143. Denton, C. P. et al. Efficacy and safety of selexipag in adults with Raynaud’s phenomenon secondary to systemic sclerosis. Arthritis Rheumatol. 69, 2370–2379 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Ruaro, B. et al. Short-term follow-up of digital ulcers by laser speckle contrast analysis in systemic sclerosis patients. Microvasc. Res. 101, 82–85 (2015).

    PubMed  Google Scholar 

  145. Murray, A. et al. Pilot study assessing pathophysiology and healing of digital ulcers in patients with systemic sclerosis using laser Doppler imaging and thermography. Clin. Exp. Rheumatol. 34, 100–105 (2016).

    PubMed  Google Scholar 

  146. Hughes, M. et al. Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate. Microvasc. Res. 111, 32–36 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Hughes, M. et al. Digital ulcers in systemic sclerosis are associated with microangiopathic abnormalities of peri-lesional skin as assessed by capillaroscopy. Scand. J. Rheumatol. 46, 81–82 (2016).

    PubMed  Google Scholar 

  148. Allanore, Y., Distler, O., Matucci-Cerinic, M. & Denton, C. P. Review: defining a unified vascular phenotype in systemic sclerosis. Arthritis Rheumatol. 70, 162–170 (2018).

    PubMed  Google Scholar 

  149. Beon, M., Harley, R., Wessels, A., Silver, R. & Ludwicka-Bradley, A. Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clin. Exp. Rheumatol. 22, 733–742 (2004).

    CAS  PubMed  Google Scholar 

  150. van Roon, A. M. et al. Abnormal nailfold capillaroscopy is common in patients with connective tissue disease and associated with abnormal pulmonary function tests. J. Rheumatol. 46, 1109–1116 (2019).

    PubMed  Google Scholar 

  151. Mihai, C. et al. Digital ulcers predict a worse disease course in patients with systemic sclerosis. Ann. Rheum. Dis. 75, 681–686 (2016).

    CAS  PubMed  Google Scholar 

  152. Allanore, Y. et al. Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research Group (EUSTAR) database of patients with systemic sclerosis. Ann. Rheum. Dis. 69, 218–221 (2010).

    CAS  PubMed  Google Scholar 

  153. Hughes, M., Baker, A., Farrington, S. & Pauling, J. D. Patient organisation-led initiatives can play an important role in raising awareness about Raynaud’s phenomenon and encourage earlier healthcare utilisation for high-risk groups. Ann. Rheum. Dis. 78, 439–441 (2018).

    PubMed  Google Scholar 

  154. Hughes, M. Effect of season on internet searches for information on Raynaud phenomenon. J. Rheumatol. 46, 1543–1544 (2019).

    PubMed  Google Scholar 

  155. Chikura, B., Moore, T., Manning, J., Vail, A. & Herrick, A. L. Thumb involvement in Raynaud’s phenomenon as an indicator of underlying connective tissue disease. J. Rheumatol. 37, 783–786 (2010).

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

    Michael Hughes

  2. Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Michael Hughes

  3. Department of Rheumatology, Cochin Hospital, AP-HP, Paris Descartes University, Paris, France

    Yannick Allanore

  4. Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine and Palo Alto VA Health Care System, Palo Alto, CA, USA

    Lorinda Chung

  5. Department of Pharmacy and Pharmacology, University of Bath, Bath, UK

    John D. Pauling

  6. Royal National Hospital for Rheumatic Diseases (part of Royal United Hospitals Bath NHS Foundation Trust), Bath, UK

    John D. Pauling

  7. Department of Rheumatology, Royal Free Hospital, University College London, London, UK

    Christopher P. Denton

  8. Division of Rheumatology, University of Florence, Florence, Italy

    Marco Matucci-Cerinic

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  1. Michael Hughes
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  2. Yannick Allanore
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  3. Lorinda Chung
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  4. John D. Pauling
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  5. Christopher P. Denton
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  6. Marco Matucci-Cerinic
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The authors contributed equally to all aspects of the article.

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Correspondence to Michael Hughes.

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Competing interests

M.H. declares he has received speaker honoraria from Actelion. Y.A. declares he has or has had a consultancy relationship and/or has received grants from Actelion, Bayer, BMS, Boehringer-Ingelheim, Inventiva, Roche, Sanofi-Aventis and Servier in the area of systemic sclerosis. L.C. declares she has consultancy or advisory relationships with BMS, Boehringer-Ingelheim, Eicos, Mitsubishi Tanabe and Reata. J.D.P. declares he has received speaker honoraria and research grant support from Actelion and has undertaken consultancy work for Actelion and Boehringer-Ingelheim. C.P.D. declares he has received research grants from CSL Behring, GlaxoSmithKline and Inventiva and consulting fees from Actelion, Bayer, Boehringer-Ingelheim, CSL Behring, Galapagos, GlaxoSmithKline, Inventiva, Leadiant, Roche and Sanofi. M.M.-C. declares he has received speaker honoraria from Actelion and Biogen.

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Glossary

Hyperaemia

A relative increase in tissue perfusion or blood flow.

Paraesthesias

Abnormal sensory symptoms, for example tingling and numbness.

Eschar

Necrotic ulcer tissue that is often dark coloured or black and that is fully adherent to the ulcer base.

Telangiectasia

Cutaneous dilated blood vessels.

Laser Doppler flowmetry

A single-point measurement of blood flow or perfusion.

Digital planimetry

Tracing or measurement of surface dimensions using computer-assisted techniques.

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Hughes, M., Allanore, Y., Chung, L. et al. Raynaud phenomenon and digital ulcers in systemic sclerosis. Nat Rev Rheumatol 16, 208–221 (2020). https://doi.org/10.1038/s41584-020-0386-4

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