Progression of Skin Fibrosis Is Associated with Decline in Lung Function in Patients with Diffuse Cutaneous Systemic Sclerosis: A European Scleroderma Trials and Research (EUSTAR) Analysis

Wanlong Wu¹, Suzana Jordan², Nicole Graf³, Janethe Pena⁴, John Curram⁵, Yannick Allanore⁶, Marco Matucci-Cerinic⁷, Janet E. Pope⁸, Christopher Denton⁹, Dinesh Khanna¹⁰ and Oliver Distler¹, ¹Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland, ²Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland, ³Graf Biostatistics, Winterthur, Switzerland, ⁴Bayer HealthCare Pharmaceuticals Inc, Whippany, NJ, ⁵Bayer Plc, Newbury, United Kingdom, ⁶Department of Rheumatology, Cochin Hospital, Paris Descartes University, Paris, France, ⁷Dept of Medicine/Div of Rheum, University of Florence, Florence, Italy, ⁸Department of Medicine, Division of Rheumatology, University of Western Ontario, St Joseph's Health Care, London, ON, Canada, ⁹Department of Rheumatology, University College London, Royal Free Hospital, London, United Kingdom, ¹⁰Division of Rheumatology, Department of Internal Medicine, Scleroderma Program, University of Michigan, Ann Arbor, MI

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: longitudinal studies, pulmonary fibrosis, recruitment, skin fibrosis and systemic sclerosis

Session Information

Date: Sunday, November 5, 2017

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:

Previously, we have identified short disease duration (≤15 months) and low baseline modified Rodnan skin score (mRSS) (≤22/51) as independent predictors of progressive skin fibrosis (>5 mRSS units and ≥25% increment within 1 year) in patients with diffuse cutaneous systemic sclerosis (dcSSc). While this strategy has resulted in recruitment of more patients with progression of skin fibrosis in clinical trials, it might lead to recruitment of patients with less severe internal organ disease. This study was designed to determine whether progression of skin fibrosis is associated with progression of internal organ disease on longitudinal follow-up of patients with dcSSc.

Methods:

This study analyzed prospectively collected data from the EUSTAR cohort. Inclusion criteria were: diagnosis of SSc fulfilling ACR criteria, diffuse cutaneous involvement, mRSS ≥7 at baseline visit in 2009 or later, valid mRSS with a time interval of 12±3 months after baseline visit, and at least one available annual follow-up visit.

Progression of skin fibrosis was defined as an increase in mRSS >5 units and ≥25% from baseline to 12±3 months later. The outcome was defined as one of the following new events occurring at any follow-up visit based on expert group consensus: 1) renal crisis; 2) decrease in forced vital capacity (FVC) ≥10%; 3) left ventricular ejection fraction (LVEF) <45% or decrease in LVEF by >10% for patients with baseline LVEF <50%; 4) pulmonary hypertension (PH) on echocardiography as judged by the investigator; 5) death.

Kaplan–Meier analyses and log-rank tests were used to compare disease progression between progressors and non-progressors for up to 6 years of follow-up.

Results:

A total of 871 dcSSc patients were eligible. The median follow-up period was 3.26 years (IQR: 1.49–5.14). Sixty-seven (7.7%) patients had worsening of skin fibrosis within 1 year (defined as progressors). Cumulatively, 235/666 (35.3%) patients had a decrease in FVC ≥10%, 96/593 (16.2%) had new PH, 22/564 (3.9%) had worsening LVEF, 16/844 (1.9%) had a new renal crisis, and 58/871 (6.7%) died. Mean FVC% at baseline was 87.2% ± 20.4%, while 134 (20.1%) patients had baseline FVC% <70%.

Log-rank tests indicated the probability for a decrease in FVC ≥10% was significantly higher for progressors than non-progressors (53.2% vs. 33.9%, p=0.004) (Figure). There were non-significant differences in probabilities for new PH (9.5% vs. 16.7%), worsening LVEF (7.3% vs. 3.6%), new renal crisis (0.0% vs. 2.1%) and death (7.5% vs. 6.6%) between progressors and non-progressors.

Conclusion:

Progression of skin fibrosis is associated with a decline in lung function in dcSSc patients over follow-up. Our data indicate that evidence-based criteria for cohort enrichment of progressive skin fibrosis might also be appropriate to recruit more dcSSc patients at higher risk of lung function decline in future clinical trials.

Disclosure: W. Wu, None; S. Jordan, None; N. Graf, Biotronik AG, 5; J. Pena, Bayer Healthcare Pharmaceuticals Inc, 3; J. Curram, Bayer Plc, 1,Bayer Plc, 3; Y. Allanore, Actelion Pharmaceuticals US, 2,Bayer AG, 2,Bristol-Myers Squibb, 2,Inventiva, 2,Medac, 2,Pfizer Inc, 2,Roche Pharmaceuticals, 2,Genentech and Biogen IDEC Inc., 2,Sanofi-Aventis Pharmaceutical, 2,Servier, 2,Actelion Pharmaceuticals US, 5,Bayer AG, 5,Bristol-Myers Squibb, 5,Inventiva, 5,Medac, 5,Pfizer Inc, 5,Roche Pharmaceuticals, 5,Genentech and Biogen IDEC Inc., 5,Sanofi-Aventis Pharmaceutical, 5; M. Matucci-Cerinic, None; J. E. Pope, Actelion, 2,Bayer AG, 2,Bristol-Myers Squibb, 2,Merck, 2,Pfizer Inc, 2,Roche, 2,Actelion, 5,Bayer AG, 5,Bristol-Myers Squibb, 5,Merck, 5,Pfizer Inc, 5,Roche, 5; C. Denton, Actelion Pharmaceuticals US, 5,Bayer AG, 5,GlaxoSmithKline, 5,CSL Behring, 5,Merck-Serono, 5,Roche Pharmaceuticals, 5,Genentech and Biogen IDEC Inc., 5,Inventiva, 5,Sanofi-Aventis Pharmaceutical, 5,Boehringer Ingelheim, 5,Actelion Pharmaceuticals US, 8,Bayer AG, 8,GlaxoSmithKline, 8,CSL Behring, 8,Merck-Serono, 8,Roche Pharmaceuticals, 8,Genentech and Biogen IDEC Inc., 8,Inventiva, 8,Sanofi-Aventis Pharmaceutical, 8,Boehringer Ingelheim, 8; D. Khanna, Bristol-Myers Squibb, 2,Genentech/Roche, 2,NIH/NIAMS, 2,NIH/NIAID,, 2,Patient-Centered Outcomes Research Institute, 2,Scleroderma Foundation, 2,Actelion Pharmaceuticals US, 5,Bayer AG, 5,Cytori, 5,EMD Serono, 5,Genkyotex, 5,Gilead, 5,GlaxoSmithKline, 5,Genentech/Roche, 5,Sanofi-Aventis Pharmaceutical, 5,Seattle Genetics, 5; O. Distler, Actelion, 5,Bayer, 5,Biogen Idec, 5,Boehringer Ingelheim, 5,ChemomAb, 5,espeRare Foundation, 5,Genentech/Roche, 5,GlaxoSmithKline, 5,Inventiva, 5,Lilly, 5,Medac, 5,MedImmune, 5,Mitsubishi Tanabe Pharma, 5,Pharmacyclics, 5,Novartis Pharmaceutical Corporation, 5,Pfizer Inc, 5,Sanofi, 5,Sinoxa, 5,UCB in the area of potential treatments of scleroderma and its complications, 5,Patent mir-29 for the treatment of systemic sclerosis licensed, 5,Actelion, 2,Bayer, 2,Biogen Idec, 2,Boehringer Ingelheim, 2,ChemomAb, 2,espeRare Foundation, 2,Genentech/Roche, 2,GlaxoSmithKline, 2,Inventiva, 2,Lilly, 2,Medac, 2,Medimmune, 2,Mitsubishi Tanabe Pharma, 2,Pharmacyclics, 2,Novartis, 2,Pfizer Inc, 2,Sanofi, 2,Sinoxa, 2,UCB in the area of potential treatments of scleroderma and its complications, 2,Patent mir-29 for the treatment of systemic sclerosis licensed, 2.

To cite this abstract in AMA style:

Wu W, Jordan S, Graf N, Pena J, Curram J, Allanore Y, Matucci-Cerinic M, Pope JE, Denton C, Khanna D, Distler O. Progression of Skin Fibrosis Is Associated with Decline in Lung Function in Patients with Diffuse Cutaneous Systemic Sclerosis: A European Scleroderma Trials and Research (EUSTAR) Analysis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/progression-of-skin-fibrosis-is-associated-with-decline-in-lung-function-in-patients-with-diffuse-cutaneous-systemic-sclerosis-a-european-scleroderma-trials-and-research-eustar-analysis/. Accessed .

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