Targeted Therapy for Scleroderma Fibrosis

Rilonacept, an IL-1 inhibitor, is also being studied in scleroderma, using a four-gene biomarker of skin disease as the primary outcome in a short-duration trial (ClinicalTrials.gov identifier: NCT01538719).

Summary

There has been significant progress in understanding the pathogenesis of scleroderma and consequently in the development of novel targeted therapies for patients with this devastating disease. Until recently, treatment has focused on traditional immunosuppressive drugs and management of specific, organ-based complications with variable success. With further advances in understanding the biology of the disease, stratifying patients, and determining comprehensive outcome measures for clinical trials, it is highly likely that effective therapies for scleroderma fibrosis will emerge in the next decade.

Sara R. Schoenfeld, MD, is a rheumatologist in the Division of Rheumatology at Massachusetts General Hospital and an instructor in medicine at Harvard Medical School in Boston.

Flavia V. Castelino, MD, is director of the Scleroderma Program in the Division of Rheumatology at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School in Boston.

References

1. Mayes MD, Lacey JV Jr., Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003 Aug;48(8):2246–2255.
2. Elhai M, Meune C, Avouac J, et al. Trends in mortality in patients with systemic sclerosis over 40 years: A systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2012 Jun;51(6):1017–1026.
3. van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2013 Nov;65(11):2737–2747.
4. Khan K, Xu S, Nihtyanova S, et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis. 2012 Jul;71(7):1235–1242.
5. Tager AM, LaCamera P, Shea BS, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med. 2008 Jan;14(1):45–54.
6. Castelino FV, Seiders J, Bain G, et al. Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum. 2011 May;63(5):1405–1415.
7. Khanna D, Berrocal VJ, Giannini EH, et al. The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2016 Feb;68(2):299–311.
8. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 26;354(25):2655–2666.
9. Tashkin DP, Roth MD, Clements PJ, 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 Sep;4(9):708–719.
10. Le EN, Wigley FM, Shah AA, et al. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2011 Jun;70(6):1104–1107.
11. Mendoza FA, Nagle SJ, Lee JB, Jimenez SA. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol. 2012 Jun;39(6):1241–1247.
12. Pope JE, Bellamy N, Seibold JR, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001 Jun;44(6):1351–1358.
13. 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 Apr;35(4):364–372.
14. Kowal-Bielecka O, Landewe R, Avouac J, 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 May;68(5):620–628.
15. Jordan S, Distler JH, 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 Jun;74(6):1188–1194.
16. Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with rituximab in scleroderma: Results from a 1-year, proof-of-principle study. Rheumatology (Oxford). 2010 Feb;49(2):271–280.
17. Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015 Jul 1;125(7):2795–2807.
18. Khanna D, Denton CP, Jagerschmidt A, et al. SAR100842, an antagonist of lysophosphatidic acid receptor 1, as a potential treatment for patients with systemic sclerosis: Results from a phase 2a study. American College of Rheumatology Annual Meeting, Abstract #876. 2014.
19. Jordan S, Distler J, Maurer B, et al. Effect of endothelin-1 receptor antagonists on skin fibrosis in scleroderma patients from the EUSTAR database. JSRD. 2016;1(2):220–225.
20. Seibold JR, Denton CP, Furst DE, et al. Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis. Arthritis Rheum. 2010 Jul;62(7):2101–2108. [Erratum in Arthritis Rheum. 2010 Oct;62(10):3005.]
21. 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 Jun 25;387(10038):2630–2640.
22. Khanna D, Albera C, Fischer A, 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. 2016 Jul 1. pii: jrheum.151322.