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  • Review Article
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State-of-the-art evidence in the treatment of systemic sclerosis

Nature Reviews Rheumatology volume 19, pages 212–226 (2023)Cite this article

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Abstract

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase 5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase 5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.

Key points

  • Treatment of systemic sclerosis (SSc) is organ-based or aimed at disease modification.

  • Autologous haematopoietic stem cell transplantation can improve survival in patients with early diffuse cutaneous SSc who are at high risk of mortality, such as those with very high skin scores (as measured by the modified Rodnan skin score) or moderate skin involvement and worsening interstitial lung disease (ILD).

  • Immunosuppressives and some biologic agents can soften skin and change the natural history of early diffuse cutaneous SSc.

  • Appropriate treatment for patients with early limited cutaneous SSc is unknown, and further research is needed.

  • ILD is usually treated by the use of mycophenolate mofetil as the initial therapy and then other immunosuppressives or biologic agents, but if ILD is fibrotic and progressing, anti-fibrotic therapy can be added, such as nintedanib (and possibly pirfenidone).

  • Raynaud phenomenon in SSc is treated with calcium channel blockers and then phosphodiesterase 5 inhibitors or intravenous iloprost.

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Fig. 1: Treatment effect on skin in SSc.
Fig. 2: Overview of management of lung fibrosis in SSc.
Fig. 3: Pulmonary hypertension treatment algorithm in SSc.
Fig. 4: Management of Raynaud phenomenon and digital ulcers in SSc.

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References

  1. Martin Calderon, L. & Pope, J. E. Scleroderma epidemiology update. Curr. Opin. Rheumatol. 33, 122–127 (2021).

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Hunzelmann, N. et al. The registry of the German Network for Systemic Scleroderma: frequency of disease subsets and patterns of organ involvement. Rheumatology 47, 1185–1192 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. De Almeida Chaves, S. et al. Sine scleroderma, limited cutaneous, and diffused cutaneous systemic sclerosis survival and predictors of mortality. Arthritis Res. Ther. 23, 295 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Marangoni, R. G. et al. Systemic sclerosis sine scleroderma: distinct features in a large Brazilian cohort. Rheumatology 52, 1520–1524 (2013).

    Article  PubMed  Google Scholar 

  6. 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).

    Article  PubMed  Google Scholar 

  7. Bellando-Randone, S. et al. Progression of patients with Raynaud’s phenomenon to systemic sclerosis: a five-year analysis of the European Scleroderma Trial and Research group multicentre, longitudinal registry study for very early diagnosis of systemic sclerosis (VEDOSS). Lancet Rheumatol. 3, e834–e843 (2021).

    Article  CAS  Google Scholar 

  8. Muangchan, C. et al. The 15% rule in scleroderma: the frequency of severe organ complications in systemic sclerosis. A systematic review. J. Rheumatol. 40, 1545–1556 (2013).

    Article  PubMed  Google Scholar 

  9. Akesson, A. & Wollheim, F. A. Organ manifestations in 100 patients with progressive systemic sclerosis: a comparison between the CREST syndrome and diffuse scleroderma. Br. J. Rheumatol. 28, 281–286 (1989).

    Article  CAS  PubMed  Google Scholar 

  10. Thoua, N. M. et al. Assessment of gastrointestinal symptoms in patients with systemic sclerosis in a UK tertiary referral centre. Rheumatology 49, 1770–1775 (2010).

    Article  PubMed  Google Scholar 

  11. Fretheim, H. et al. Multidimensional tracking of phenotypes and organ involvement in a complete nationwide systemic sclerosis cohort. Rheumatology 59, 2920–2929 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Steen, V. D. & Medsger, T. A. Jr Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 43, 2437–2444 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Bussone, G. & Mouthon, L. Interstitial lung disease in systemic sclerosis. Autoimmun. Rev. 10, 248–255 (2011).

    Article  PubMed  Google Scholar 

  14. Pope, J. E. et al. Systemic sclerosis and associated interstitial lung disease in Ontario, Canada: an examination of prevalence and survival over 10 years. J. Rheumatol. 48, 1427–1434 (2021).

    Article  PubMed  Google Scholar 

  15. Fernandez-Codina, A. et al. Treatment algorithms for systemic sclerosis according to experts. Arthritis Rheumatol. 70, 1820–1828 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Khanna, D. et al. Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J. Scleroderma Relat. Disord. 2, 11–18 (2017).

    Article  PubMed  Google Scholar 

  17. Herrick, A. L. et al. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study. Ann. Rheum. Dis. 77, 563–570 (2018).

    Article  CAS  PubMed  Google Scholar 

  18. Khanna, D. et al. The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis. Arthritis Care Res. 68, 167–178 (2016).

    Article  Google Scholar 

  19. Spiera, R. et al. Safety and efficacy of lenabasum in a phase II, randomized, placebo-controlled trial in adults with systemic sclerosis. Arthritis Rheumatol. 72, 1350–1360 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chung, L. et al. Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis (ASSET): open-label extension of a phase 2, double-blind randomised trial. Lancet Rheumatol. 2, e743–e753 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Khanna, D. et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 387, 2630–2640 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Khanna, D. et al. Evaluation of American college of rheumatology provisional composite response index in systemic sclerosis (ACR CRISS) in a phase 3 randomized controlled trial [abstract]. Arthritis Rheumatol. 70, 2938 (2018).

    Google Scholar 

  23. Nevskaya, T. et al. Skin improvement is a surrogate for favourable changes in other organ systems in early diffuse cutaneous systemic sclerosis. Rheumatology 59, 1715–1724 (2020).

    Article  PubMed  Google Scholar 

  24. Zheng, B. et al. Changes in skin score in early diffuse cutaneous systemic sclerosis are associated with changes in global disease severity. Rheumatology 59, 398–406 (2020).

    Article  PubMed  Google Scholar 

  25. Burt, R. K. et al. Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days. Bone Marrow Transpl. 56, 50–59 (2021).

    Article  CAS  Google Scholar 

  26. Sullivan, K. M. et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N. Engl. J. Med. 378, 35–47 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  27. van Laar, J. M. et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 311, 2490–2498 (2014).

    Article  PubMed  Google Scholar 

  28. Burt, R. K. et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 378, 498–506 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Shouval, R. et al. Autologous hematopoietic stem cell transplantation for systemic sclerosis: a systematic review and meta-analysis. Biol. Blood Marrow Transpl. 24, 937–944 (2018).

    Article  Google Scholar 

  30. Maltez, N. et al. Association of autologous hematopoietic stem cell transplantation in systemic sclerosis with marked improvement in health-related quality of life. Arthritis Rheumatol. 73, 305–314 (2021).

    Article  PubMed  Google Scholar 

  31. van Bijnen, S. et al. Predictive factors for treatment-related mortality and major adverse events after autologous haematopoietic stem cell transplantation for systemic sclerosis: results of a long-term follow-up multicentre study. Ann. Rheum. Dis. 79, 1084–1089 (2020).

    Article  PubMed  Google Scholar 

  32. Guillaume-Jugnot, P. et al. Autologous haematopoietic stem cell transplantation (AHSCT) in autoimmune disease adult patients in France: analysis of the long-term outcome from the French society for bone marrow transplantation and cellular therapy (SFGM-TC). Clin. Rheumatol. 38, 1501–1511 (2019).

    Article  PubMed  Google Scholar 

  33. Henes, J. et al. Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow transplantation autoimmune disease working party. Haematologica 106, 375–383 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Tashkin, D. P. et al. Cyclophosphamide versus placebo in scleroderma lung disease. N. Engl. J. Med. 354, 2655–2666 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Tashkin, D. P. et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir. Med. 4, 708–719 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pope, J. E. et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 44, 1351–1358 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. van den Hoogen, F. H. et al. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br. J. Rheumatol. 35, 364–372 (1996).

    Article  PubMed  Google Scholar 

  38. Gordon, J. K. et al. Belimumab for the treatment of early diffuse systemic sclerosis: results of a randomized, double-blind, placebo-controlled, pilot trial. Arthritis Rheumatol. 70, 308–316 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Khanna, D. et al. Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol. 72, 125–136 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Khanna, D. et al. A phase 2a randomized, double-blind, placebo-controlled study of ziritaxestat in early diffuse cutaneous systemic sclerosis (NOVESA) [abstract]. Arthritis Rheumatol. 72, L09 (2020).

    Article  Google Scholar 

  41. Khanna, D. et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir. Med. 8, 963–974 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Khanna, D. et al. Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial. Ann. Rheum. Dis. 79, 618–625 (2020).

    Article  PubMed  Google Scholar 

  43. Hudson, M. et al. Cyclophosphamide for the treatment of skin fibrosis in systemic sclerosis: a systematic review [abstract]. Arthritis Rheumatol. 71, 2593 (2019).

    Google Scholar 

  44. Allanore, Y. et al. A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis. Ann. Rheum. Dis. 79, 1600–1607 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. GlobeNewswire. Corbus Pharmaceuticals announces topline results from RESOLVE-1 phase 3 study of lenabasum for treatment of systemic sclerosis. GlobeNewswire https://www.globenewswire.com/news-release/2020/09/08/2089940/0/en/Corbus-Pharmaceuticals-Announces-Topline-Results-from-RESOLVE-1-Phase-3-Study-of-Lenabasum-for-Treatment-of-Systemic-Sclerosis.html (2020).

  46. Distler, O. et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N. Engl. J. Med. 380, 2518–2528 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Fernandez-Codina, A., Nevskaya, T. & Pope, J. Brentuximab vedontin for skin involvement in refractory diffuse cutaneous systemic sclerosis, interim results of a phase IIb open-label trial. Ann. Rheum. Dis. 80, 103–104 (2021).

    Article  Google Scholar 

  48. Khanna, D. et al. Tofacitinib in early diffuse cutaneous systemic sclerosis — results of phase I/II investigator-initiated, double-blind randomized placebo-controlled trial [abstract 863]. Arthritis Rheumatol. 71, 1493–1495 (2019).

    Google Scholar 

  49. Karalilova, R. V. et al. Tofacitinib in the treatment of skin and musculoskeletal involvement in patients with systemic sclerosis, evaluated by ultrasound. Rheumatol. Int. 41, 1743–1753 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hoa, S. et al. Association between immunosuppressive therapy and course of mild interstitial lung disease in systemic sclerosis. Rheumatology 59, 1108–1117 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Kowal-Bielecka, O. et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann. Rheum. Dis. 76, 1327–1339 (2017).

    Article  PubMed  Google Scholar 

  52. Gernert, M. et al. Immunosuppressive therapy after autologous hematopoietic stem cell transplantation in systemic sclerosis patients-high efficacy of rituximab. Front. Immunol. 12, 817893 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Gressenberger, P. et al. Rituximab as a treatment option after autologous hematopoietic stem cell transplantation in a patient with systemic sclerosis. J. Pers. Med. 11, 600 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Arruda, L. C. et al. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. Curr. Res. Transl. Med. 64, 107–113 (2016).

    CAS  PubMed  Google Scholar 

  55. Nihtyanova, S. I. et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol. 66, 1625–1635 (2014).

    Article  PubMed  Google Scholar 

  56. Steen, V. D. & Medsger, T. A. Changes in causes of death in systemic sclerosis, 1972–2002. Ann. Rheum. Dis. 66, 940–944 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Elhai, M. et al. Mapping and predicting mortality from systemic sclerosis. Ann. Rheum. Dis. 76, 1897–1905 (2017).

    Article  PubMed  Google Scholar 

  58. Hoffmann-Vold, A. M. et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann. Rheum. Dis. 80, 219–227 (2021).

    Article  CAS  PubMed  Google Scholar 

  59. Hoffmann-Vold, A. M. et al. POS0063 Progressive interstitial lung disease is frequent also in late disease stages in systemic sclerosis patients from EUSTAR. Ann. Rheum. Dis. 81, 248 (2022).

    Article  Google Scholar 

  60. Nihtyanova, S. I. et al. Using autoantibodies and cutaneous subset to develop outcome-based disease classification in systemic sclerosis. Arthritis Rheumatol. 72, 465–476 (2020).

    Article  CAS  PubMed  Google Scholar 

  61. Savarino, E. et al. Possible connection between gastroesophageal reflux and interstitial pulmonary fibrosis in patients with systemic sclerosis. Recenti Prog. Med. 100, 512–516 (2009).

    PubMed  Google Scholar 

  62. Zhang, X. J. et al. Association of gastroesophageal factors and worsening of forced vital capacity in systemic sclerosis. J. Rheumatol. 40, 850–858 (2013).

    Article  PubMed  Google Scholar 

  63. Goh, N. S. et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am. J. Respir. Crit. Care Med. 177, 1248–1254 (2008).

    Article  PubMed  Google Scholar 

  64. Hoffmann-Vold, A. M. et al. Assessment of recent evidence for the management of patients with systemic sclerosis-associated interstitial lung disease: a systematic review. ERJ Open Res 7, 00235-2020 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Montesi, S. B. & Caravan, P. Novel imaging approaches in systemic sclerosis-associated interstitial lung disease. Curr. Rheumatol. Rep. 21, 25 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Goh, N. S. et al. Short-term pulmonary function trends are predictive of mortality in interstitial lung disease associated with systemic sclerosis. Arthritis Rheumatol. 69, 1670–1678 (2017).

    Article  CAS  PubMed  Google Scholar 

  67. Volkmann, E. R. et al. Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts. Ann. Rheum. Dis. 78, 122–130 (2019).

    Article  PubMed  Google Scholar 

  68. Stock, C. J. W. et al. Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression. Respirology 26, 461–468 (2021).

    Article  PubMed  Google Scholar 

  69. De Lauretis, A. et al. Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J. Rheumatol. 40, 435–446 (2013).

    Article  PubMed  Google Scholar 

  70. Renaud, L. et al. Prominence of IL6, IGF, TLR, and bioenergetics pathway perturbation in lung tissues of scleroderma patients with pulmonary fibrosis. Front. Immunol. 11, 383 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bonhomme, O. et al. Biomarkers in systemic sclerosis-associated interstitial lung disease: review of the literature. Rheumatology 58, 1534–1546 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Roofeh, D. et al. Management of systemic sclerosis-associated interstitial lung disease. Curr. Opin. Rheumatol. 31, 241–249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Bukiri, H. & Volkmann, E. R. Current advances in the treatment of systemic sclerosis. Curr. Opin. Pharmacol. 64, 102211 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hoyles, R. K. et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 54, 3962–3970 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Ebata, S. et al. Safety and efficacy of rituximab for systemic sclerosis: a double-blind, parallel-group comparison, investigators initiated confirmatory randomized clinical trial (DESIRES Study) [abstract]. Arthritis Rheumatol. 73, 0496 (2021).

    Google Scholar 

  76. Hughes, M., Denton, C. P. & Khanna, D. Rituximab for the treatment of systemic sclerosis-interstitial lung disease. Rheumatology 60, 489–491 (2021).

    Article  PubMed  Google Scholar 

  77. Goswami, R. P. et al. Rituximab in the treatment of systemic sclerosis-related interstitial lung disease: a systematic review and meta-analysis. Rheumatology 60, 557–567 (2021).

    Article  CAS  PubMed  Google Scholar 

  78. Sircar, G. et al. Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial. Rheumatology 57, 2106–2113 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. Denton, C. P. et al. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann. Rheum. Dis. 77, 1362–1371 (2018).

    Article  CAS  PubMed  Google Scholar 

  80. Khanna, D. et al. STRATUS: a phase II study of abituzumab in patients with systemic sclerosis-associated interstitial lung disease. J. Rheumatol. 48, 1295–1298 (2021).

    Article  CAS  PubMed  Google Scholar 

  81. Maher, T. M. et al. Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial. Lancet Respir. Med. 11, 45–54 (2023).

    CAS  PubMed  Google Scholar 

  82. Flaherty, K. R. et al. Nintedanib in progressive fibrosing interstitial lung diseases. N. Engl. J. Med. 381, 1718–1727 (2019).

    Article  CAS  PubMed  Google Scholar 

  83. Khanna, D. et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: the LOTUSS trial. J. Rheumatol. 43, 1672–1679 (2016).

    Article  PubMed  Google Scholar 

  84. Behr, J. et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir. Med. 9, 476–486 (2021).

    Article  CAS  PubMed  Google Scholar 

  85. Khanna, D. et al. Combination therapy of mycophenolate mofetil and pirfenidone vs. mycophenolate alone: results from the Scleroderma Lung Study III [abstract]. Arthritis Rheumatol. 74, 0520 (2022).

    Google Scholar 

  86. Perelas, A. et al. Systemic sclerosis-associated interstitial lung disease. Lancet Respir. Med. 8, 304–320 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. Waxman, A. et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N. Engl. J. Med. 384, 325–334 (2021).

    Article  CAS  PubMed  Google Scholar 

  88. Hoffmann-Vold, A. M. et al. The need for a holistic approach for SSc-ILD — achievements and ambiguity in a devastating disease. Respir. Res. 21, 197 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Bernstein, E. J. et al. Survival of adults with systemic sclerosis following lung transplantation: a nationwide cohort study. Arthritis Rheumatol. 67, 1314–1322 (2015).

    Article  PubMed  Google Scholar 

  90. Crespo, M. M. et al. Lung transplant in patients with scleroderma compared with pulmonary fibrosis. Short- and long-term outcomes. Ann. Am. Thorac. Soc. 13, 84–92 (2016).

    Article  Google Scholar 

  91. Kreuter, M. et al. Impact of lung function decline on time to hospitalisation events in systemic sclerosis-associated interstitial lung disease (SSc-ILD): a joint model analysis. Arthritis Res. Ther. 24, 19 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hoa, S. et al. Association between immunosuppressive therapy and incident risk of interstitial lung disease in systemic sclerosis. Chest 160, 2158–2162 (2021).

    Article  PubMed  Google Scholar 

  93. Naidu, G. S. R. S. N. K. et al. Effect of mycophenolate mofetil (MMF) on systemic sclerosis-related interstitial lung disease with mildly impaired lung function: a double-blind, placebo-controlled, randomized trial. Rheumatol. Int. 40, 207–216 (2020).

    Article  CAS  PubMed  Google Scholar 

  94. Yomono, K. & Kuwana, M. Outcomes in patients with systemic sclerosis undergoing early vs delayed intervention with potential disease-modifying therapies. Rheumatology 61, 3677–3685 (2022).

    Article  PubMed  Google Scholar 

  95. Vonk, M. C., Vandecasteele, E. & van Dijk, A. P. Pulmonary hypertension in connective tissue diseases, new evidence and challenges. Eur. J. Clin. Invest. 51, e13453 (2021).

    Article  PubMed  Google Scholar 

  96. Morrisroe, K. et al. Epidemiology and disease characteristics of systemic sclerosis-related pulmonary arterial hypertension: results from a real-life screening programme. Arthritis Res. Ther. 19, 42 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Simonneau, G. et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur. Respir. J. 53, 1801913 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Jiang, Y., Turk, M. A. & Pope, J. E. Factors associated with pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc). Autoimmun. Rev. 19, 102602 (2020).

    Article  CAS  PubMed  Google Scholar 

  99. Connolly, M. J. et al. Prognostic significance of computed tomography criteria for pulmonary veno-occlusive disease in systemic sclerosis-pulmonary arterial hypertension. Rheumatology 56, 2197–2203 (2017).

    Article  PubMed  Google Scholar 

  100. Johnson, S. R. et al. Venous thromboembolism in systemic sclerosis: prevalence, risk factors, and effect on survival. J. Rheumatol. 45, 942–946 (2018).

    Article  PubMed  Google Scholar 

  101. Ende-Verhaar, Y. M. et al. Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature. Eur. Respir. J. 49, 1601792 (2017).

    Article  PubMed  Google Scholar 

  102. Weatherald, J. et al. Screening for pulmonary arterial hypertension in systemic sclerosis. Eur. Respir. Rev. 28, 190023 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Lee, P. et al. Mortality in systemic sclerosis (scleroderma). Q. J. Med. 82, 139–148 (1992).

    CAS  PubMed  Google Scholar 

  104. Johnson, S. R. et al. Pulmonary veno-occlusive disease and scleroderma associated pulmonary hypertension. J. Rheumatol. 33, 2347–2350 (2006).

    PubMed  Google Scholar 

  105. Galie, N. et al. 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, 67–119 (2016).

    Article  PubMed  Google Scholar 

  106. Johnson, S. R., Granton, J. T. & Mehta, S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest 130, 545–552 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Johnson, S. R., Mehta, S. & Granton, J. T. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur. Respir. J. 28, 999–1004 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Lei, Y. et al. The effects of oral treatment for systemic sclerosis related pulmonary arterial hypertension: a systematic review and meta-analysis. Mod. Rheumatol. 31, 151–161 (2021).

    Article  PubMed  Google Scholar 

  109. Hitzerd, E. et al. Endothelin receptor antagonism during preeclampsia: a matter of timing? Clin. Sci. 133, 1341–1352 (2019).

    Article  CAS  Google Scholar 

  110. Humbert, M. et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann. Rheum. Dis. 76, 422–426 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Galie, N. et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur. Respir. J. 53, 1801889 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Galie, N. et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N. Engl. J. Med. 373, 834–844 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Belge, C. & Delcroix, M. Treatment of pulmonary arterial hypertension with the dual endothelin receptor antagonist macitentan: clinical evidence and experience. Ther. Adv. Respir. Dis. 13, 1753466618823440 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Coghlan, J. G. et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann. Rheum. Dis. 76, 1219–1227 (2017).

    Article  CAS  PubMed  Google Scholar 

  115. Paul, G. A. et al. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br. J. Clin. Pharmacol. 60, 107–112 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zamanian, R. T. et al. Safety and efficacy of B-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension: a multicenter, double-blind, randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 204, 209–221 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Meier, F. M. 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).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  119. 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).

    Article  Google Scholar 

  120. 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).

    Article  PubMed  Google Scholar 

  121. Hughes, M. et al. Raynaud phenomenon and digital ulcers in systemic sclerosis. Nat. Rev. Rheumatol. 16, 208–221 (2020).

    Article  PubMed  Google Scholar 

  122. Pauling, J. D. The challenge of establishing treatment efficacy for cutaneous vascular manifestations of systemic sclerosis. Expert. Rev. Clin. Immunol. 14, 431–442 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Denton, C. P. et al. BSR and BHPR guidelines for the treatment of systemic sclerosis. Rheumatology 55, 1906–1910 (2016).

    Article  PubMed  Google Scholar 

  124. University of Oxford. Oxford Centre for Evidence-Based Medicine: levels of evidence (March 2009). CEBM https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009 (2009).

  125. Fernández-Codina, A., Cañas-Ruano, E. & Pope, J. E. Management of Raynaud’s phenomenon in systemic sclerosis — a practical approach. J. Scleroderma Relat. Disord. 4, 102–110 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Rirash, F. et al. Calcium channel blockers for primary and secondary Raynaud’s phenomenon. Cochrane Database Syst. Rev. 12, CD000467 (2017).

    PubMed  Google Scholar 

  127. Roustit, M. et al. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials. Ann. Rheum. Dis. 72, 1696–1699 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Pope, J. et al. Iloprost and cisaprost for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst. Rev. 1998, CD000953 (2000).

    PubMed  Google Scholar 

  129. Ingegnoli, F. et al. Practical suggestions on intravenous iloprost in Raynaud’s phenomenon and digital ulcer secondary to systemic sclerosis: systematic literature review and expert consensus. Semin. Arthritis Rheum. 48, 686–693 (2019).

    Article  CAS  PubMed  Google Scholar 

  130. Marasini, B. et al. Comparison between iloprost and alprostadil in the treatment of Raynaud’s phenomenon. Scand. J. Rheumatol. 33, 253–256 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Curtiss, P. et al. A systematic review and meta-analysis of the effects of topical nitrates in the treatment of primary and secondary Raynaud’s phenomenon. J. Am. Acad. Dermatol. 78, 1110–1118.e3 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Dziadzio, M. et al. Losartan therapy for Raynaud’s phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum. 42, 2646–2655 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. van der Meer, J. et al. A double-blind controlled trial of low dose acetylsalicylic acid and dipyridamole in the treatment of Raynaud’s phenomenon. VASA Suppl. 18, 71–75 (1987).

    PubMed  Google Scholar 

  134. 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 

  135. Coleiro, B. et al. Treatment of Raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology 40, 1038–1043 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Wasserman, A. & Brahn, E. Systemic sclerosis: bilateral improvement of Raynaud’s phenomenon with unilateral digital sympathectomy. Semin. Arthritis Rheum. 40, 137–146 (2010).

    Article  PubMed  Google Scholar 

  137. Bank, J. et al. Fat grafting to the hand in patients with Raynaud phenomenon: a novel therapeutic modality. Plast. Reconstr. Surg. 133, 1109–1118 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Motegi, S. I. et al. Efficacy of botulinum toxin B injection for Raynaud’s phenomenon and digital ulcers in patients with systemic sclerosis. Acta Derm. Venereol. 97, 843–850 (2017).

    Article  CAS  PubMed  Google Scholar 

  139. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tingey, T. et al. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res. 65, 1460–1471 (2013).

    Article  CAS  Google Scholar 

  141. Shenoy, P. D. et al. Efficacy of tadalafil in secondary Raynaud’s phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial. Rheumatology 49, 2420–2428 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. 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).

    Article  CAS  PubMed  Google Scholar 

  143. 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).

    Article  CAS  PubMed  Google Scholar 

  144. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  145. 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).

    Article  PubMed  Google Scholar 

  146. 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).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  148. Malenfant, D., Catton, M. & Pope, J. E. The efficacy of complementary and alternative medicine in the treatment of Raynaud’s phenomenon: a literature review and meta-analysis. Rheumatology 48, 791–795 (2009).

    Article  PubMed  Google Scholar 

  149. Benza, R. L. et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest 141, 354–362 (2012).

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Rheumatology, St Joseph’s Health Care, London, ON, Canada

    Janet E. Pope, Andreu Fernandez-Codina & Tatiana Nevskaya

  2. Department of Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada

    Janet E. Pope

  3. Division of Medicine, University College London, London, UK

    Christopher P. Denton

  4. Toronto Scleroderma Program, Toronto Western Hospital, Mount Sinai Hospital, Toronto, ON, Canada

    Sindhu R. Johnson

  5. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada

    Sindhu R. Johnson

  6. General Internal Medicine, Windsor Regional Hospital, Windsor, ON, Canada

    Andreu Fernandez-Codina

  7. Critical Care, Emergency and Systemic Autoimmune Diseases, Hospital Clinic, Barcelona, Spain

    Andreu Fernandez-Codina

  8. Department of Medicine, McGill University, Montreal, QC, Canada

    Marie Hudson

  9. Division of Rheumatology and Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada

    Marie Hudson

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Correspondence to Janet E. Pope.

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Competing interests

J.E.P. declares that she has research grants from AbbVie, Bayer, BI, BMS, Frensenius Kabi, Lilly, Mallinckrodt Pharmaceuticals, Merck, Roche, Seattle Genetics; that she has consulted for AbbVie, Amgen, BI, BMS, Celltrion, EMERALD, Frensenius Kabi, Galapagos, Gilead, Janssen, Lilly, Mallinckrodt Pharmaceuticals, Medexus, Merck, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sandoz, Samsung, Sanofi, Sobi, Teva, Viatris; and that she has been a speaker or attended an advisory board for AbbVie, Amgen, BI, BMS, Frensenius Kabi, Galapagos, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, Sandoz, Sanofi, UCB. C.P.D. declares that he has received consultancy or speaker fees from GlaxoSmithKline, Roche, Boehringer Ingelheim, Sanofi-Aventis, Galapagos, Inventiva, Corbus, Acceleron, Horizon, Gesynta; and that he has received research grants to his institution from GlaxoSmithKline, ARXX Therapeutics, Servier and Horizon Therapeutics. S.R.J. declares that he has been a site investigator for clinical trials sponsored by Bayer, Boehringer Ingelheim, Corbus, GlaxoSmithKline; that he has served on advisory boards for Boehringer Ingelheim, Corbus and Ikaria; and that he has been supported by the Oscar and Eleonor Markovitz Scleroderma Research Fund and the Gurmej Kaur Dhanda Scleroderma Research Fund. A.F.-C. declares that he has received grant support from the Scleroderma Society of Ontario and honoraria from Actelion, Bayer, Boehringer-Ingelheim. M.H. declares that she has received research grants from Boehringer Ingelheim and Bristol Myers Squibb and that she has participated in advisory boards for Boehringer Ingelheim, Alexion and Mallinckrodt. T.N. declares no competing interests.

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Pope, J.E., Denton, C.P., Johnson, S.R. et al. State-of-the-art evidence in the treatment of systemic sclerosis. Nat Rev Rheumatol 19, 212–226 (2023). https://doi.org/10.1038/s41584-023-00909-5

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