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 FVC HRCT Deaths SLS I [31] 12 months (double-blind) Placebo: n=72
CYC: n=7313 >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 IndexChange 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: 2/79SLS II [33] 24 months (double-blind) CYC: n=63
MMF: n=6314 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 IndexChange 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: 5/69faSScinate [34] 48 weeks (double-blind)
96 weeks (open-label extension)Placebo: n=44
TCZ: n=43
Placebo-TCZ: n=24
Continuous TCZ: n=2735 >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 weeksNot recorded No deaths reported focuSSced [35] 48 weeks (double-blind)
96 weeks (open-label extension)Placebo: n=106
TCZ: n=10483 Diagnosis of SSc as per ACR/EULAR criteria, meeting criteria for active disease
Total disease duration ≤60 months
mRSS score 10–35Change 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: 1/104RTX versus CYC [36] 6 months (open-label) RTX: n=30
CYC: n=301 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 IIIChange in mean FVC % pred:
RTX: +6.2%
CYC: −1.3%Not recorded RTX: 1/30
CYC: 1/30SENSCIS [37] 52 weeks (double-blind) Placebo: n=288
Nintedanib: n=287195 >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%
DLCO % 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: 10/288ASSET [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: 2/44ASSIST [40] 24 months (open-label) CYC: n=9
HSCT: n=101 <60 years of age
dcSSc (mRSS score >14 and cutaneous involvement proximal to the elbow or knee)
Internal organ involvement: DLCO % pred <80%; decline in FVC % pred >10% within past 12 months; lung fibrosis or ground-glass opacities on HRCT; ECG or GI involvementChange 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 mLNo deaths ASTIS [41] 24 months# (open-label) CYC: n=64
HSCT: n=6729 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 monthsChange 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=3626 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 DLCO <70% pred renal involvementNot 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: 1/36FVC: 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; DLCO: 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 DLCO <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 DLCO pred <77%, higher age at baseline (adjusted for FVC and DLCO) 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 DLCO, presence of anti-topoisomerase I antibodies Clinically significant pulmonary fibrosis (FVC or DLCO <55% pred or documented decline in FVC or DLCO <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, DLCO <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 DLCO 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; DLCO: 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.