Early Radiographic Progression of Scleroderma

Abstract

BackgroundRadiographic end points commonly are included in therapeutic trials for systemic sclerosis (SSc)-interstitial lung disease (ILD); however, the relationship between these outcomes and long-term mortality is unclear.Research QuestionDo short-term changes in radiographic measures of ILD predict long-term survival in patients with SSc?Study Design and MethodsThe Scleroderma Lung Study (SLS) I and II evaluated the safety and efficacy of cyclophosphamide (in SLS I and II) and mycophenolate mofetil (in SLS II) for the treatment of SSc-ILD. Changes in the extent of ILD over time were assessed on high-resolution CT scans of the chest by quantitative image analysis, an approach that applies a computer-based algorithm to assess changes in the radiographic extent of ILD objectively. Participants subsequently were followed for up to 12 years (SLS I) and 8 years (SLS II). Cox proportional hazards models determined whether the change in the quantitative radiographic extent of ILD predicted survival, adjusting for other known predictors of survival.ResultsAmong SLS I and II participants, 82 and 90 had follow-up imaging scans, respectively, and were included in the analysis. Participants in both trials who showed an increase in the total quantitative radiographic extent of ILD scores of ≥ 2% at 12 months (SLS I) or 24 months (SLS II) experienced significantly worse long-term survival than those with change scores of < 2% (P ≤ .01, log-rank test). In the multivariate Cox models, radiographic progression remained associated with worse long-term survival in SLS I (P = .089) and SLS II (P = .014).InterpretationData from two independent clinical trial cohorts with extensive long-term follow-up demonstrated that radiographic progression of ILD over 12 to 24 months, in both treatment and placebo arms, can predict increased risk for long-term mortality in patients with SSc. These findings suggest that radiographic end points may serve as surrogates for mortality in SSc-ILD. Radiographic end points commonly are included in therapeutic trials for systemic sclerosis (SSc)-interstitial lung disease (ILD); however, the relationship between these outcomes and long-term mortality is unclear. Do short-term changes in radiographic measures of ILD predict long-term survival in patients with SSc? The Scleroderma Lung Study (SLS) I and II evaluated the safety and efficacy of cyclophosphamide (in SLS I and II) and mycophenolate mofetil (in SLS II) for the treatment of SSc-ILD. Changes in the extent of ILD over time were assessed on high-resolution CT scans of the chest by quantitative image analysis, an approach that applies a computer-based algorithm to assess changes in the radiographic extent of ILD objectively. Participants subsequently were followed for up to 12 years (SLS I) and 8 years (SLS II). Cox proportional hazards models determined whether the change in the quantitative radiographic extent of ILD predicted survival, adjusting for other known predictors of survival. Among SLS I and II participants, 82 and 90 had follow-up imaging scans, respectively, and were included in the analysis. Participants in both trials who showed an increase in the total quantitative radiographic extent of ILD scores of ≥ 2% at 12 months (SLS I) or 24 months (SLS II) experienced significantly worse long-term survival than those with change scores of < 2% (P ≤ .01, log-rank test). In the multivariate Cox models, radiographic progression remained associated with worse long-term survival in SLS I (P = .089) and SLS II (P = .014). Data from two independent clinical trial cohorts with extensive long-term follow-up demonstrated that radiographic progression of ILD over 12 to 24 months, in both treatment and placebo arms, can predict increased risk for long-term mortality in patients with SSc. These findings suggest that radiographic end points may serve as surrogates for mortality in SSc-ILD. Take-home PointsStudy Question: Do short-term changes in radiographic measures of interstitial lung disease (ILD) predict long-term survival in patients with systemic sclerosis (SSc)?Results: In patients with SSc-ILD enrolled in two large randomized controlled trials, an increase in the quantitative radiographic extent of ILD of ≥ 2% over 1 to 2 years was associated with worse long-term survival.Interpretation: Short-term changes in the radiographic extent of ILD in patients with SSc receiving treatment or placebo may serve as a proxy for long-term mortality. Future SSc-ILD clinical trials should consider including radiographic end points to assess treatment response. Study Question: Do short-term changes in radiographic measures of interstitial lung disease (ILD) predict long-term survival in patients with systemic sclerosis (SSc)? Results: In patients with SSc-ILD enrolled in two large randomized controlled trials, an increase in the quantitative radiographic extent of ILD of ≥ 2% over 1 to 2 years was associated with worse long-term survival. Interpretation: Short-term changes in the radiographic extent of ILD in patients with SSc receiving treatment or placebo may serve as a proxy for long-term mortality. Future SSc-ILD clinical trials should consider including radiographic end points to assess treatment response. Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc)1Tyndall A.J. Bannert B. Vonk M. et al.Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database.Ann Rheum Dis. 2010; 69: 1809-1815Crossref PubMed Scopus (760) Google Scholar,2Elhai M. Meune C. Boubaya M. et al.Mapping and predicting mortality from systemic sclerosis.Ann Rheum Dis. 2017; 76: 1897-1905Crossref PubMed Scopus (240) Google Scholar and a major focus for therapeutic drug discovery in this field. Despite the burgeoning SSc-ILD therapeutic pipeline, no universally accepted end points exist that define an optimal treatment response. End points that directly measure how a patient with SSc-ILD feels and functions are lacking, and although mortality is an unequivocal end point, most SSc clinical trials are powered inadequately and are designed to use mortality as an end point. The most commonly used surrogate end point in SSc-ILD clinical trials is FVC.3Tashkin D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google Scholar, 4Tashkin D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar, 5Distler O. Highland K.B. Gahlemann M. et al.Nintedanib for systemic sclerosis-associated interstitial lung disease.N Engl J Med. 2019; 380: 2518-2528Crossref PubMed Scopus (534) Google Scholar Although studies have demonstrated that the course of FVC is related to survival in SSc-ILD,6Goh N.S. Hoyles R.K. Denton C.P. et al.Short-term pulmonary function trends are predictive of mortality in interstitial lung disease associated with systemic sclerosis.Arthritis Rheum. 2017; 69: 1670-1678Crossref PubMed Scopus (163) Google D.P. M. et al.Short-term progression of interstitial lung disease in systemic sclerosis long-term survival in two independent clinical trial Rheum Dis. 2019; PubMed Scopus Google Scholar the of this as a measure of lung disease may in can and sclerosis the chest M. M. as a for in systemic lung PubMed Scopus Google Scholar in pulmonary function with patient and can the of the FVC in clinical and In studies have demonstrated that the FVC with the radiographic extent of ILD in D.P. et between quantitative radiographic of interstitial lung disease and and clinical of systemic sclerosis.Ann Rheum Dis. 2016; PubMed Scopus Google Scholar an for the discovery of SSc-ILD study end points that are and and can predict mortality outcomes in patients with SSc. the radiographic extent of ILD may a of lung disease and may the of patient and factors that can the of as as the and in radiographic change M. et CT in systemic sclerosis: with lung and of Full Text Full Text PDF PubMed Scopus Google Scholar have demonstrated that increased radiographic extent of ILD at to et of lung function in scleroderma-related interstitial lung disease on high-resolution for in systemic sclerosis-associated interstitial lung disease PubMed Scopus Google M.D. Clements P.J. et treatment outcomes and in scleroderma-related interstitial lung Rheum. PubMed Scopus Google Scholar studies have that the radiographic ILD end point is to change in patients with SSc-ILD M. Elashoff et of changes in on in scleroderma lung disease with oral PubMed Scopus Google Scholar, D.P. et to of interstitial lung disease in scleroderma with and Rheum Dis. 2016; PubMed Scopus Google Scholar, et changes in quantitative lung disease on CT in the Scleroderma Lung Study PubMed Scopus Google Scholar, et in systemic sclerosis: a double-blind, trial.Lancet Respir Med. Full Text Full Text PDF PubMed Scopus Google Scholar no studies have evaluated whether a change in the radiographic extent of ILD mortality in this this the study whether radiographic progression of ILD in patients with SSc receiving treatment long-term mortality. from the Scleroderma Lung Study (SLS) D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google Scholar and D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar that those patients who experienced increased radiographic progression of ILD over the course of these trials worse long-term survival. The findings of this may of efficacy in SSc-ILD and may the of clinical trials for this enrolled in SLS D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google Scholar and and SLS D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar who a high-resolution CT of the chest were to in this SLS I and II were randomized controlled trials that included an of both and patients with SSc-ILD followed up at the for these trials were D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar The of the studies and long-term was from In SLS were randomized to oral cyclophosphamide or placebo for 12 months and were followed up for an 12 months of D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google Scholar In SLS patients were randomized to mycophenolate mofetil for 24 months or oral cyclophosphamide for 12 months followed by an 12 months of D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar The FVC SLS I and II end was months the study D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar imaging was at and at the of treatment in both trials at 12 months in SLS I and at 24 months in SLS II). Design M. Elashoff et of changes in on in scleroderma lung disease with oral PubMed Scopus Google Scholar, D.P. et to of interstitial lung disease in scleroderma with and Rheum Dis. 2016; PubMed Scopus Google Scholar, et changes in quantitative lung disease on CT in the Scleroderma Lung Study PubMed Scopus Google Scholar was used to the quantitative ILD for the lung at and follow-up 1 on the imaging and The included the of including with increased and with The to define radiographic ILD progression of ≥ was determined by a of the cohorts a quantitative imaging algorithm in et imaging a of for algorithm PubMed Scopus Google Scholar both and clinical et imaging a of for algorithm PubMed Scopus Google Scholar was as in the the of was by the of the two scans, in a of was up to of a ≥ 2% increase in as change in FVC and mortality. In the SLS I and II an increase of of ≥ 2% was associated with a in FVC Clements et and of from the Scleroderma Lung and J Respir Med. PubMed Scopus Google Scholar most patients the for FVC predicted experienced an increase in of The for FVC to were on an of two Clements et and of from the Scleroderma Lung and J Respir Med. PubMed Scopus Google Scholar a the relationship between of ≥ ≥ ≥ and ≥ and survival, and the ≥ 2% increase in demonstrated the with survival in both of the SLS I and II the SLS I and II trials, mortality were and of death were by safety and the trials, patients or surrogates were to assess and mortality the patient or and death and as as was for up to 12 and 8 years the of SLS I and were and were were for from the two were and 2 The was mortality. The was used to survival and the log-rank was used to survival between who experienced progression of ILD 2% increase in those who experienced or of ILD 2% increase in Cox proportional models subsequently were a in D.P. M. et al.Short-term progression of interstitial lung disease in systemic sclerosis long-term survival in two independent clinical trial Rheum Dis. 2019; PubMed Scopus Google Scholar the were to associated significantly with mortality in in both the SLS I and II and FVC the were included in the Cox was associated significantly with mortality in SLS I or D.P. M. et al.Short-term progression of interstitial lung disease in systemic sclerosis long-term survival in two independent clinical trial Rheum Dis. 2019; PubMed Scopus Google however, the between treatment and change in Cox models that included treatment Cox models that included associated with mortality on SSc and for of models were to the course of the FVC predicted months over 24 between patients who experienced progression of ILD 2% increase in those who experienced or of ILD 2% increase in included the FVC treatment and the change in Among of the SLS I = and II = participants, 82 and respectively, follow-up scans of the chest and were included in the analysis. In SLS the follow-up was of a that was in the to patients who had the follow-up In SLS the patients had an of the chest at 24 months was or The disease and of the SLS I and II who follow-up scans were and those of the study patients were with SSc years from the of the to and a of on pulmonary function In SLS experienced an increase in of ≥ 2% for the lung at 12 Among these participants, were randomized to cyclophosphamide and were randomized to between treatment is with the of cyclophosphamide on the change in at 12 months in M.D. Clements P.J. et treatment outcomes and in scleroderma-related interstitial lung Rheum. PubMed Scopus Google Scholar In SLS experienced an increase in of ≥ 2% for the lung at 24 Among these participants, were randomized to cyclophosphamide and were randomized to In to the in SLS in of the no in treatment was between the two treatment and in SLS D.P. et to of interstitial lung disease in scleroderma with and Rheum Dis. 2016; PubMed Scopus Google Scholar were in the of who experienced an increase in of ≥ 2% and those who in SLS I or with the of a predicted in SLS I who experienced an increase in of ≥ 2% of SLS I and II Participants a in of ≥ 2% < 2% at 12 and 24 in of ≥ 2% = in of < 2% = in of ≥ 2% = in of < 2% = disease = and = in SLS I and = in SLS of = in SLS are as or = for = = quantitative interstitial lung = quantitative lung SLS = Scleroderma Lung SSc = systemic disease = and = in SLS I and = in SLS in a Data are as or = for = = quantitative interstitial lung = quantitative lung SLS = Scleroderma Lung SSc = systemic SLS I who experienced an increase in of ≥ 2% over 12 months were to a in FVC predicted over the course of the SLS I who experienced a change in of < 2% were to or in FVC predicted in SLS those who experienced an increase in of ≥ 2% over 24 months were to a in FVC predicted over the course of the those who experienced a change in of < 2% were to or in FVC predicted In SLS patients of the had 12 years the patient was randomized group, = placebo group, = were the of and the from were the of In the SLS I with follow-up scans at 12 months, the long-term follow-up group, = placebo group, = In SLS patients of the had 8 years the patient was randomized group, = group, = were the of and the from were the of In the SLS II with follow-up scans at 24 months, the long-term follow-up group, = group, = the long-term follow-up SLS I who experienced an increase in of ≥ 2% for the lung at 1 showed a significantly increased risk of death (P = .01, log-rank the long-term follow-up SLS II who experienced an increase in of ≥ 2% for the lung at 2 years showed a significantly increased risk of death (P = log-rank survival for with ≥ 2% < 2% increase in for the lung from to 24 months in SLS = quantitative interstitial lung SLS = Scleroderma Lung image adjusting for and FVC a was between increase in of ≥ 2% and mortality in SLS I = .089) In adjusting for the an increase in of ≥ 2% was associated with a significantly increased risk of mortality in SLS II = treatment as as the of SSc and predicted to the Cox models, an increase in of ≥ 2% remained associated with mortality in both SLS I and SLS II for in SLS I = change of ≥ change in FVC change of ≥ = = quantitative interstitial lung SLS = Scleroderma Lung in a for in SLS II = change of ≥ change in FVC change of ≥ = = quantitative interstitial lung SLS = Scleroderma Lung in a = = quantitative interstitial lung SLS = Scleroderma Lung = = quantitative interstitial lung SLS = Scleroderma Lung In an analysis, progression of ILD was for the FVC predicted as a in the Cox progression was to the in as FVC predicted of ≥ or FVC predicted of between and and predicted of ≥ N.S. Hoyles R.K. Denton C.P. et al.Short-term pulmonary function trends are predictive of mortality in interstitial lung disease associated with systemic sclerosis.Arthritis Rheum. 2017; 69: 1670-1678Crossref PubMed Scopus (163) Google R. et interstitial lung from PubMed Scopus Google Scholar In SLS patients the for ILD progression at 12 adjusting for and progression of ILD at 12 months, an increase in of ≥ 2% remained associated significantly with an increased risk of mortality = In analysis, included the change in FVC predicted at 12 months as a and this was associated significantly with mortality (P = In SLS patients = the for ILD progression at 24 a Cox that included this to SLS a Cox that included the change in FVC predicted at 24 months as a and a was between change in FVC predicted with mortality = from two independent cohorts with extensive clinical and the study demonstrated that radiographic progression of SSc-ILD by a ≥ 2% increase in over the course of 1 to 2 years is associated with an increased risk of long-term mortality. adjusting for other factors known to survival in this patient quantitative radiographic extent of ILD remained associated significantly with mortality in SLS II for SLS of end points in for SSc-ILD is an of with for drug discovery and no outcomes exist for this disease and an of over trial D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google Scholar, 4Tashkin D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar, 5Distler O. Highland K.B. Gahlemann M. et al.Nintedanib for systemic sclerosis-associated interstitial lung disease.N Engl J Med. 2019; 380: 2518-2528Crossref PubMed Scopus (534) Google Scholar an for and surrogate end points for SSc-ILD The FVC as the end point for of the SSc-ILD D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google Scholar, 4Tashkin D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar, 5Distler O. Highland K.B. Gahlemann M. et al.Nintedanib for systemic sclerosis-associated interstitial lung disease.N Engl J Med. 2019; 380: 2518-2528Crossref PubMed Scopus (534) Google however, these trials used for FVC change over in SLS a was that used for to outcomes in the FVC predicted over 1 D.P. Elashoff R. Clements P.J. et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1201) Google Scholar In SLS a that a with a survival to for from treatment and was used to the course of the FVC predicted over 2 D.P. Roth M.D. Clements P.J. et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease: Scleroderma Lung Study II (SLS II), a double-blind, parallel group, randomized controlled trial.Lancet Respir Med. 2016; 4: 708-719Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar In the and of in trial with placebo for O. Highland K.B. Gahlemann M. et al.Nintedanib for systemic sclerosis-associated interstitial lung disease.N Engl J Med. 2019; 380: 2518-2528Crossref PubMed Scopus (534) Google Scholar the of in FVC over 1 was assessed with a that used for In the trial of for the treatment of FVC was a end point, and that study evaluated the in of change from to in the FVC et in systemic sclerosis: a double-blind, trial.Lancet Respir Med. 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