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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
European Respiratory Review 2021 30: 200340; DOI: 10.1183/16000617.0340-2020
Madelon C. Vonk
1Dept of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
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Ulrich A. Walker
2Dept of Rheumatology, University Hospital Basel, Basel, Switzerland
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Elizabeth R. Volkmann
3Dept of Medicine, Division of Rheumatology, University of California, David Geffen School of Medicine, Los Angeles, CA, USA
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Michael Kreuter
4Center for Interstitial and Rare Lung Diseases, Pneumology and Respiratory Care Medicine, Thoraxklinik, University of Heidelberg and German Center for Lung Research, Heidelberg, Germany
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Sindhu R. Johnson
5University Health Network, Mount Sinai Hospital, Institute for Health Policy Management and Evaluation, University of Toronto, Toronto, ON, Canada
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Yannick Allanore
6Dept of Rheumatology A, Descartes University, APHP, Cochin Hospital, Paris, France
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Tables

  • 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.

    • 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 numbersIndependent risk factor(s)Measure of progression
      Steen [73]Analysis of 890 patients evaluated in a US centre between 1972 and 1989Disease severity (FVC % pred)10-year cumulative survival
      Tyndall [4]Analysis of data from 2940 patients in the EUSTAR databaseFVC <80% pred and DLCO <80% predMortality
      Zhang [74]Analysis of 1043 patients from the Canadian Scleroderma Research Group (multicentre database)Symptoms of oesophageal dysmotilityLow FVC (<70%)
      Ahmed [75]Observational cohort of 188 patients form the Toronto Scleroderma ProgrammeBaseline 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 yearsHigher age at onset, dcSSc, lower FVC and DLCO, presence of anti-topoisomerase I antibodiesClinically 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 clinicBaseline FVC, 6-min walk distance1-year mortality
      Okamoto [77]Retrospective analysis of 35 patients with SSc-ILDUsual interstitial pattern on HRCT, higher score for ground-glass attenuation with traction bronchiectasis on HRCTMortality
      Elhai [5]Analysis of data from 11 193 patients in the EUSTAR databaseILD, DLCO <60% pred, FVC <70% predMortality
      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 mRSSMortality
      Becker [79]Analysis of 706 patients with diffuse SSc and 12 months of follow-up from the EUSTAR databaseAdvanced age (>60 years), active digital ulcer; lung fibrosis (FVC <60% or FVC <70% with presence of fibrosis on HRCT), muscle weakness, elevated C-reactive proteinDisease progression#
      Hoffmann-Vold [2]Prospective Norwegian cohort study of 815 patients with SSc>25% fibrosis on HRCTMortality
      Hoffmann-Vold [30]Analysis of 826 patients with FVC measures available at baseline and after 12 months from the EUSTAR databaseMale sex, higher mRSS, presence of gastro-oesophageal reflux disease at baselineFVC 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.

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      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
      European Respiratory Review Mar 2021, 30 (159) 200340; DOI: 10.1183/16000617.0340-2020

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      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
      European Respiratory Review Mar 2021, 30 (159) 200340; DOI: 10.1183/16000617.0340-2020
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      • Article
        • Abstract
        • Abstract
        • Introduction
        • Definitions of progression in SSc-ILD
        • Patterns of disease progression in SSc-ILD
        • Risk factors for development and progression of SSc-ILD
        • Implications for treatment
        • Conclusions
        • Acknowledgements
        • Footnotes
        • References
      • Figures & Data
      • Info & Metrics
      • PDF

      Subjects

      • Pulmonary vascular disease
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