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Clinical Trial Design Issues in Systemic Sclerosis: an Update

Current Rheumatology Reports volume 18, Article number: 38 (2016) Cite this article

Abstract

Systemic sclerosis (scleroderma, SSc) is a multisystem disease characterized by vasculopathy, autoimmunity, and fibrosis. SSc has the highest disease-related mortality rate among the rheumatologic illnesses. In the USA, there remains no FDA-approved therapy. As our understanding of SSc pathogenesis improves, targeted therapies interrupting key pathways and mediators will be studied in clinical trials. However, clinical trials in SSc are fraught with challenges. Validated clinical outcome measures do not exist for all disease manifestations. It can be difficult to discern disease activity from damage. SSc is highly heterogeneous, with multiple different phenotypes, and predicting who will have progressive disease is not currently well understood. Biomarkers are in early stages of development and do not represent surrogate outcomes at this time. Given that SSc is uncommon, studies of similar disease aspects or populations can lead to competition for patients. This review will focus on current issues in SSc clinical trial design.

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References

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  1. Bryan C, Howard Y, Brennan P, Black C, Silman A. Survival following the onset of scleroderma: results from a retrospective inception cohort study of the UK patient population. Br J Rheumatol. 1996;35:1122–6.

    CAS  Article  PubMed  Google Scholar 

  2. Rubio-Rivas M, Royo C, Simeon CP, Corbella X, Fonollosa V. Mortality and survival in systemic sclerosis: systematic review and meta-analysis. Semin Arthritis Rheum. 2014;44:208–19.

    Article  PubMed  Google Scholar 

  3. Mayes MD, Lacey Jr JV, Beebe-Dimmer J, et al. Prevalanece, incidence, survival, and disease characteristics of systemic sclerosiss in a large US population. Arthritis Rheum. 2003;48:2246–55.

    Article  PubMed  Google Scholar 

  4. Clements PJ, Hurwitz EL, Wong WK, et al. Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial. Arthritis Rheum. 2000;43:2445–54.

    CAS  Article  PubMed  Google Scholar 

  5. Domsic RT. Scleroderma: the role of serum autoantibodies in defining specific clinical phenotypes and organ system involvement. Curr Opin Rheumatol. 2015;26:646–52. This paper summarizes recent advances in serologic testing for SSc-associated antibodies and the role of auto-antibodies in diagnosis and prognosis of SSc.

  6. Domsic RT, Nihtyanova SI, Wisniewski SR, et al. Derivation and validation of a prediction ruule for two-year mortality in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2014;66:1616–24. This paper describes four independent predictors of mortality in early diffuse: age, skin thickness progression rate, gastrointestinal tract severity, and anemia.

  7. Meyer OC et al. Disease subsets, antinuclear antibody profile and clinical features in 127 French and 247 US adult patients with systemic sclerosis. J Rheumatol. 2007;34:104–9.

    PubMed  Google Scholar 

  8. Kuwana M et al. Racial differences in the distribution of systemic sclerosis-related serum antinuclear antibodies. Arthritis Rheum. 1994;37:902.

    CAS  Article  PubMed  Google Scholar 

  9. Nihtyanova SI, Schreiber BE, Ong VH. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheum. 2014;66:1625–35. This study provides outcome data based on up to a 15-year follow-up of SSc and derives predictive models which could be used as clinical tools for patient risk stratification and cohort enrichment in clinical trials.

  10. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35:35.

    CAS  Article  PubMed  Google Scholar 

  11. Perera A, Fertig N, Lucas M, Rodriguez-Reyna TS, Hu P, Steen VD, et al. Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody. Arthritis Rheum. 2007;56:2740–6.

    Article  PubMed  Google Scholar 

  12. Furst DE, Clements PJ, Steen VD, et al. The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis. J Rheumatol. 1998;25:84–8.

    CAS  PubMed  Google Scholar 

  13. Clements P, Lachenbruch P, Siebold JR, et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995;22:1281–5.

    CAS  PubMed  Google Scholar 

  14. Kaldas M, Khanna PP, Furst DE, et al. Sensitivity to change of the modified Rodnan skin score in diffuse systemic sclerosis—assessment of individual body sites in two large randomized controlled trials. Rheumatology (Oxford). 2009;48:1143–6.

    Article  Google Scholar 

  15. Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69:1809–15.

    Article  PubMed  Google Scholar 

  16. Steele R, Hudson M, Lo E, Baron M, sclerosis ObotCSRGCdrtptpoildis. Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Care Res (Hoboken). 2012;64:519–24.

    Article  Google Scholar 

  17. Yorke J, Swigris J, Russell AM, et al. Dyspnea-12 is a valid and reliable measure of breathlessness in patients with interstitial lung disease. Chest. 2011;139:159–64.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Nishiyama O, Taniguchi H, Kondoh Y, et al. A simple assessment of dyspnoea as a prognostic indicator in idiopathic pulmonary fibrosis. Eur Respir J. 2010;36:1067–72.

    CAS  Article  PubMed  Google Scholar 

  19. Saketkoo LA, Mittoo S, Huscher D, et al. Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials. Thorax. 2014;69:428–36.

    Article  PubMed  Google Scholar 

  20. Bassel M, Hudson M, Taillefer SS, Schieir O, Baron M, Thombs BD. Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian National Survey. Rheumatology (Oxford). 2011;50:762–7.

    Article  Google Scholar 

  21. Khanna D, Lovell DJ, Giannini E, et al. Development of a provisional core set of response measures for clinical trials of systemic sclerosis. Annals Rheumatic Dis. 2008;67:703–9.

    CAS  Article  Google Scholar 

  22. Merkel PA, Herlyn K, Martin RW, et al. Measuring disease activity and functional status in patients with scleroderma and Raynaud’s phenomenon. Arthritis and rheumatism Arthritis and Rheumatism. 2002;46:2410–20.

    Article  PubMed  Google Scholar 

  23. Gladue H, Maranian P, Paulus HE, Khanna D. Evaluation of test characteristics for outcome measures used in Raynaud’s phenomenon clinical trials. Arthritis Care Res. 2013;65:630–6. This study analyzed core set measures from 249 patients in the placebo-treated groups from three RP RCTs including the RCS and other measures and found that outcome measures used in RCTs of RP are associated with marked variability but that a combination of outcome measures is associated with lower placebo responses. This provides a rationale to perform future studies to assess whether a composite score would perform better.

  24. Rosato E, Molinaro I, Borghese F, Rossi C, Pisarri S, Salsano F. Bosentan improves skin perfusion of hands in patients with systemic sclerosis with pulmonary artery hypertension. J Rheumatol. 2010;37:2531–9.

    Article  PubMed  Google Scholar 

  25. Bose N, Bena J, Chatterjee S. Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser Doppler perfusion imaging: a 12-week randomized double-blind placebo controlled trial. Arthritis Res Ther. 2015;5:44.

    Article  Google Scholar 

  26. Correa MJ, Mariz HA, Andrade LE, Kayser C. Oral N-acetylcysteine in the treatment of Raynaud’s phenomenon secondary to systemic sclerosis: a randomized, double-blind, placebo-controlled clinical trial. Rev Bras Rheumatol. 2014;54:452–8.

    Article  Google Scholar 

  27. Hummers LK, Dugowson CE, Dechow FJ, 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. 2013;72:1962–7.

    CAS  Article  Google Scholar 

  28. Della Rossa A, Cazzato M, d-Ascanio A, et al. Alteration of microcirculation is a hallmark of very early systemic sclerosis patients: a slaser speckle contrast analysis. Clin Exp Rheumatol. 2013;31:109–14.

    PubMed  Google Scholar 

  29. Gaillard-Bigot F, Roustit M, Blaise S, et al. Abnormal amplitude and kinetics of digital postocclusive reactive hyperemia in systemic sclerosis. Microvas Res. 2014;94:90–5.

    CAS  Article  Google Scholar 

  30. Pauling JD, Shipley JA, Hart DJ, McGrogan A, McHugh NJ. Use of laser speckle contrast imaging to assess digital microvascular function in primary raynuad phenomenon and syustemic sclerosis: a comparison using the Raynaud condition score diary. J Rheumatol. 2015;42:1163–68.

    CAS  Article  PubMed  Google Scholar 

  31. Akesson A. Organ manifestations in 100 patients with progressive systemic sclerosis: a comparison between the CREST syndrome and diffuse scleroderma. Br J Rheumatol. 1989;28:281.

    CAS  Article  PubMed  Google Scholar 

  32. Thoua NM, Bunce C, Brough G, Forbes A, Emmanuel AV, Denton CP. Assessment of gastrointestinal symptoms in patients with systemic sclerosis in a UK tertiary referral centre. Rheumatology (Oxford). 2010;49:1770.

    Article  Google Scholar 

  33. Steen VD, Medsger Jr TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000;43:2437–44.

    CAS  Article  PubMed  Google Scholar 

  34. Khanna D, Nagaraja V, Gladue H, Chey W, Pimentel M, Frech T. Measuring response in the gastrointestinal tract in systemic sclerosis. Curr Opin Rheumatol. 2013;25:700–6. This review discusses the outcome measures to assess gastrointestinal tract involvement in SSc.

  35. Khanna D, Hays RD, Maranian P, et al. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium gastrointestinal tract instrument. Arthritis Rheum. 2009;61:1257.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Khanna D, Furst DE, Hays RD, et al. Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum Dis. 2006;65:1325–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Frech TM, Khanna D, Maranian P, Frech EJ, Sawitzke AD, Murtaugh MA. Probiotics for the treatment of systemic sclerosis-associated gastrointestinal bloating/distention. Clin Exp Rheumatol. 2011;38:1920–24.

    Google Scholar 

  38. Safety and tolerability of pirfenidone in patients with systemic sclerosis-associated interstitial lung disease—the LOTUSS study. Am J Respir Crit Care Med 2015;191:A1175

  39. Barst RJ. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296–301.

    CAS  Article  PubMed  Google Scholar 

  40. Galie et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834–44.

    CAS  Article  PubMed  Google Scholar 

  41. Pulido et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–18.

    CAS  Article  PubMed  Google Scholar 

  42. http://sites.bu.edu/sctc_activities/.

  43. 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;68:299–311. This study describes the development of the composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs).

  44. Ferdowsi N, Huq M, Burchell J, Mancuso S, Tay T, Stevens W, Rabusa C, Hudson M, Sundararajan V, Prior D, Proudman S, Baron M, Nikpour M. Development of a disease damage index in systemic sclerosis using consensus and data driven methods [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/development-of-a-disease-damage-index-in-systemic-sclerosis-using-consensus-and-data-driven-methods/. Accessed February 19, 2016

  45. Group BDW. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.

    Article  Google Scholar 

  46. Mohan C, Assassi S. Biomarkers in rheumatic diseases: how can they facilitate diagnosis and assessment of disease activity? Brit Medical J. 2015;351:h5079. This review describes the biomarkers in various rheumatic diseases earlier including SSc.

  47. 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. Ann Rheum Dis. 2013;72:1747–55.

    Article  PubMed  Google Scholar 

  48. Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB. Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med. 2005;118:2–10.

    Article  PubMed  Google Scholar 

  49. Nihtyanova SI, Denton CP. Autoantibodies as predictive tools in systemic sclerosis. Nat Rev Rheumatol. 2010;5:112–6.

    Article  Google Scholar 

  50. Muangchan C, Harding S, Khimdas S, et al. Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group. Arthritis Care Res (Hoboken). 2012;6:1405–14.

    Article  Google Scholar 

  51. Tan FK, Zhou X, Mayes MD, et al. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford). 2006;45:694–702.

    CAS  Article  Google Scholar 

  52. Assassi S, Mayes MD, Arnett FC, et al. Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum. 2010;62:589–98.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Whitfield ML, Finlay DR, Murray JI, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003;100:12319–24.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Hinchliff M, Huang CC, Wood TA, et al. Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. J Invest Dermatol. 2013;133:1979–89.

    Article  Google Scholar 

  55. Milano A, Pendergrass SA, Sargent JL, et al. Molecular subsets in the gene expression signatures of scleroderma skin. PLoS One. 2008;3:e2696.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Chakravarty EF, Martyanov V, Fiorentino D, et al. Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis Res Ther. 2015;17:159.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Gordon JK, Martyanov V, Magro C, et al. Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial. Arthritis Res Ther. 2015;17:213.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Rice LM, Ziemek J, Stratton EA, et al. A longitudinal biomarker for the extent of skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2015;67:3004–15. This group defines a pharmacodynamic biomarker based on skin-gene expression performed reproducibly on a NanoString platform that correlates with the MRSS in clinical trials.

  59. Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest 2015 125. This paper reports the results of a trial of fresolimumab in SSc. This was an open-label trial which showed both clinical effect and rapid decrease of TGF-β-regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP).

  60. van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. 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

  61. Pope JE, Bellamy N, Seibold JR, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44:1351.

    CAS  Article  PubMed  Google Scholar 

  62. 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;68:620.

    CAS  Article  PubMed  Google Scholar 

  63. Le EN, Wigley FM, Shah AA, Boin F, Hummers LK. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2011;70:1104.

    CAS  Article  PubMed  Google Scholar 

  64. 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;39:1241–7.

    CAS  Article  PubMed  Google Scholar 

  65. Derk CT, Grace E, Shenin M, Naik M, Schulz S, Xiong W. A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis. Rheumatology (Oxford). 2009;48:1595.

    CAS  Article  Google Scholar 

  66. White B, Bauer EA, Goldsmith LA, et al. Guidelines for clinical trials in systemic sclerosis (scleroderma). I. Disease-modifying interventions. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis. Arthritis Rheum. 1995;38:351–60.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Thomas Medsger for his review of this manuscript.

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  1. Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA

    Jessica K. Gordon

  2. University of Pittsburgh, Pittsburgh, PA, USA

    Robyn T. Domsic

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Correspondence to Jessica K. Gordon.

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Conflicts of Interest

JKG declares that she has no conflicts of interest. RTD reports personal fees from and research activities and consultancy for Biogen-Idec, and personal fees from and research activities and consultancy for Bayer Healthcare, during the conduct of the study.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and were in compliance with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Funding

JKG reports grant funding from the Kellen Foundation - Hospital for Special Surgery Clinician Scientist Development Award. RTD reports grant funding from the NIH-NIAMS (R21 AR066405-01) during the conduct of the study.

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Topical Collection on Scleroderma

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Gordon, J.K., Domsic, R.T. Clinical Trial Design Issues in Systemic Sclerosis: an Update. Curr Rheumatol Rep 18, 38 (2016). https://doi.org/10.1007/s11926-016-0582-z

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Keywords

  • Systemic sclerosis
  • Scleroderma
  • Clinical trial design