Surfactant Protein D and Krebs Von Den Lungen-6 Predict Severity of Systemic Sclerosis-Related Interstitial Lung Disease in Two Independent Cohorts

Elizabeth R. Volkmann¹, Donald P. Tashkin², Faye N. Hant³, Galina S. Bogatkevich⁴, Michael Roth⁵, Kim Hyun⁶, Jonathan Goldin¹, Tanjina Akter⁷, Holly Wilhalme¹, Chi-hong Tseng⁵, Shervin Assassi⁸, Dinesh Khanna⁹, Philip J. Clements⁵, Daniel E. Furst¹, Robert Elashoff¹⁰ and Richard Silver¹¹, 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, ³Medicine/Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, ⁴Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, ⁵Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, ⁶Radiology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, ⁷Department of Rheumatology, Medical University of South Carolina, Charleston, SC, ⁸Department of Internal Medicine - Rheumatology, University of Texas-McGovern Medical School, Houston, TX, ⁹University of Michigan, Ann Arbor, MI, ¹⁰Biomathematics, University of California, Los Angeles, Los Angeles, CA, ¹¹Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC

Meeting: ACR/ARHP Annual Meeting 2016

Date of first publication: September 28, 2016

Keywords: Biomarkers, interstitial lung disease and systemic sclerosis

Session Information

Date: Wednesday, November 16, 2016

Title: Systemic Sclerosis, Fibrosing Syndromes, and Raynaud's – Clinical Aspects and Therapeutics III

Session Type: ACR Concurrent Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: A prior study of patients with systemic sclerosis-related interstitial lung disease (SSc-ILD) demonstrated that serum concentrations of surfactant protein D (SP-D) and Krebs von den Lungen-6 (KL-6), were higher in patients with active alveolitis compared with patients without alveolitis.¹ This present study aimed to further investigate the relationship between KL-6 and SP-D and extent and progression of SSc-ILD in two independent cohorts.

Methods: Patients enrolled in Scleroderma Lung Study (SLS) I and II were included. For SLS I, 158 patients were randomized to oral cyclophosphamide (CYC) versus placebo for 1 year. For SLS II, 142 patients were randomized to receive mycophenolate (MMF) for 2 years or oral CYC for 1 year followed by 1 year of placebo. ELISA kits determined the baseline levels of circulating SP-D and KL-6 in 66 and 136 SLS I and II participants, respectively. Extent of ILD was assessed using pulmonary function tests (FVC, DLCO) and quantitative image analysis (extent of fibrosis [QLF] and ILD [QILD] for the whole lung [WL] and zone of maximum involvement [ZM]). To investigate the relationship between baseline SP-D and KL-6 and progression of ILD, a mixed model was created with the outcome of the course of DLCO over 2 years, and a linear regression model was created with the outcome of QLF/QILD score at 2 years (SLS II cohort). Both models controlled for treatment assignment and baseline ILD severity.

Results: We observed significant correlations between KL-6 and SP-D and extent of ILD. In SLS II, KL-6 was correlated with (r; P-value): DLCO (-0.3; 0.0002), QLF-ZM (0.4; <0.0001), QLF-WL (0.5; <0.0001); QILD-ZM (0.5; <0.0001); QILD-WL (0.5; <0.0001); while SP-D was correlated with: DLCO (-0.3; 0.0005), QLF-WL (0.2; 0.03); QILD-ZM (0.3; 0.003); QILD-WL (0.3; 0.0007). In SLS I, KL-6 was correlated with (r; P-value): DLCO (-0.4; 0.003), QLF-ZM (0.3; 0.01); while SP-D was correlated with: DLCO (-0.3; 0.05), QLF-ZM (0.3; 0.02). However, neither KL-6, nor SP-D was significantly correlated with FVC in both cohorts (P>0.4). There were no significant differences in KL-6 or SP-D levels between patients with diffuse versus limited cutaneous disease or between treatment arms in SLS II. In the mixed model (SLS II data), patients with low KL-6 at baseline had a trend for an improvement in the DLCO over 24 months (P=0.06) (Table 1a). Low KL-6 at baseline was significantly associated with improvement in QILD-WL (P=0.03) (Table 1b).

Conclusion: KL-6 and SP-D each were associated with extent of ILD as measured by quantitative fibrosis and DLCO, but not by FVC, in SLS I and II participants. Patients with lower baseline KL-6 appeared to respond more favorably to immunosuppression with MMF/CYC, suggesting that levels of this glycoprotein may be used in conjunction with clinical factors to predict prognosis in SSc-ILD. References: 1. Hant FN, et al. J Rheumatol 2009;36:773-80.

Table 1a. Low baseline KL-6 is associated with improved course of DLCO over 24 months in SLS II participants in mixed model
Variable	Estimate	Standard Error	P-Value
Treatment arm*	-3.9	1.4	0.005
Baseline DLCO	0.8	0.06	<0.001
Low KL-6	2.7	1.5	0.06
Table 1b. Low baseline KL-6 is associated with improved QILD-WL at 24 months in SLS II participants in linear regression model
Variable	Estimate	Standard Error	P-Value
Treatment arm*	0.7	1.8	0.7
Baseline QILD-WL	-0.3	0.08	0.0003
Low KL-6	-4.3	2.0	0.03
*Reference group is CYC; MMF participants had improved course of DLCO.

Disclosure: E. R. Volkmann, None; D. P. Tashkin, None; F. N. Hant, None; G. S. Bogatkevich, None; M. Roth, None; K. Hyun, None; J. Goldin, None; T. Akter, None; H. Wilhalme, None; C. H. Tseng, None; S. Assassi, Boehringer Ingelheim, 5,Genentech and Biogen IDEC Inc., 2,Bayer HealthCare, 2; 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; 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; R. Silver, NIAMS-NIH, 2,PCORI, 2,IBio, 5,inPractice Rheumatology, 5,Bayer, 2,Bristol-Myers Squibb, 2,Boehringer Ingelheim, 2,Actelion Pharmaceuticals US, 5.

To cite this abstract in AMA style:

Volkmann ER, Tashkin DP, Hant FN, Bogatkevich GS, Roth M, Hyun K, Goldin J, Akter T, Wilhalme H, Tseng CH, Assassi S, Khanna D, Clements PJ, Furst DE, Elashoff R, Silver R. Surfactant Protein D and Krebs Von Den Lungen-6 Predict Severity of Systemic Sclerosis-Related Interstitial Lung Disease in Two Independent Cohorts [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/surfactant-protein-d-and-krebs-von-den-lungen-6-predict-severity-of-systemic-sclerosis-related-interstitial-lung-disease-in-two-independent-cohorts/. Accessed .

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