Impact of SSc-ILD

Interstitial lung disease (ILD) is an important cause of mortality in patients with systemic sclerosis (SSc) and can have a negative impact on quality of life1-6

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ILD IS THE LEADING CAUSE OF DEATH IN SSc1

Pulmonary fibrosis is the leading cause of mortality in SSc, accounting for ~35% of SSc-related deaths1,2
Pulmonary fibrosis is the leading cause of morality in SSc, accounting for ~35% of SSc-related deaths

Causes of SSc-related deaths (1997–2001).
Adapted from: Steen VD and Mediger TA Ann Rheum Dis. 2007;66;944 and Tyndall AJ, et al. Ann Rheum Dis. 2010;69(10):1809-1815

 

1-, 5- and 10-year survival rates for SSc-ILD patients vs. SSc patients without ILD7

In a Canadian cohort of SSc-ILD patients, 5- and 10-year survival rates were 44.4% and 22% respectively7

Increased mortality / lower percentage survival rates for SSc-ILD patients compared to SSc patients

Adapted from: Pope JE, et al. Poster presented at the 6th Systemic Sclerosis World E-Congress 2020.

 

LUNG FIBROSIS AT BASELINE IS ASSOCIATED WITH INCREASED MORTALITY COMPARED WITH NO LUNG FIBROSIS IN PATIENTS WITH SSc-ILD8

In the Norwegian SSc-ILD cohort, fibrosis per se confers increased mortality risk in SSc-ILD8

Any extent of lung fibrosis at baseline has been shown to carry increased mortality risk in patients with SSc-ILD compared with the general population.8 This standard mortality rate increases with increasing extent of fibrosis.8

Norwegian SSc-ILD cohort cumulative survival was lower for patients with lung fibrosis

Cumulative survival rates at 1, 5 and 10 years after ILD diagnosis shown by Kaplan-Meier curves in a Norwegian cohort. Time to death in patients with normal ranged FVC% (FVC 80–100%) stratified by presence or absence of lung fibrosis by HRCT p<0.001.
Reprinted from Annals of the American Thoracic Society , 200(10),  Hoffmann-Vold et al, Tracking Impact of Interstitial Lung Disease in Systemic Sclerosis in a Complete Nationwide Cohort, 1258–1266, ©2022.

 

In a Norwegian SSc-ILD patient cohort, >10% extent of fibrosis on HRCT was associated with significantly higher standard mortality rates8

Lung fibrosis per se confers increased mortality risk in SSc, shown for the first time in a Norwegian cohort study of patients with SSc (N=630).8 The SMR correlated with extent of fibrosis, with the highest SMR seen in patients with >10% fibrosis (SMR increased from 2.2 with no fibrosis to 8.0 with >25% fibrosis).8

Standard mortality rates in Norwegian SSc-ILD cohort positively correlate with extent of lung fibrosis

Adapted from: Hoffmann-Vold A-M, et al. Am J Respir Crit Care Med. 2019;200:1258–1266.

Extensive lung disease, classified as >20% disease extent on HRCT, is associated with higher mortality (HR 2.48, 95% CI 1.57–3.92, p<0.0005)9

A threshold of 20% disease extent on HRCT is associated with a substantial increase in mortality9

Extent of lung fibrosis on HRCT for SSc-ILD is a predictor of mortality

Kaplan-Meier survival curve of SSc-ILD patients with HRCT disease extent >20% (n=64) and patients with HRCT and patients with HRCT disease extent ≤20% (n=151).
Reprinted from Annals of the American Thoracic Society, 177(137), Cappelli et al, Interstitial lung disease in systemic sclerosis: where do we stand?, 411-419, ©2022.

>10% extent of fibrosis on HRCT is associated with significantly higher mortality8

Ensure your SSc patients undergo baseline lung HRCT screening for ILD8,10,11

 

EVEN SMALL ANNUAL FVC DECLINES OF <5% PREDICTED CAN LEAD TO MORTALITY WITHIN 4–8 YEARS IN PATIENTS WITH SSc-ILD12

Some studies have suggested FVC decline is most rapid early in the course of SSc-ILD and may stabilize after the first 4 years.12 However, recent evidence indicates that FVC decline in SSc-ILD does not plateau after an initial period of progression but instead progresses at distinct rates that correlate with different mortality time frames.12

SSc-ILD shows heterogenous rates of progression but is fundamentally progressive over the long term12,13

Progression of FVC % predicted in patients with SSc-ILD categorized by prognostic groups12
FVC percentage predicted progression was significantly lower in patients

Progression of FVC (% predicted) in 171 patients with SSc-ILD categorized by prognostic groups.
Reprinted from Annals of the American Thoracic Society, 15(12), Guler et al, Does Systemic Sclerosis-associated Interstitial Lung Disease Burn Out?, 1427–1433, ©2022.

Low FVC (% predicted) and decline in FVC are predictors of mortality in SSc-ILD14

In a long-term UK study, annual relative FVC declines of ≥10% predicted over 12 months were strongly associated with mortality of SSc-ILD patients over 15 years (HR 1.84, 95% CI 1.14–2.97, p=0.01)14

FVC decline predicted / FVC decline of 10% or more is a greater predictor of SSc-ILD mortality

Kaplan-Meier survival curve for a cohort of 162 SSc-ILD patients according to FVC decline <10% and FVC decline ≥10%.
Short-Term Pulmonary Function Trends Are Predictive of Mortality in Interstitial Lung Disease Associated With Systemic Sclerosis, Goh et al, ©2022. Reproduced with permission of John Wiley & Sons Inc.

FVC <80% predicted at baseline is a predictor of mortality in SSc-ILD1
FVC decline predicted / FVC decline of 10% or more is a greater predictor of SSc-ILD mortality

Kaplan-Meier graphs for SSc survival on the basis of the follow-up data of 2,940 patients of whom 294 died. SSc mortality is plotted according to the presence or absence of pulmonary restrictions.
Reproduced from Annals of the Rheumatic Diseases, Tyndall et al, 69(10), 1809-1815, ©2022 with permission from BMJ Publishing Group Ltd.

Aim to slow decline in FVC as part of the treatment goal to delay ILD progression in SSc-ILD10

 

OLDER AGE AT PRESENTATION, MALE SEX, EXTENT OF LUNG FIBROSIS, LOW BASELINE VALUES AND DECLINES IN FVC AND DLCO ARE ALL RISK FACTORS FOR MORTALITY IN SSc-ILD1,8,14-16

 

 

Risk factors for mortality in SSc-ILD

Age

Older age at presentation15,17

Sex

Male15,17

FVC

<80%1

DLCO

Baseline DLCO % predicted <40%18

DLCO % predicted <40%1

Decline DLCO predicted <15%19

Extent of fibrosis on HRCT

>10% disease extent on HRCT8

Smoking

Active smoking and history of smoking12,15

Older age at diagnosis has been shown to negatively affect survival
(HR 1.04, 95% CI 1.03–1.05)17

Older age at diagnosis has been shown to negatively affect survival (HR 1.04, 95% CI 1.03–1.05)17
Male sex is associated with early mortality in SSc-ILD
(HR 1.81, 95% CI 1.29–2.55)17,20

Male sex is associated with early mortality in SSc-ILD (HR 1.81, 95% CI 1.29–2.55)17,20

SYMPTOMS OF ILD CAN HAVE A NEGATIVE IMPACT ON QUALITY OF LIFE IN PATIENTS WITH SSc-ILD3-6

Symptoms of cough and dyspnea may compromise patients’ quality of life and adversely affect patients’ ability to perform activities central to their daily lives21

Symptoms of SSc-ILD can be significant contributors to reduced quality of life21,22
Social impact

Social impact
Impacts sleep and health

Impacts sleep and health
Impact on well-being and productivity

Impact on well-being and productivity
Emotional impact

Emotional impact

SSc-ILD patients experience fatigue, depression as well as significant impacts on their well-being and productivity.22

Symptoms of ILD can have negative effects on patients’ quality of life22

Impact on well-being

Productivity loss

Need for support

22.6% of SSc-ILD patients have depression

40.4% of SSc-ILD patients retire early

2.0% of SSc-ILD patients need paid caregiver
support (e.g. nurse)

40.3% of SSc patients experience fatigue

11.9 Years between actual retirement and legal
age for it

37.7% of SSc-ILD patients need support from an
unpaid caregiver (e.g. family memeber)

44.7% of extensive SSc-ILD have permanent
            disability (8.5% of limited SSc-ILD)

22.3 Hours of work unpaid carers dedicate to a
SSc-ILD patient, weekly

29.3% of extensive SSc-ILD lost their job due to
their disease (5% of limited SSc-ILD)

100% of panelists agree that unpaid caregivers
have impacted quality of life

Adapted from: Wuyts W, et al. 2020. Poster presented at the 6th Systemic Sclerosis World E-Congress 2020.

 

ACUTE EXACERBATION OF ILD IS A SIGNIFICANT PREDICTOR OF POOR OUTCOME AND SHORTER SURVIVAL IN SSc-ILD23

In a Japanese cohort, 4 out of 35 patients with SSc-ILD developed acute exacerbation of ILD during the follow-up period and all 4 died23

In a Japanese cohort, 4 out of 35 patients with SSc-ILD developed acute exacerbation of ILD during the follow-up period and all 4 died23
Survival curves for acute exacerbation of ILD in SSc-ILD in a Japanese study23

AE-ILD was a significant predictor of poor outcome in SSc-ILD (p=0.0013).

Survival of patients with SSc-ILD is lower following acute exacerbation of ILD

Reprinted from Respiratory Investigation, 54(6), Okamoto et al, A retrospective cohort study of outcome in systemic sclerosis-associated interstitial lung disease, 445–453, ©2022, with permission from Elsevier.

 
 
How can you identify, treat and manage ILD in patients with SSc?
Footnotes
  • AE, acute exacerbation; CI, confidence interval; DLCO, diffusing capacity of the lung for carbon monoxide; DM, dermatomyositis; FVC, forced vital capacity; HR, hazard ratio; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; KL-6, Krebs von den Lungen-6; PM, polymyositis; SMR, standard mortality rate; SSc, systemic sclerosis; SSc-ILD, systemic sclerosis-associated interstitial lung disease; UIP, usual interstitial pneumonia.

  1. Tyndall AJ, 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;1809–1815.

  2. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum D. 2007;66;940–944.

  3. Cheng JZ, Wilcox PG, Glaspole I, et al. Cough is less common and less severe in systemic sclerosis-associated interstitial lung disease compared to other fibrotic interstitial lung diseases: Cough severity in fibrotic ILD. Respirology. 2017;22:1592–1597.

  4. Tashkin D, Volkmann E, Tseng C et al. Improved cough and cough-specific quality of life in patients treated for scleroderma-related interstitial lung disease results of scleroderma lung study II. Chest. 2017;151(4):813–820.

  5. Baron M, Sutton E, Hudson M, et al. The relationship of dyspnoea to function and quality of life in systemic sclerosis. Ann Rheum Dis. 2008;67; 644–650.

  6. Theodore AC, Tseng CH, Li N, E et al. Correlation of cough with disease activity and treatment with cyclophosphamide in scleroderma interstitial lung disease: findings from the scleroderma lung study. Chest. 2012;142;614–21.

  7. Pope JE, Quansah K, Kolb M, et al. Systemic sclerosis (SSc) with interstitial lung disease (SSc-ILD) in Canada’s largest province: an estimate of the prevalence and survival of SSc and SSc-ILD in Ontario over 10 years. Poster presented at the 6th Systemic Scelerosis World E-Congress 2020.

  8. Hoffmann-Vold AM, Fretheim H, Halse AK, et al. Tracking impact of interstitial lung disease in systemic sclerosis in a complete nationwide cohort. Am J Respir Crit Care Med. 2019;200;1258–1266.

  9. Goh NS, Desai SR., Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008;177:1248–1254.

  10. Hoffmann-Vold AM, Maher TM, Philpot EE, et al. The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements. Lancet Rheum. 2020;2 e71–e83.

  11. Asano Y, Jinnin M, Kawaguchi Y, et al. Diagnostic criteria, severity classification and guidelines of systemic sclerosis: Guideline of SSc. J Dermatol. 2018;45;633–691.

  12. Guler, S.A., Winstone, T.A., Murphy, D., et al. Does systemic sclerosis–associated interstitial lung disease burn out? Specific phenotypes of disease progression. Annals ATS. 2018;15;1427–1433.

  13. Hoffmann-Vold AM, Allanore Y, Alves M, et al. Progressive interstitial lung disease in patients with systemic sclerosis- associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis. 2020. Epub ahead of print: doi:10.1136/annrheumdis-2020-217455.

  14. Goh NS, Hoyles RK, Denton CP, et al. Short-term pulmonary function trends are predictive of mortality in interstitial lung disease associated with systemic sclerosis. Arthritis Rheumatol. 2017;69;1670–1678.

  15. Perelas A, Silver RM, Arrossi AV, et al. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med. 2020;8;304–320.

  16. Volkmann ER, Tashkin DP, Sim M. et al. Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts. Ann Rheum Dis. 2019;78(1);122–130.

  17. Mayes M, Lacey J, Beebe-Dimmer J et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246–2255.

  18. Morisset J, Vittinghoff E, Elicker BM, et al. Mortality risk prediction in scleroderma-related interstitial lung disease: the SADL model. Chest. 2017;152(5):999–1007.

  19. Suliman YA, Dobrota R, Huscher D, et al. Brief Report: Pulmonary Function Tests: High Rate of False-Negative Results in the Early Detection and Screening of Scleroderma-Related Interstitial Lung Disease. Arthritis Rheumatol. 2015;67;3256–3261.

  20. Volkmann ER, Tashkin DP. Treatment of systemic sclerosis–related interstitial lung disease: a review of existing and emerging therapies. Annals ATS. 2016;13;2045–2056.

  21. Distler O, Volkmann ER, Hoffmann-Vold AM, et al. Current and future perspectives on management of systemic sclerosis-associated interstitial lung disease. Expert Rev Clin Immunol. 2019;15;1009–1017.

  22. Wuyts W, Romild Davidson J, Kilpelainen M et al. Management and burden of disease of SSc-ILD in eight European countries: Results of the BUILDup project. Poster presented at the 6th Systemic Sclerosis World E-Congress 2020.

  23. Okamoto M, Fujimoto K, Sadohara J, et al. A retrospective cohort study of outcome in systemic sclerosis-associated interstitial lung disease. Respiratory Investigation. 2016;54;445–453.

  24. Denton C, Hughes M, Gak N et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology. 2016;55;1906–1910.

  25. Roofeh D, Jaafar S, Vummidi D, et al. Management of systemic sclerosis-associated interstitial lung disease. Curr Opin Rheumatol. 2019;31;241–249.

  26. Fischer A, Patel NM, Volkmann ER. Interstitial lung disease in systemic sclerosis: focus on early detection and intervention. OARRR. 2019;11;283–307.

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