Vol 9, No 3 (2023)
Review paper
Published online: 2023-07-05

open access

Page views 241
Article views/downloads 343
Get Citation

Connect on Social Media

Connect on Social Media

Everything you always wanted to know about systemic sclerosis but were afraid to ask: Part 4. Treatment of patients with systemic sclerosis characteristics and recommendations concerning treatment of skin involvement, Raynaud’s phenomenon, calcinosis

Monika Patrycja Bultrowicz1, Magdalena Kopeć-Mędrek12, Olga Gumkowska-Sroka23, Klaudia Palka1, Barbara Buc-Piorun1, Przemysław Kotyla123
Rheumatology Forum 2023;9(3):125-139.

Abstract

Systemic sclerosis (SSc) is a systemic connective tissue disease marked by diffuse microangiopathy and excessively immune-stimulated fibroblast activity, leading to fibrosis of the skin and internal organs. In the literature, the first report of the disease dates back to 1753 and is attributed to the physician Carlo Curzio of Naples, who described the case of a 17-year-old girl who developed sclerosis of the skin all over her body. The disease is a rare condition. It is estimated that 1 in 10 000 people in Poland suffer from SSc. Women predominate among the patients, with a 3–4-fold prevalence compared to men. Typically, the disease has its onset between 30 and 50 years of age. Early detection and treatment of organ complications are key to improving quality of life and reducing mortality in patients with SSc. Given the significant variability in the clinical course, an individualised approach to patients and multidisciplinary collaboration appear to be justified, both in the diagnostic and treatment phases. The treatment is based on the organ-specific therapeutic strategy, which involves tailoring the pharmacotherapy to the clinical presentation, disease stage, and organ complications. Treatment of patients should include, in addition to pharmacology, education of the patient and family and, if necessary, surgical treatment or other necessary interventions.

Article available in PDF format

View PDF (Polish) Download PDF file

References

  1. Pokeerbux MR, Giovannelli J, Dauchet L, et al. Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature. Arthritis Res Ther. 2019; 21(1): 86.
  2. Levien TL. Advances in the treatment of Raynaud's phenomenon. Vasc Health Risk Manag. 2010; 6: 167–177.
  3. Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2016; 76(8): 1327–1339.
  4. Denton CP, Hughes M, Gak N, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford). 2016; 55(10): 1906–1910.
  5. Hachulla E, Agard C, Allanore Y, et al. Collaborators. French recommendations for the management of systemic sclerosis. Orphanet J Rare Dis. 2021; 16(Suppl 2): 322.
  6. Abraham S, Steen V. Optimal management of digital ulcers in systemic sclerosis. Ther Clin Risk Manag. 2015; 11: 939–947.
  7. Ennis H, Hughes M, Anderson ME, et al. Calcium channel blockers for primary Raynaud's phenomenon. Cochrane Database Syst Rev. 2016; 2(2): CD002069.
  8. Landry GJ. Current medical and surgical management of Raynaud's syndrome. J Vasc Surg. 2013; 57(6): 1710–1716.
  9. Zhao H, Lian Y. Clinical and image improvement of Raynaud's phenomenon after botulinum toxin type A treatment. Australas J Dermatol. 2015; 56(3): 202–205.
  10. Żebryk P, Puszczewicz MJ. Botulinum toxin A in the treatment of Raynaud's phenomenon: a systematic review. Arch Med Sci. 2016; 12(4): 864–870.
  11. Granel B, Daumas A, Jouve E, et al. Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial. Ann Rheum Dis. 2015; 74(12): 2175–2182.
  12. Wolska-Gawron K, Michalska-Jakubus M, Krasowska D. Localized scleroderma – current treatment options. Dermatol Rev. 2017; 104(6): 606–618.
  13. Walecka I, Wislinska P, Kulak A, et al. Use of sulodexide for the treatment of disorders of peripheral microcirculation in patients with systemic sclerosis. Acta Angiol. 2017; 23(3): 139–143.
  14. Nihtyanova SI, Brough GM, Black CM, et al. Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2008; 67(1): 120–123.
  15. Hachulla E, Clerson P, Launay D, et al. Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J Rheumatol. 2007; 34(12): 2423–2430.
  16. Giuggioli D, Manfredi A, Colaci M, et al. Osteomyelitis complicating scleroderma digital ulcers. Clin Rheumatol. 2013; 32(5): 623–627.
  17. Knobler R, Moinzadeh P, Hunzelmann N, et al. European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes. J Eur Acad Dermatol Venereol. 2017; 31(9): 1401–1424.
  18. Tingey T, Shu J, Smuczek J, et al. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken). 2013; 65(9): 1460–1471.
  19. Ferreira MEG, Scheinberg MA. Successful treatment with bosentan of non-digital skin ulcers in severe scleroderma. Ann Rheum Dis. 2008; 67(12): 1784–1785.
  20. Bali G, Schwantzer G, Aberer F, et al. [Iloprost therapy in systemic sclerosis]. Hautarzt. 2003; 54(9): 845–851.
  21. Krasowska D, Rudnicka L, Dańczak-Pazdrowska A, et al. [Twardzina układowa – rekomendacje diagnostyczno-terapeutyczne Polskiego Towarzystwa Dermatologicznego. Część 2: Leczenie]. Dermatol Rev/Przegl Dermatol. 2017; 104(6): 583–596.
  22. Khor CG, Chen XLF, Lin TS, et al. Rituximab for refractory digital infarcts and ulcers in systemic sclerosis. Clin Rheumatol. 2014; 33(7): 1019–1020.
  23. Giuggioli D, Manfredi A, Colaci M, et al. Systemic sclerosis and cryoglobulinemia: our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of the literature. Autoimmun Rev. 2013; 12(11): 1058–1063.
  24. Shanmugam VK. Vasculitic diseases and prothrombotic states contributing to delayed healing in chronic wounds. Curr Dermatol Rep. 2016; 5(4): 270–277.
  25. Moran ME. Scleroderma and evidence based non-pharmaceutical treatment modalities for digital ulcers: a systematic review. J Wound Care. 2014; 23(10): 510–516.
  26. Gabrielli A, Avvedimento E, Krieg T. Scleroderma. N Engl J Med. 2009; 360(19): 1989–2003.
  27. Gutierrez A, Wetter DA. Calcinosis cutis in autoimmune connective tissue diseases. Dermatol Ther. 2012; 25(2): 195–206.
  28. Valenzuela A, Chung L. Management of calcinosis associated with systemic sclerosis. Curr Treat Options Rheum. 2016; 2(1): 85–96.
  29. Valenzuela A, Baron M, Herrick AL, et al. Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study. Semin Arthritis Rheum. 2016; 46(3): 344–349.
  30. Robertson LP, Marshall RW, Hickling P. Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Ann Rheum Dis. 2003; 62(3): 267–269.
  31. Park YM, Lee SJ, Kang H, et al. Large subcutaneous calcification in systemic lupus erythematosus: treatment with oral aluminum hydroxide administration followed by surgical excision. J Korean Med Sci. 1999; 14(5): 589–592.
  32. Schanz S, Ulmer A, Fierlbeck G. Response of dystrophic calcification to intravenous immunoglobulin. Arch Dermatol. 2008; 144(5): 585–587.
  33. Tosounidou S, MacDonald H, Situnayake D. Successful treatment of calcinosis with infliximab in a patient with systemic sclerosis/myositis overlap syndrome. Rheumatology (Oxford). 2014; 53(5): 960–961.
  34. Daoussis D, Antonopoulos I, Liossis SNC, et al. Treatment of systemic sclerosis-associated calcinosis: a case report of rituximab-induced regression of CREST-related calcinosis and review of the literature. Semin Arthritis Rheum. 2012; 41(6): 822–829.
  35. de Paula DR, Klem FB, Lorencetti PG, et al. Rituximab-induced regression of CREST-related calcinosis. Clin Rheumatol. 2013; 32(2): 281–283.
  36. Giuggioli D, Lumetti F, Colaci M, et al. Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature. Autoimmun Rev. 2015; 14(11): 1072–1078.
  37. Hurabielle C, Allanore Y, Kahan A, et al. Flare of calcinosis despite rituximab therapy. Semin Arthritis Rheum. 2014; 44(2): e5–e6.
  38. van den Hoogen FH, Boerbooms AM, Swaak AJ, 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. 1996; 35(4): 364–372.
  39. Pope JE, Bellamy N, Seibold JR, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001; 44(6): 1351–1358, doi: 10.1002/1529-0131(200106)44:6<1351::AID-ART227>3.0.CO;2-I.
  40. Walker KM, Pope J. Treatment of systemic sclerosis complications: what to use when first-line treatment fails — a consensus of systemic sclerosis experts. Semin Arthritis Rheum. 2012; 42(1): 42–55.
  41. Nagaraja V, Denton CP, Khanna D. Old medications and new targeted therapies in systemic sclerosis. Rheumatology (Oxford). 2015; 54(11): 1944–1953.
  42. Poelman CL, Hummers LK, Wigley FM, et al. Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol. 2015; 42(2): 236–242.
  43. Jordan S, Distler JHW, Maurer B, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015; 74(6): 1188–1194.
  44. Elhai M, Distler O, Smith V, et al. OP0142 Rituximab in systemic sclerosis: safety and efficacy data from the EUSTAR network. Ann Rheum Dis. 2018; 77: 122.
  45. Daoussis D, Liossis SNC, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford). 2010; 49(2): 271–280.
  46. Daoussis D, Liossis SNC, Tsamandas AC, et al. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. 2012; 30(2 Suppl 71): S17–S22.
  47. Smith V, Van Praet JT, Vandooren B, et al. Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis. 2010; 69(1): 193–197.
  48. Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009; 60(2): 578–583.
  49. Khanna D, Lin CJF, Furst DE, et al. focuSSced investigators. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020; 8(10): 963–974.
  50. Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016; 387(10038): 2630–2640.
  51. Shima Y, Kawaguchi Y, Kuwana M. Add-on tocilizumab versus conventional treatment for systemic sclerosis, and cytokine analysis to identify an endotype to tocilizumab therapy. Mod Rheumatol. 2019; 29(1): 134–139.
  52. Elhai M, Meunier M, Matucci-Cerinic M, et al. EUSTAR (EULAR Scleroderma Trials and Research group). Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis. 2013; 72(7): 1217–1220.
  53. Hoffmann-Vold AM, Allanore Y, Alves M, et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis. 2021; 80(2): 219–227.
  54. Tashkin DP, Roth M, Clements 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. 2016; 4(9): 708–719.
  55. Ebata S, Yoshizaki A, Oba K, et al. Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial. Lancet Rheumatol. 2021; 3(7): e489–e497.
  56. Naidu G, Sharma S, Dhir V, et al. AB0633 Rituximab in scleroderma related interstitial lung disease: a single centre experience from North India. Ann Rheum Dis. 2017; 76: 1273–1274.
  57. Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022; 205(9): e18–e47.
  58. Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019; 380(26): 2518–2528.
  59. Wells AU, Flaherty KR, Brown KK, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019; 381(18): 1718–1727.
  60. Mularek-Kubzdela T, Ciurzyński M, Kowal Bielecka O, et al. An expert opinion of the Polish Cardiac Society Working Group on Pulmonary Circulation and the Polish Society for Rheumatology on the diagnosis and treatment of pulmonary hypertension in patients with connective tissue disease. Kardiol Pol. 2021; 79(7-8): 917–929.
  61. Kronbichler A, Mayer G. Renal involvement in autoimmune connective tissue diseases. BMC Med. 2013; 11: 95.
  62. Shanmugam VK, Steen VD. Renal disease in scleroderma: an update on evaluation, risk stratification, pathogenesis and management. Curr Opin Rheumatol. 2012; 24(6): 669–676.
  63. Avouac J, Walker U, Tyndall A, et al. Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol. 2010; 37(7): 1488–1501.
  64. Doré A, Lucas M, Ivanco D, et al. Significance of palpable tendon friction rubs in early diffuse cutaneous systemic sclerosis. Arthritis Care Res (Hoboken). 2013; 65(8): 1385–1389.
  65. Sanges S, Rivière S, Mekinian A, et al. Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature. Autoimmun Rev. 2017; 16(4): 377–384.
  66. Kondo M, Murakawa Y, Matsumura T, et al. A case of overlap syndrome successfully treated with tocilizumab: a hopeful treatment strategy for refractory dermatomyositis? Rheumatology (Oxford). 2014; 53(10): 1907–1908.
  67. Fasano S, Gordon P, Hajji R, et al. Rituximab in the treatment of inflammatory myopathies: a review. Rheumatology (Oxford). 2017; 56(1): 26–36.
  68. Wielosz E, Borys O, Zychowska I, et al. Gastrointestinal involvement in patients with systemic sclerosis. Pol Arch Med Wewn. 2010; 120(4): 132–136.
  69. Shreiner AB, Murray C, Denton C, et al. Gastrointestinal manifestations of systemic sclerosis. J Scleroderma Relat Disord. 2016; 1(3): 247–256.
  70. Polkowska-Pruszyńska B, Gerkowicz A, Szczepanik-Kułak P, et al. Small intestinal bacterial overgrowth in systemic sclerosis: a review of the literature. Arch Dermatol Res. 2019; 311(1): 1–8.
  71. Sullivan KM, Goldmuntz E, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018; 378(1): 35–47.
  72. Bongi SM, Del Rosso A, Passalacqua M, et al. Manual lymph drainage improving upper extremity edema and hand function in patients with systemic sclerosis in edematous phase. Arthritis Care Res (Hoboken). 2011; 63(8): 1134–1141.
  73. Valentini G, Della Rossa A, Bombardieri S, et al. European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes. Ann Rheum Dis. 2001; 60(6): 592–598.