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
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Vascular injury and Raynaud phenomenon are the earliest manifestations of systemic sclerosis (SSc).
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Patients with Raynaud phenomenon need careful assessment to identify secondary causes such as SSc using investigations including nailfold capillaroscopy and autoantibody detection.
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Raynaud phenomenon and ischaemic complications such as digital ulcers are the main causes of disease-related morbidity in patients with SSc.
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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.
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A number of treatments are available to both prevent and heal digital ulcers, including vasoactive drug therapies and ulcer debridement.
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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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09 March 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41584-021-00591-5
References
Katsumoto, T. R. & Whitfield, M. L. The pathogenesis of systemic sclerosis. Annu. Rev. Pathol. 6, 509–537 (2011).
Denton, C. P. & Khanna, D. K. Systemic sclerosis. Lancet 390, 1685–1699 (2017).
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).
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).
LeRoy, E. C. et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J. Rheumatol. 15, 202–205 (1988).
Hughes, M. & Herrick, A. L. Digital ulcers in systemic sclerosis. Rheumatology 56, 14–25 (2017).
Hachulla, E. et al. Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J. Rheumatol. 34, 2423–2430 (2007).
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).
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).
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).
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).
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).
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).
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).
Amanzi, L. et al. Digital ulcers in scleroderma: staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatology 49, 1374–1382 (2010).
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).
Pauling, J. D., Hughes, M. & Pope, J. E. Raynaud’s phenomenon - an update on diagnosis, classification and management. Clin. Rheumatol. 38, 3317–3330 (2019).
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).
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).
LeRoy, E. C. & Medsger, T. A. Raynaud’s phenomenon: a proposal for classification. Clin. Exp. Rheumatol. 10, 485–488 (1992).
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).
Maricq, H. R. & Weinrich, M. C. Diagnosis of Raynaud’s phenomenon assisted by color charts. J. Rheumatol. 15, 454–459 (1988).
Wigley, F. M. Raynaud’s phenomenon. N. Engl. J. Med. 347, 1001–1008 (2002).
Maverakis, E. et al. International consensus criteria for the diagnosis of Raynaud’s phenomenon. J. Autoimmun. 48–49, 60–65 (2014).
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).
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).
Mouthon, L. et al. Ischemic digital ulcers affect hand disability and pain in systemic sclerosis. J. Rheumatol. 41, 1317–1323 (2014).
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).
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).
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).
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).
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).
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).
Giuggioli, D., Manfredi, A., Colaci, M., Lumetti, F. & Ferri, C. Osteomyelitis complicating scleroderma digital ulcers. Clin. Rheumatol. 32, 623–627 (2013).
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).
Herrick, A. L. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat. Rev. Rheumatol. 8, 469–479 (2012).
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).
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).
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).
Smith, V. et al. Do worsening scleroderma capillaroscopic patterns predict future severe organ involvement? A pilot study. Ann. Rheum. Dis. 71, 1636–1639 (2012).
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).
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).
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).
Manetti, M. et al. Progressive loss of lymphatic vessels in skin of patients with systemic sclerosis. J. Rheumatol. 38, 297–301 (2011).
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).
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).
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).
Hughes, M. et al. Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis. Rheumatology 54, 2015–2024 (2015).
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).
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).
Ho, K. T. & Reveille, J. D. The clinical relevance of autoantibodies in scleroderma. Arthritis Res. Ther. 5, 80 (2003).
Ho, M., Veale, D., Eastmond, C., Nuki, G. & Belch, J. Macrovascular disease and systemic sclerosis. Ann. Rheum. Dis. 59, 39–43 (2000).
Au, K. et al. Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis. Arthritis Rheum. 63, 2078–2090 (2011).
Park, J. H. et al. Ulnar artery vasculopathy in systemic sclerosis. Rheumatol. Int. 29, 1081–1086 (2009).
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).
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).
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).
Baron, M. et al. Office capillaroscopy in systemic sclerosis. Clin. Rheumatol. 26, 1268–1274 (2007).
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).
Mihai, C. et al. The emerging application of semi-quantitative and quantitative capillaroscopy in systemic sclerosis. Microvasc. Res. 118, 113–120 (2018).
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).
Cutolo, M., Sulli, A., Pizzorni, C. & Accardo, S. Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis. J. Rheumatol. 27, 155–160 (2000).
Smith, V. et al. Fast track algorithm: how to differentiate a “scleroderma pattern” from a “non-scleroderma pattern”. Autoimmun. Rev. 18, 102394 (2019).
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).
Ruaro, B. et al. Correlations between skin blood perfusion values and nailfold capillaroscopy scores in systemic sclerosis patients. Microvasc. Res. 105, 119–124 (2016).
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).
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).
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).
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).
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).
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).
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).
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).
Dinsdale, G. & Herrick, A. L. Vascular diagnostics for Raynaud’s phenomenon. J. Vasc. Diagn. 2, 127–139 (2014).
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).
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).
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).
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).
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).
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).
Bruni, C. et al. Preliminary validation of the digital ulcer clinical assessment score in systemic sclerosis. J. Rheumatol. 46, 603–608 (2019).
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).
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).
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).
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).
Suliman, Y. A. et al. Ultrasound characterization of cutaneous ulcers in systemic sclerosis. Clin. Rheumatol. 37, 1555–1561 (2018).
Hughes, M. Response to ‘Ultrasound characterization of cutaneous ulcers in systemic sclerosis’. Clin. Rheumatol. 37, 2013 (2018).
Li, W. & Frech, T. M. The critical need for accurately defining digital ulcers in scleroderma. J. Scleroderma Relat. Disord. 2, 69–71 (2017).
Herrick, A. L. et al. Lack of agreement between rheumatologists in defining digital ulceration in systemic sclerosis. Arthritis Rheum. 60, 878–882 (2009).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Lebedoff, N. et al. Review of local wound management for scleroderma-associated digital ulcers. J. Scleroderma Relat. Disord. 3, 66–70 (2017).
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).
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).
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).
Markus, Y. M., Bell, M. J. & Evans, A. W. Ischemic scleroderma wounds successfully treated with hyperbaric oxygen therapy. J. Rheumatol. 33, 1694–1696 (2006).
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).
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).
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).
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).
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).
Ladak, K. & Pope, J. E. A review of the effects of statins in systemic sclerosis. Semin. Arthritis Rheum. 45, 698–705 (2016).
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).
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).
Hughes, M. & Herrick, A. in Novel Insights into Systemic Sclerosis Management. (eds M. Cutolo & V. Smith) 232–241 (Future Medicine, 2013).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Hughes, M. et al. Prediction and impact of attacks of Raynaud’s phenomenon, as judged by patient perception. Rheumatology 54, 1443–1447 (2015).
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).
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).
Hughes, M. & Pauling, J. D. Exploring the patient experience of digital ulcers in systemic sclerosis. Semin. Arthritis Rheum. 48, 888–894 (2019).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Mihai, C. et al. Digital ulcers predict a worse disease course in patients with systemic sclerosis. Ann. Rheum. Dis. 75, 681–686 (2016).
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).
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).
Hughes, M. Effect of season on internet searches for information on Raynaud phenomenon. J. Rheumatol. 46, 1543–1544 (2019).
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).
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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
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A relative increase in tissue perfusion or blood flow.
- Paraesthesias
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Abnormal sensory symptoms, for example tingling and numbness.
- Eschar
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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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DOI: https://doi.org/10.1038/s41584-020-0386-4
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