Mycophenolate Versus Placebo for the Treatment of Systemic Sclerosis-Related Interstitial Lung Disease

Elizabeth R. Volkmann¹, Donald P. Tashkin², Ning Li³, Michael Roth⁴, Dinesh Khanna⁵, Anna-Maria Hoffmann-Vold⁶, Philip J. Clements⁴, Daniel E. Furst¹, Robert Elashoff⁷ and Scleroderma Lung Study II Group, ¹University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, ²David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, ³UCLA, Los Angeles, CA, ⁴Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, ⁵University of Michigan, Ann Arbor, MI, ⁶Oslo University Hospital, Oslo, Norway, ⁷Biomathematics, University of California, Los Angeles, Los Angeles, CA

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: interstitial lung disease, mycophenolate mofetil, Systemic sclerosis and therapy

Session Information

Date: Sunday, November 13, 2016

Title: Systemic Sclerosis, Fibrosing Syndromes, and Raynaud's – Clinical Aspects and Therapeutics - Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Compared with placebo, treatment with cyclophosphamide (CYC) improved lung function and dyspnea in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD).¹ While treatment with mycophenolate (MMF) is also associated with improvements in lung function,² no studies have directly compared mycophenolate with placebo for the treatment of SSc-ILD.

Methods: Participants enrolled in the placebo arm (N=79) of Scleroderma Lung Study (SLS) I and the MMF arm of SLS II (N=69) were included in these analyses. SLS I randomized participants to oral CYC versus placebo for 1 year, while SLS II randomized participants to MMF for 2 years versus oral CYC for 1 year followed by 1 year of placebo. Eligibility criteria for SLS I and II were nearly identical. The primary outcome was FVC%-predicted and key secondary outcomes included the DLCO%-predicted and quantitative radiographic extent of ILD. FVC and DLCO were measured every 3 months. Because radiographic imaging outcomes were evaluated at 12 and 24 months for SLS I and SLS II, respectively, we could not directly compare these outcomes. Mixed models were created to evaluate the treatment effect on the course of the FVC, DLCO, and patient-reported outcomes, over 12-months while controlling for baseline disease severity.

Results: SLS II participants assigned to MMF had similar baseline characteristics compared with SLS I participants assigned to placebo in terms of gender (65% vs. 70%), disease duration (mean [SD] years: 2.6 [1.7] vs. 3.1 [1.8]), SSc subtype (62% vs. 57% diffuse), and FVC%-predicted (mean [SD]: 66.5 [8.3] vs. 68.6 [13]), respectively. SLS II MMF patients were slightly older (mean [SD] years: 52.6 [9.7] vs. 48.1 [12.4]; P=0.015) and had a higher DLCO%-predicted (mean [SD]: 54.0 [11.1] vs. 46.2 [13.3]; P=0.0002) than SLS I placebo participants. After adjusting for baseline quantitative lung fibrosis in the zone of maximum involvement (QLF-ZM) and baseline FVC%-predicted, treatment with MMF was associated with an improved course of FVC%-predicted over 12 months (P=0.0008; Table 1a). Treatment with MMF was also associated with an improved course of DLCO%-predicted over 12 months (P=0.038; Table 1b), after adjusting for baseline QLF-ZM and baseline DLCO%-predicted.

Conclusion: Although there are inherent limitations in comparing participants from two different trials, the baseline characteristics of the SLS I and SLS II participants were relatively similar. Compared with placebo, treatment with MMF was associated with improved course of the FVC and DLCO over 12 months in patients with SSc-ILD, and this treatment effect appeared more robust than the treatment effect reported in SLS I comparing CYC with placebo. These results further substantiate the use of MMF for the treatment of SSc-ILD. References:

1. Tashkin DP, et al. NEJM 2006;354:2655-66.

2. Tashkin DP, et al. Lancet Resp Med 2016 (In press).

Table 1a. Treatment with MMF is associated with improved course of FVC%-predicted over 3-12 months compared with placebo
Variable	Estimate	Standard Error	P-Value
Baseline FVC	0.85	0.03	<0.001
Baseline QLF-ZM	-0.05	0.01	<0.001
Treatment Group x Time*	0.37	0.11	0.0008
Table 1b. Treatment with MMF is associated with improved course of DLCO%-predicted over 3-12 months compared with placebo
Variable	Estimate	Standard Error	P-Value
Baseline DLCO	0.96	0.04	<0.001
Baseline QLF-ZM	0.09	0.03	0.0027
Treatment Group x Time*	0.56	0.27	0.038
*Reference group is placebo; MMF participants had improved course of FVC and DLCO.

Disclosure: E. R. Volkmann, None; D. P. Tashkin, None; N. Li, None; M. Roth, None; D. Khanna, Bristol-Myers Squibb, 2,Pfizer Inc, 2,Roche Pharmaceuticals, 5,Sanofi-Aventis Pharmaceutical, 5,BAYER, 5,CYTORI, 5,EMD Serono, 5,Roche Pharmaceuticals, 2,Actelion Pharmaceuticals US, 5; A. M. Hoffmann-Vold, None; P. J. Clements, None; D. E. Furst, AbbVie, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech,UCB Consultant AbbVie, Amgen, BMS, Cytori, Janssen, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB Speaker's Bureau (CME ONLY) AbbVie, Actelion, UCB, 2; R. Elashoff, None.

To cite this abstract in AMA style:

Volkmann ER, Tashkin DP, Li N, Roth M, Khanna D, Hoffmann-Vold AM, Clements PJ, Furst DE, Elashoff R. Mycophenolate Versus Placebo for the Treatment of Systemic Sclerosis-Related Interstitial Lung Disease [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/mycophenolate-versus-placebo-for-the-treatment-of-systemic-sclerosis-related-interstitial-lung-disease/. Accessed .

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