Natural variability in the disease course of SSc-ILD: implications for treatment

Madelon C. Vonk; Ulrich A. Walker; Elizabeth R. Volkmann; Michael Kreuter; Sindhu R. Johnson; Yannick Allanore

doi:10.1183/16000617.0340-2020

Tables

TABLE 1

Progression in clinical trials of systemic sclerosis-associated interstitial lung disease (SSc-ILD)

Study [ref.]	Duration	Sample size	Treatment centres n	Inclusion criteria	Measures of progression
Study [ref.]	Duration	Sample size	Treatment centres n	Inclusion criteria	FVC	HRCT	Deaths
SLS I [31]	12 months (double-blind)	Placebo: n=72 CYC: n=73	13	>18 years of age dcSSc or lcSSc Evidence of acute alveolitis on BAL examination or ground-glass opacity on HRCT Onset of first (non-Raynaud) SSc symptom within 7 years FVC % pred 45–85% Grade 2 exertional dyspnoea on Mahler Dyspnoea Index	Change in mean±se FVC % pred: Placebo: −2.6±0.9% CYC: −1.0±0.9%	Proportion of patients with worsening of fibrosis after 12 months [32]: Placebo: 26/49 (53%) CYC: 14/49 (29%)	During randomised treatment period: Placebo: 3/79 CYC: 2/79
SLS II [33]	24 months (double-blind)	CYC: n=63 MMF: n=63	14	18–75 years of age dcSSc or lcSSc FVC % pred 45–85% Any ground-glass opacity on HRCT (whether associated with reticulations or not) Onset of first (non-Raynaud) SSc symptom within 7 years Grade 2 exertional dyspnoea on Mahler Dyspnoea Index	Change in mean±se FVC % pred: CYC: +3.0±1.2% MMF: +3.3±1.1%	Change in whole lung scores: QLF score: CYC: +1.13% MMF: +2.15% QILD score: CYC: −1.84% MMF: −0.95%	During randomised treatment period: CYC: 11/73 MMF: 5/69
faSScinate [34]	48 weeks (double-blind) 96 weeks (open-label extension)	Placebo: n=44 TCZ: n=43 Placebo-TCZ: n=24 Continuous TCZ: n=27	35	>18 years of age Diagnosis of SSc as per 1980 ACR criteria Onset of first (non-Raynaud) SSc symptom within 5 years mRSS score 15–40 Active disease (defined by pre-specified mRSS/biomarker criteria)	Change in mean (95% CI) FVC % pred: Placebo −0.06% (−0.10– −0.03) at 48 weeks −0.03% (−0.07–0.01) at 96 weeks TCZ −0.02% (−0.04–0.00) at 48 weeks −0.01% (−0.03–0.02) at 96 weeks	Not recorded	No deaths reported
focuSSced [35]	48 weeks (double-blind) 96 weeks (open-label extension)	Placebo: n=106 TCZ: n=104	83	Diagnosis of SSc as per ACR/EULAR criteria, meeting criteria for active disease Total disease duration ≤60 months mRSS score 10–35	Change in median (95% CI) FVC % pred: Placebo: −3.9% (−4.8– −1.6) TCZ: −0.6% (−2.4– −0.9)	Change in whole lung scores: QLF in double-blind period (mean (95% CI)): Placebo: 0.4 (0–0.7) TCZ: −0.4 (−0.9–0.1) QILD: Placebo: 0.1 (−1.4–1.6) TCZ: −1.7 (−3.0– −0.4)	In double-blind period: Placebo: 1/106 TCZ: 1/104
*RTX versus* CYC [36]**	6 months (open-label)	RTX: n=30 CYC: n=30	1	18–60 years of age dcSSc, as per ACR classification criteria Scl-70 antibody positivity ILD confirmed by HRCT and PFTs (FVC % pred 45–85%) Onset of first (non-Raynaud) SSc symptom within 3 years Baseline dyspnoea level of NYHA class II and III	Change in mean FVC % pred: RTX: +6.2% CYC: −1.3%	Not recorded	RTX: 1/30 CYC: 1/30
SENSCIS [37]	52 weeks (double-blind)	Placebo: n=288 Nintedanib: n=287	195	>18 years of age SSc as per ACR/EULAR classification criteria Onset of first (non-Raynaud) SSc symptom within 7 years ILD confirmed by >10% fibrosis on HRCT within 12 months of screening FVC % pred >40% D_LCO % pred 30–89%	Annual rate±se of decline in FVC % pred: Placebo: −2.6±0.4% Nintedanib: −1.4±0.4%	Data collected, to be reported	Placebo: 9/288 Nintedanib: 10/288
ASSET [38]	12 months (double-blind)	Placebo: n=44 Abatacept: n=44		≥18 years old SSc as per ACR/EULAR criteria, and dcSSc defined as per early SSc criteria [39] Disease duration of ≤36 months (time from the first non-Rayaud symptom)	Change in FVC % pred (LSM±se): Placebo: −4.1±1.2% Abatacept: −1.3±1.2%	Not recorded	Placebo: 1/44 Abatacept: 2/44
ASSIST [40]	24 months (open-label)	CYC: n=9 HSCT: n=10	1	<60 years of age dcSSc (mRSS score >14 and cutaneous involvement proximal to the elbow or knee) Internal organ involvement: D_LCO % pred <80%; decline in FVC % pred >10% within past 12 months; lung fibrosis or ground-glass opacities on HRCT; ECG or GI involvement	Change in mean±sd FVC % pred: At 12 months: CYC: −6% HSCT: +12% At 24 months: HSCT: +12%	Volume of diseased lung on HRCT: At 12 months: CYC: +108 mL HSCT: −272 mL At 24 months: HSCT: −341 mL	No deaths
ASTIS [41]	24 months^# (open-label)	CYC: n=64 HSCT: n=67	29	18–65 years of age dcSSc as per ACR criteria Maximum disease duration of 4 years mRSS score >15 Involvement of heart, lungs or kidneys Prior treatment with CYC allowed up to a cumulative dose of 5 g intravenously, or up to 2 mg·kg⁻¹ body weight orally for 3 months	Change in mean±sd FVC % pred: HSCT: +6.3±18.3% CYC: −2.8±17.2%	Not recorded	HR for overall survival: 1 year=0.48 (95% CI 0.25–0.91; p=0.02) 2 years=0.29 (0.13–0.65; p=0.002) 4 years=0.29 (0.13–0.64; p=0.002)
SCOT [42]	54 months (open-label)	CYC: n=39 HSCT: n=36	26	18–69 years of age SSc as per ACR criteria Maximum disease duration of 5 years Active ILD (determined by BAL composition or chest CT) FVC or D_LCO <70% pred renal involvement	Not recorded	Change from baseline in QILD score (±se) at 54 months [43]: CYC: 0±5% HSCT: −7±2% Change from baseline in QLF score (±se) at 54 months [65]: CYC: +3±3% HSCT: −1±1%	Treatment-related mortality at 54 months: CYC: 0/39 HSCT: 1/36

FVC: forced vital capacity; HRCT: high-resolution computed tomography; SLS: Scleroderma Lung Study; RTX: rituximab; CYC: cyclophosphamide; dcSSc: diffuse cutaneous SSc; lcSSc: limited cutaneous SSc; BAL: bronchoalveolar lavage; MMF: mycophenolate mofetil; QLF: quantitative lung fibrosis; QILD: quantitative ILD; TCZ: tocilizumab; ACR: American College of Rheumatology; mRSS: modified Rodnan skin score; EULAR: European League Against Rheumatism; PFT: pulmonary function test; NYHA: New York Heart Association; D_LCO: diffusing capacity for carbon monoxide; LSM: least squares mean; HSCT: haematopoietic stem cell transplantation; GI: gastrointestinal; CT: computed tomography. ^#: after 10 years of follow-up, HSCT was associated with improved overall and event-free survival compared with CYC.

TABLE 2

Risk factors for mortality and disease progression in systemic sclerosis-associated interstitial lung disease (SSc-ILD)

First author [ref.]	Study design and patient numbers	Independent risk factor(s)	Measure of progression
Steen [73]	Analysis of 890 patients evaluated in a US centre between 1972 and 1989	Disease severity (FVC % pred)	10-year cumulative survival
Tyndall [4]	Analysis of data from 2940 patients in the EUSTAR database	FVC <80% pred and D_LCO <80% pred	Mortality
Zhang [74]	Analysis of 1043 patients from the Canadian Scleroderma Research Group (multicentre database)	Symptoms of oesophageal dysmotility	Low FVC (<70%)
Ahmed [75]	Observational cohort of 188 patients form the Toronto Scleroderma Programme	Baseline FVC pred <70% and D_LCO pred <77%, higher age at baseline (adjusted for FVC and D_LCO)	Mortality
Nihtyanova [71]	Single-centre cohort of 398 consecutive patients with SSc followed for up to 15 years	Higher age at onset, dcSSc, lower FVC and D_LCO, presence of anti-topoisomerase I antibodies	Clinically significant pulmonary fibrosis (FVC or D_LCO <55% pred or documented decline in FVC or D_LCO <15%)
Ryerson [76]	Application of four risk-prediction models (derived from IPF) to 156 patients recruited from a specialised SSc-ILD clinic	Baseline FVC, 6-min walk distance	1-year mortality
Okamoto [77]	Retrospective analysis of 35 patients with SSc-ILD	Usual interstitial pattern on HRCT, higher score for ground-glass attenuation with traction bronchiectasis on HRCT	Mortality
Elhai [5]	Analysis of data from 11 193 patients in the EUSTAR database	ILD, D_LCO <60% pred, FVC <70% pred	Mortality
Volkmann [78]	Long-term, follow-up analysis of patients in SLS I and II (up to 12 years in SLS I (median 8 years), n=158; up to 8 years in SLS II (median 4 years), n=142)	Decline in FVC and D_LCO over 24 months, increased age, increased mRSS	Mortality
Becker [79]	Analysis of 706 patients with diffuse SSc and 12 months of follow-up from the EUSTAR database	Advanced age (>60 years), active digital ulcer; lung fibrosis (FVC <60% or FVC <70% with presence of fibrosis on HRCT), muscle weakness, elevated C-reactive protein	Disease progression^#
Hoffmann-Vold [2]	Prospective Norwegian cohort study of 815 patients with SSc	>25% fibrosis on HRCT	Mortality
Hoffmann-Vold [30]	Analysis of 826 patients with FVC measures available at baseline and after 12 months from the EUSTAR database	Male sex, higher mRSS, presence of gastro-oesophageal reflux disease at baseline	FVC decline over a 5-year period

FVC: forced vital capacity; EUSTAR: European Scleroderma Trials and Research; D_LCO: diffusing capacity of the lungs for carbon monoxide; dcSSc: diffuse cutaneous SSc; IPF: idiopathic pulmonary fibrosis; HRCT: high-resolution computed tomography; SLS: Scleroderma Lung Study; mRSS: modified Rodnan skin score. ^#: new renal crisis, decrease of lung or heart function, new echocardiography-suspected pulmonary hypertension or death.