TABLE 1

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

Study [ref.]DurationSample sizeTreatment centres nInclusion criteriaMeasures of progression
FVCHRCTDeaths
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
1418–75 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 recordedNo deaths reported
focuSSced [35]48 weeks (double-blind)
96 weeks (open-label extension)
Placebo: n=106
TCZ: n=104
83Diagnosis 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
118–60 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 recordedRTX: 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%
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 reportedPlacebo: 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 recordedPlacebo: 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: DLCO % 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
2918–65 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 recordedHR 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
2618–69 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 involvement
Not recordedChange 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; 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.