It's time to treat systemic sclerosis

EDITORIAL

It's time to treat systemic sclerosis

Percival Degrava Sampaio-Barros

Assistant Rheumatologist, Rheumatology Division, Department of Clinical Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP). National coordinator of GEPRO (Systemic Sclerosis Group of Pronuclear Project) of the Brazilian Society of Rheumatology. Chairman of the Pan American League of Associations for Rheumatology (PANLAR) Group for the Study of Systemic Sclerosis

Correspondence to

Systemic sclerosis (SSc) is still one of the most difficult therapeutic challenges in the field of rheumatic autoimmune diseases. However, many developments took place in the last decade, linked to an earlier diagnosis and treatment and better characterization of the clinical and epidemiological profile of the disease. If an early diagnosis of the cutaneous and visceral involvement is established, more efficient organ-specific strategies can be proposed. Within this philosophy, 2009 began with the first publication of recommendations for the SSc treatment by expert members of the EULAR Scleroderma Trials and Research Group (EUSTAR).¹ Another sign of this growing interest is that the current edition of the Brazilian Journal of Rheumatology (BJR) has two national studies about therapeutics on SSc.^2,3

Two situations exert striking influence in the treatment of systemic sclerosis: fibrosis and an altered vascular endothelium. Several drugs have been used for its anti-fibrotic activity, especially in diffuse thickening of the skin and interstitial lung disease. The use of cyclophosphamide⁴ and immunosuppressants⁵ in SSc has been recently described and analyzed. However, the only randomized, double-blind, placebo-controlled studies with cyclophosphamide were only published in 2006,^6,7 with favorable results but without significant statistic expression. The Scleroderma Lung Study (SLS), a multicenter study conducted in the United States under the sponsorship of the National Institute of Health (NIH), has evaluated 158 patients using oral cyclophosphamide (or placebo) for a period of one year, and the patients have been followed for a total of two years; there was statistically significant improvement in primary and secondary endpoints.⁶ In subsequent years, the SLS Research Group has published several other articles, deeply analyzing different aspects of the study, such as lung function and skin score,⁸ the SSc clinical forms,⁹ the quality of life,¹⁰ the bronchoalveolar lavage,¹¹ and assessment parameters of thorax high-resolution computed tomography (HRCT).¹² The other study was the FAST, which evaluated 45 patients with SSc and active alveolitis in England and treated with intravenous cyclophosphamide (or placebo) for 12 months, then using azathioprine for other 12 months. The primary and secondary endpoints were not statistically significant and the statistical trend in forced vital capacity (FVC) improvement was only observed in patients who used cylophosphamide.⁷ The results of these two controlled studies have enabled that the cyclophosphamide could be considered and indicated as treatment of SSc interstitial lung disease according to EUSTAR¹ recommendations, which still require further work to consider cyclophosphamide as treatment for aggressive cutaneous features, which are predominant in early diffuse SSc.

In the current edition of BJR, Macedo et al.² have examined the clinical course of nine patients with diffuse SSc and total skin score (TSS) > 30 without severe visceral involvement who made use of intravenous cyclophosphamide for 18 months and were followed at the Universidade de São Paulo (USP). Significant TSS reduction in the 12 months was observed (Mean TSS ± standard deviation (SD): 37.77 ± 4.08 vs. 29.22 ± 8.13, P = 0009), held after 18 months of treatment (Mean TSS ± SD: 26.42 ± 10.08, P = 0.01), without serious side effects. Ten years ago, we also published on BJR the experience at the Universidade Estadual de Campinas (UNICAMP) with intravenous cyclophosphamide in the treatment of 45 patients with SSc. Thirteen of them had rapidly progressive diffuse SSc and also presented statistical improvement at the TSS.¹³ Further studies with more patients and a longer follow-up are needed to confirm the capacity of improvement of skin thickening with the use of cyclophosphamide in SSc.

Among the vasoactive drugs, there are some with excellent safety profile and efficacy in the treatment of scleroderma renal crisis¹⁴ and pulmonary hypertension.¹⁵ As the patients with SSc present an improvement in their mean survival, events such as the occurrence of digital ischemic ulcers become more frequent.^16,17 The traditional calcium-channel blockers (such as nifedipine and diltiazen) are more effective in preventing new attacks in patients with primary Raynaud's phenomenon.¹⁸ The most complicated ischemic ulcers can be treated with the use of iloprost^19,20, treprostinil²¹, bosentan^22,23, and sildenafil.^24,25 However, beyond the treatment of crisis, these extremely painful and disabling ulcers should also have a prevention treatment. The EUSTAR group's recommendations for the SSc treatment consider that nifedipine, the prostanoids (especially the intravenous iloprost) and bosentan may be used to prevent the recurrence of ischemic ulcers in SSc.¹

Two prospective multicenter, randomized, double-blind, placebo-controlled studies (Rapids-1 and Rapids-2), examining patients in 17 centers in Europe and North America, showed that bosentan can prevent the occurrence of new digital ulcers, but not accelerate the healing of ulcers present at the time of randomization, in SSc patients with recurrent ulcers.^{26, 27} Based on the results of these studies, Mariz et al.³ (at this issue BJR), used the oral bosentan in the treatment of active refractory ischemic ulcers in three patients at the Universidade Federal de São Paulo (UNIFESP), contributing to the healing and prevention of the occurrence of new ulcers in a short follow-up of 12 weeks. The different healing responses seem to reside in the heterogeneity of the definition of active ischemic ulcers.²⁸

Concluding, for rheumatologists interested in early diagnosis and treatment of SSc, the detailed analysis of different epidemiological and clinical parameters, that govern the different therapeutic responses in the disease, is essential in choosing the best medication for each phase of the development of SSc, thus optimizing patients' expectations, treatment costs and side effects.

REFERENCES

• ¹
  Kowal-Bielecka O, Landewé R, Avouac J, Chwiesco S, Miniatti I, Czirjak L et al EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR). Ann Rheum Dis 2009;69:620-8.
• ²
  Macedo PA, Borges CTL, Souza RBC. Ciclofosfamida: eficaz no tratamento do quadro cutâneo grave na esclerose sistêmica. Rev Bras Reumatol 2009;49(3):261-71.
• ³
  Mariz HA, Corrêa MJU, Kayser C. Bosentana no tratamento de úlceras de extremidades refratárias na esclerose sistêmica. Rev Bras Reumatol 2009;49(3):250-60.
• ⁴
  Berezné A, Valeyre D, Ranque B, Guillevin L, Mouthon L. Interstitial lung disease associated with systemic sclerosis: what is the evidence for efficacy of cyclophosphamide? Ann N Y Acad Sci 2007;1110(9):271-84.
• ⁵
  Hunzelmann N, Moinzadeh P, Genth E, Krieg T, Lehmacher W, Melchers I et al High frequency of corticosteroids and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy. Arthritis Res Ther 2009;11:R30.
• ⁶
  Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE et al Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354(25):2655-66.
• ⁷
  Hoyles RK, Elis RW, Wellsbury J, Lee B, Newlands P, Goh NS et al A multicenter, prospective, randomized, placebo controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006;54(12):3962-70.
• ⁸
  Tashkin DP, Elashoff R, Clements PJ, Roth MD, Furst DE, Silver RM et al Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 2007;176(10):1026-34.
• ⁹
  Clements PJ, Roth MD, Elashoff R, Tashkin DP, Goldin J, Silver RM et al Scleroderma Lung Study (SLS): differences in the presentation and course of patients with limited versus diffuse systemic sclerosis. Ann Rheum Dis 2007;66(12):1641-7.
• ¹⁰
  Khanna D, Yan X, Tashkin DP, Furst DE, Elashoff R, Roth MD et al Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease. Arthritis Rheum 2007;56(5):1676-84.
• ¹¹
  Strange C, Bolster MB, Roth MD, Silver RM, Theodore A, Goldin J et al Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med 2008;177(1):91-8.
• ¹²
  Goldin JG, Lynch DA, Strollo DC, Suh RD, Schraufnagel DE, Clements PJ et al High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest 2008;134(2):358-67.
• ¹³
  Marques Neto JF, Sampaio-Barros PD, Samara AM. Uso da ciclofosfamida endovenosa na esclerose sistêmica. Rev. Bras. Reumatol. 1999;39(2):91-7.
• ¹⁴
  Penn H, Howe AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black CM et al Scleroderma renal crisis: patient characteristics and long-term outcomes. Q J Med 2007;100(8):485-94.
• ¹⁵
  Bull TM. Screening and therapy of pulmonary hypertension in systemic sclerosis. Curr Opin Rheumatol 2007;15(6):598-603.
• ¹⁶
  Hachulla E, Clerson P, Launay D, Lambert M, Morrell-Dubois, Queyrel V et al. Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J Rheumatol 2007;34(12):2423-30.
• ¹⁷
  Nihtyanova SI, Brough GM, Black CM, Denton CP. Clinical burden of digital vasculopathy in limited ande diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2008;67(1):120-3.
• ¹⁸
  Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud´s phenomenon: a meta-analysis. Rheumatology 2005;44(2):145-50.
• ¹⁹
  Zulian F, Corona V, Gerloni V, Falcini F, Buoncompagni A, Scarazatti M et al. Safety and efficacy of iloprost for the treatment of ischaemic digits in paediatric connective tissue diseases. Rheumatology 2004;43(2):229-33.
• ²⁰
  Herrgott I, Riemekasten G, Hunzelmann N, Sunderkotter C. Management of cutaneous vascular complications in systemic scleroderma: experience from the German network. Rheumatol Int 2008;28(10):1023-9.
• ²¹
  Chung L, Fiorentino D. A pilot trial of treprostinil for the treatment and prevention of digital ulcers in patients with systemic sclerosis. J Am Acad Dermatol 2006;54:880-2.
• ²²
  Launay D, Diot E, Pasquier E, Mouthon L, Boullanger N, Fain O et al. Le bosentan dans le traitment des ulceres digitaux evolutifs au cours de la sclerodermie systemique (9 cas). Presse Med 2006;35(4):587-92.
• ²³
  García de la Peña-Lefebvre P, Rodríguez RS, Valero Expósito M, Carmona L, Gámir Gámir ML, Beltrán Gutiérrez J et al. Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis patients. Rheumatology 2008;47(4):464-6.
• ²⁴
  Gore J, Silver R. Oral sildenafil for the treatment of Raynaud´s phenomenon and digital ulcers secondary to systemic sclerosis. Ann Rheum Dis 2005;64(9):1387.
• ²⁵
  Colglazier CL, Sutej PG, O´Rourke KS. Severe refractory fingertip ulcerations in a patient with scleroderma: successful treatment with sildenafil. J Rheumatol 2005;32(12):2440-2.
• ²⁶
  Korn JH, Mayes M, Matucci-Cerinic M, Rainisio M, Pope J, Hachulla E et al. Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004;50(12):3985-93.
• ²⁷
  Seilbold JR, Denton CP, Furst DE, Matucci-Cerinic M, Mayes M, Morganti A et al. Bosentan reduces the number of new digital ulcers in patients with systemic sclerosis. Arthritis Rheum 2006;52(Supl. II):552.
• ²⁸
  Herrick AL, Roberts C, Tracey A, Silman A, Anderson M, Goodfield M et al. Lack of agreement between rheumatologists in defining digital ulceration in systemic sclerosis. Arthritis Rheum 2009;60(3):878-82.

Publication Dates

• Publication in this collection
  07 July 2009
• Date of issue
  June 2009