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Published in: Arthritis Research & Therapy 1/2020

01-12-2020 | Systemic Sclerosis | Research article

Immunosuppressive treatment in diffuse cutaneous systemic sclerosis is associated with an improved composite response index (CRISS)

Authors: Boyang Zheng, Marie Hudson, Mianbo Wang, Murray Baron, for the Canadian Scleroderma Research Group

Published in: Arthritis Research & Therapy | Issue 1/2020

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Abstract

Background

Outcomes of therapeutic studies in diffuse cutaneous systemic sclerosis (dcSSc) have mainly been measured for specific organs, particularly the skin and lungs. A new composite response index in dcSSc (CRISS) has been developed for clinical trials. The goal of this study was to determine whether, in an observational dcSSc cohort, immunosuppression was associated with global disease improvement measured with the CRISS.

Methods

We conducted a retrospective cohort study in a multi-centered SSc registry comparing 47 patients newly exposed to immunosuppression for ≥ 1 year to 254 unexposed patients. Inverse probability of treatment weighting (IPTW) was performed to create comparable exposed and unexposed groups by balancing for age, sex, disease duration, modified Rodnan skin score (mRSS), forced vital capacity, patient and physician global assessments, and Health Assessment Questionnaire score. A CRISS score ≥ 0.6 at 1 year was defined as improvement.

Results

Exposed patients had shorter disease duration (5.5 versus 11.7 years, p < 0.01), more interstitial lung disease (67.4% versus 40.3%, p < 0.01), and worse physician global severity scores (4.2 versus 2.5 points, p < 0.01) compared to unexposed patients. Improvement in CRISS scores was more common in exposed patients after IPTW (odds ratio 1.85, 95% confidence interval 1.11, 3.09). Of the individual CRISS variables, only mean patient global assessment scores were significantly better among exposed than unexposed patients (− 0.4 versus 0 points, p = 0.03) while other variables including mRSS were similar.

Conclusion

Using a composite response measure, immunosuppression was associated with better outcomes at 1 year in a dcSSc cohort. These results provide real-world data that align with clinical trials to support our current use of immunosuppression.
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Literature
1.
go back to reference Clements PJ, Hurwitz EL, Wong WK, Seibold JR, Mayes M, White B, 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(11):2445–54.CrossRef Clements PJ, Hurwitz EL, Wong WK, Seibold JR, Mayes M, White B, 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(11):2445–54.CrossRef
2.
go back to reference Geirsson AJ, Wollheim FA, Akesson A. Disease severity of 100 patients with systemic sclerosis over a period of 14 years: using a modified Medsger scale. Ann Rheum Dis. 2001;60(12):1117–22.CrossRef Geirsson AJ, Wollheim FA, Akesson A. Disease severity of 100 patients with systemic sclerosis over a period of 14 years: using a modified Medsger scale. Ann Rheum Dis. 2001;60(12):1117–22.CrossRef
3.
go back to reference Hachulla E, Carpentier P, Gressin V, Diot E, Allanore Y, Sibilia J, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinerAIR-Sclerodermie study. Rheumatology (Oxford). 2009;48(3):304–8.CrossRef Hachulla E, Carpentier P, Gressin V, Diot E, Allanore Y, Sibilia J, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinerAIR-Sclerodermie study. Rheumatology (Oxford). 2009;48(3):304–8.CrossRef
4.
go back to reference Scussel-Lonzetti L, Joyal F, Raynauld JP, Roussin A, Rich E, Goulet JR, et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore). 2002;81(2):154–67.CrossRef Scussel-Lonzetti L, Joyal F, Raynauld JP, Roussin A, Rich E, Goulet JR, et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore). 2002;81(2):154–67.CrossRef
5.
go back to reference LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–5.PubMed LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–5.PubMed
6.
go back to reference Cappelli S, Bellando-Randone S, Guiducci S, Matucci-Cerinic M. Is immunosuppressive therapy the anchor treatment to achieve remission in systemic sclerosis? Rheumatology (Oxford). 2014;53(6):975–87.CrossRef Cappelli S, Bellando-Randone S, Guiducci S, Matucci-Cerinic M. Is immunosuppressive therapy the anchor treatment to achieve remission in systemic sclerosis? Rheumatology (Oxford). 2014;53(6):975–87.CrossRef
7.
go back to reference Denton CP, Hughes M, Gak N, Vila J, Buch MH, Chakravarty K, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford). 2016;55(10):1906–10.CrossRef Denton CP, Hughes M, Gak N, Vila J, Buch MH, Chakravarty K, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford). 2016;55(10):1906–10.CrossRef
8.
go back to reference Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327–39.CrossRef Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327–39.CrossRef
9.
go back to reference 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.CrossRef 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.CrossRef
10.
go back to reference Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, 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):708–19.CrossRef Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, 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):708–19.CrossRef
11.
go back to reference Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, 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. 2006;54(12):3962–70.CrossRef Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, 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. 2006;54(12):3962–70.CrossRef
12.
go back to reference Johnson SR, Feldman BM, Pope JE, Tomlinson GA. Shifting our thinking about uncommon disease trials: the case of methotrexate in scleroderma. J Rheumatol. 2009;36(2):323–9.CrossRef Johnson SR, Feldman BM, Pope JE, Tomlinson GA. Shifting our thinking about uncommon disease trials: the case of methotrexate in scleroderma. J Rheumatol. 2009;36(2):323–9.CrossRef
13.
go back to reference Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44(6):1351–8.CrossRef Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44(6):1351–8.CrossRef
14.
go back to reference Khanna D, Berrocal VJ, Giannini EH, Seibold JR, Merkel PA, Mayes MD, et al. The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2016;68(2):299–311.CrossRef Khanna D, Berrocal VJ, Giannini EH, Seibold JR, Merkel PA, Mayes MD, et al. The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2016;68(2):299–311.CrossRef
15.
go back to reference Johnson SR, Tomlinson GA, Hawker GA, Granton JT, Feldman BM. Propensity score methods for bias reduction in observational studies of treatment effect. Rheum Dis Clin N Am. 2018;44(2):203–13.CrossRef Johnson SR, Tomlinson GA, Hawker GA, Granton JT, Feldman BM. Propensity score methods for bias reduction in observational studies of treatment effect. Rheum Dis Clin N Am. 2018;44(2):203–13.CrossRef
16.
go back to reference Kang EH, Jin Y, Tong AY, Desai RJ, Kim SC. Risk of serious infection among initiators of TNF inhibitors plus methotrexate versus triple therapy for rheumatoid arthritis: a cohort study. Arthritis Care Res (Hoboken). 2020. https://doi.org/10.1002/acr.24038. Kang EH, Jin Y, Tong AY, Desai RJ, Kim SC. Risk of serious infection among initiators of TNF inhibitors plus methotrexate versus triple therapy for rheumatoid arthritis: a cohort study. Arthritis Care Res (Hoboken). 2020. https://​doi.​org/​10.​1002/​acr.​24038.
17.
go back to reference Johnson SR, Granton JT, Tomlinson GA, Grosbein HA, Le T, Lee P, et al. Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. J Rheumatol. 2012;39(2):276–85.CrossRef Johnson SR, Granton JT, Tomlinson GA, Grosbein HA, Le T, Lee P, et al. Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. J Rheumatol. 2012;39(2):276–85.CrossRef
18.
go back to reference Alhajeri H, Hudson M, Fritzler M, Pope J, Tatibouet S, Markland J, et al. 2013 American College of Rheumatology/European league against rheumatism classification criteria for systemic sclerosis outperform the 1980 criteria: data from the Canadian Scleroderma Research Group. Arthritis Care Res (Hoboken). 2015;67(4):582–7.CrossRef Alhajeri H, Hudson M, Fritzler M, Pope J, Tatibouet S, Markland J, et al. 2013 American College of Rheumatology/European league against rheumatism classification criteria for systemic sclerosis outperform the 1980 criteria: data from the Canadian Scleroderma Research Group. Arthritis Care Res (Hoboken). 2015;67(4):582–7.CrossRef
19.
go back to reference Khanna D, Furst DE, Hays RD, Park GS, Wong WK, Seibold JR, et al. Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum Dis. 2006;65(10):1325–9.CrossRef Khanna D, Furst DE, Hays RD, Park GS, Wong WK, Seibold JR, et al. Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum Dis. 2006;65(10):1325–9.CrossRef
20.
go back to reference Kafaja S, Clements PJ, Wilhalme H, Tseng CH, Furst DE, Kim GH, et al. Reliability and minimal clinically important differences of forced vital capacity: results from the Scleroderma Lung Studies (SLS-I and SLS-II). Am J Respir Crit Care Med. 2017;197(5):644–52.CrossRef Kafaja S, Clements PJ, Wilhalme H, Tseng CH, Furst DE, Kim GH, et al. Reliability and minimal clinically important differences of forced vital capacity: results from the Scleroderma Lung Studies (SLS-I and SLS-II). Am J Respir Crit Care Med. 2017;197(5):644–52.CrossRef
21.
go back to reference Sultan N, Pope JE, Clements PJ, Scleroderma Trials Study G. The health assessment questionnaire (HAQ) is strongly predictive of good outcome in early diffuse scleroderma: results from an analysis of two randomized controlled trials in early diffuse scleroderma. Rheumatology (Oxford). 2004;43(4):472–8.CrossRef Sultan N, Pope JE, Clements PJ, Scleroderma Trials Study G. The health assessment questionnaire (HAQ) is strongly predictive of good outcome in early diffuse scleroderma: results from an analysis of two randomized controlled trials in early diffuse scleroderma. Rheumatology (Oxford). 2004;43(4):472–8.CrossRef
22.
go back to reference Steele R, Hudson M, Lo E, Baron M, Canadian Scleroderma Research G. Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Care Res (Hoboken). 2012;64(4):519–24.CrossRef Steele R, Hudson M, Lo E, Baron M, Canadian Scleroderma Research G. Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Care Res (Hoboken). 2012;64(4):519–24.CrossRef
23.
go back to reference Baron M, Hudson M, Steele R, Lo E. Validation of the UCLA Scleroderma Clinica Trial Gastrointestinal Tract Instrument version 2.0 for systemic sclerosis. J Rheumatol. 2011;38(9):1925–30.CrossRef Baron M, Hudson M, Steele R, Lo E. Validation of the UCLA Scleroderma Clinica Trial Gastrointestinal Tract Instrument version 2.0 for systemic sclerosis. J Rheumatol. 2011;38(9):1925–30.CrossRef
24.
go back to reference Hsu VM, Moreyra AE, Wilson AC, Shinnar M, Shindler DM, Wilson JE, et al. Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization. J Rheumatol. 2008;35(3):458–65.PubMed Hsu VM, Moreyra AE, Wilson AC, Shinnar M, Shindler DM, Wilson JE, et al. Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization. J Rheumatol. 2008;35(3):458–65.PubMed
25.
go back to reference He H, Hu J, He J. Overview of propensity score methods. In: He H, Wu P, Chen D-G, editors. Statistical causal inferences and their applications in public health research. Cham: Springer International Publishing; 2016. p. 29–48.CrossRef He H, Hu J, He J. Overview of propensity score methods. In: He H, Wu P, Chen D-G, editors. Statistical causal inferences and their applications in public health research. Cham: Springer International Publishing; 2016. p. 29–48.CrossRef
26.
go back to reference Austin PC. Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement. J Thor Cardiovasc Surg. 2007;134(5):1128–35.e3.CrossRef Austin PC. Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement. J Thor Cardiovasc Surg. 2007;134(5):1128–35.e3.CrossRef
27.
go back to reference Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64(5):640–7.CrossRef Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012;64(5):640–7.CrossRef
28.
go back to reference Mikdashi J, Nived O. Measuring disease activity in adults with systemic lupus erythematosus: the challenges of administrative burden and responsiveness to patient concerns in clinical research. Arthritis Res Ther. 2015;17(1):183.CrossRef Mikdashi J, Nived O. Measuring disease activity in adults with systemic lupus erythematosus: the challenges of administrative burden and responsiveness to patient concerns in clinical research. Arthritis Res Ther. 2015;17(1):183.CrossRef
29.
go back to reference Herrick AL, Pan X, Peytrignet S, Lunt M, Hesselstrand R, Mouthon L, et al. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Ann Rheum Dis. 2017;76(7):1207–18.CrossRef Herrick AL, Pan X, Peytrignet S, Lunt M, Hesselstrand R, Mouthon L, et al. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Ann Rheum Dis. 2017;76(7):1207–18.CrossRef
30.
go back to reference Valentini G, Paone C, La Montagna G, Chiarolanza I, Menegozzo M, Colutta E, et al. Low-dose intravenous cyclophosphamide in systemic sclerosis: an open prospective efficacy study in patients with early diffuse disease. Scand J Rheumatol. 2006;35(1):35–8.CrossRef Valentini G, Paone C, La Montagna G, Chiarolanza I, Menegozzo M, Colutta E, et al. Low-dose intravenous cyclophosphamide in systemic sclerosis: an open prospective efficacy study in patients with early diffuse disease. Scand J Rheumatol. 2006;35(1):35–8.CrossRef
31.
go back to reference McSweeney PA, Nash RA, Sullivan KM, Storek J, Crofford LJ, Dansey R, et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood. 2002;100(5):1602–10.CrossRef McSweeney PA, Nash RA, Sullivan KM, Storek J, Crofford LJ, Dansey R, et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood. 2002;100(5):1602–10.CrossRef
32.
go back to reference van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311(24):2490–8.CrossRef van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311(24):2490–8.CrossRef
33.
go back to reference Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378(1):35–47.CrossRef Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378(1):35–47.CrossRef
34.
go back to reference Siegert E, Riemekasten G. Are we too lenient with immunosuppression in severe cases of systemic sclerosis? Rheumatology. 2016;55(10):1914–6.CrossRef Siegert E, Riemekasten G. Are we too lenient with immunosuppression in severe cases of systemic sclerosis? Rheumatology. 2016;55(10):1914–6.CrossRef
35.
go back to reference Melsens K, De Keyser F, Decuman S, Piette Y, Vandecasteele E, Smith V. Disease activity indices in systemic sclerosis: a systematic literature review. Clin Exp Rheumatol. 2016;34 Suppl 100(5):186–92.PubMed Melsens K, De Keyser F, Decuman S, Piette Y, Vandecasteele E, Smith V. Disease activity indices in systemic sclerosis: a systematic literature review. Clin Exp Rheumatol. 2016;34 Suppl 100(5):186–92.PubMed
36.
go back to reference Tay T, Ferdowsi N, Baron M, Stevens W, Hudson M, Proudman SM, et al. Measures of disease status in systemic sclerosis: a systematic review. Semin Arthritis Rheum. 2017;46(4):473–87.CrossRef Tay T, Ferdowsi N, Baron M, Stevens W, Hudson M, Proudman SM, et al. Measures of disease status in systemic sclerosis: a systematic review. Semin Arthritis Rheum. 2017;46(4):473–87.CrossRef
Metadata
Title
Immunosuppressive treatment in diffuse cutaneous systemic sclerosis is associated with an improved composite response index (CRISS)
Authors
Boyang Zheng
Marie Hudson
Mianbo Wang
Murray Baron
for the Canadian Scleroderma Research Group
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2020
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-020-02220-0

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