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Impact of RA-ILD

Interstitial lung disease (ILD) triples the risk of death in patients with RA and reduces their day-to-day quality of life1–3

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ILD IS A LEADING CAUSE OF DEATH IN PATIENTS WITH RA4–6 – ACCOUNTING FOR UP TO 35% OF DEATHS7–10

ILD is second only to cardiovascular disease as a leading cause of RA-related deaths and is rising6,10

~35% of RA-ILD patients are likely to die from ILD8


ILD was the most frequent average annual underlying cause of death in patients with RA-ILD in a US population from 1988–20048

Graph representing average annual underlying cause of death for patients with RA-ILD and RA alone.

Average annual underlying cause of death for patients with RA-ILD (n=10,725) and RA alone (n=151,322) in the United States over the entire study period 1988 to 2004.8

 

THE RISK OF DEATH TRIPLES WHEN PATIENTS WITH RA HAVE ILD1

Patients with RA-ILD have a significantly worse survival than those without ILD in the US1*

In the US, risk of death in RA patients with ILD increases ~3-fold vs. those without ILD (HR 2.86; 95% CI: 1.98, 4.12)1

Curve showing survival rate from ILD diagnosis in RA patients with ILD vs. without ILD

Kaplan–Meier curve showing survival rate from ILD diagnosis in RA patients with ILD vs. without ILD1
*   After adjusting for age, sex and smoking (HR=2.86; 95% CI=1.98, 4.12; p<0.001).
Incidence and mortality of interstitial lung disease in rheumatoid arthritis: A population based study. Bongartz T, Nannini C, Medina-Velasquez YF, et al. Copyright © 2022, Arthritis Rheum. Reproduced with permission of John Wiley & Sons Inc.

 

39% OF RA-ILD PATIENTS MAY DIE WITHIN 5 YEARS OF DIAGNOSIS5

RA-ILD patients have a higher 1-, 5- and 10-year mortality rates vs. RA patients without ILD in Europe5
Curve showing mortality in RA-ILD patients vs. RA patients without ILD

Kaplan–Meier curve showing mortality in RA-ILD patients vs. RA patients without ILD (matched by age, sex, and time of RA diagnosis in a Danish study)5
Reproduced from Annals of the Rheumatic Diseases, Hyldgaard et al, 76(10),700-1706, ©2022 with permission from BMJ Publishing Group Ltd.

 

ILD IN PATIENTS WITH RA CAN SIGNIFICANTLY REDUCE SURVIVAL BY 7.3 YEARS VS. RA PATIENTS WITHOUT ILD1

Median survival for patients with RA overall is 9.9 years vs. 2.6 years median survival after ILD diagnosis1,6

Patients with RA-ILD may only live between 2.6 and 7.8 years after diagnosis1,6,11

 

ADVANCED AGE, MALE SEX AND SEVERITY OF LUNG FUNCTION IMPAIRMENT ALL PREDICT HIGH MORTALITY IN RA-ILD PATIENTS12-15

Risk factors for mortality in RA-ILD
Age
Sex
HRCT pattern and extent
PFTs

  • Severe lung function impairment/decline14,15
Disease history

  • Acute exacerbation of ILD12

A lower baseline % predicted FVC is independently associated with an increased risk of death in RA-ILD (HR 1.46; p<0.0001)15

A 10% decline in FVC % predicted from baseline increases mortality risk in RA-ILD patients by 2.5-fold (HR 2.57; p<0.0001)15

10% decline in FVC and/or >15% decline in DLCO are associated with reduced survival in patients with RA-ILD with UIP pattern on HRCT20
Graph showing that 10% decline in FVC or greater than 15% decline in DLco are associated with reduced RA-ILD survival in patients with UIP HRCT pattern

Comparison of survival curves among RA-ILD patients with UIP pattern on HRCT with different follow-up courses20
Improved (n=5), stable (n=37), progressed (n=28).
Improvement and progression were defined as >10% respective change in FVC and/or >15% change in DLCO.
Adapted from: Song JW, et al. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30:103–112.

RA-ILD patients with radiological honeycombing show poorer survival than those without (p=0.024)12

RA-ILD patients who develop honeycombing on lung HRCT face poor survival regardless of HRCT pattern at diagnosis12,19

Curve visualizing poorer survival in RA-ILD patients with lung honeycombing on HRCT over disease course compared with discovery at diagnosis

Kaplan-Meier survival curves of all-cause mortality.
Used with permission of Nancy International LtdS ubsidiary AME Publishing Company, from Journal of Thoracic Disease, Yamakawa et al, 11(12), ©2022; permission conveyed through Copyright Clearance Center, Inc.

 

ACUTE EXACERBATION OF ILD IS OFTEN DEADLY IN PATIENTS WITH RA-ILD9,12,20,21

Acute exacerbation of ILD in RA-ILD patients with UIP pattern on HRCT carries a very poor prognosis20
Visualization of the survival based on different follow-up courses, including acute exacerbation of ILD, of RA-ILD patients with UIP pattern on HRCT

Comparison of survival curves among RA-ILD patients with UIP pattern on HRCT with different follow-up courses20
Improved (n-5), stable (n-37), progressd (n-28), acute excerbation of ILD (n-14).
Improvement and progression were defined as >10% respective changed in FVC and/or 15% change in DLCO.
Adapted from: Song JW.et al Sarcoldosis Vasc Diffuse Lung Dis. 2013;30:103-112.

Acute exacerbation of ILD as the first manifestation of RA-ILD is common,20 with high risk of death within 30 days of ILD diagnosis in some cases being due to acute exacerbation of previously undiagnosed ILD:5

17% of patients with RA-ILD experienced acute exacerbation of ILD over 33 months in a South Korean retrospective review of 84 patients with RA-ILD20

17% of patients with RA-ILD experienced acute exacerbation of ILD over 33 months in a South Korean retrospective review of 84 patients with RA-ILD20
SouthKorean study

In a South Korean study, 93% (13/14) RA-ILD patients who experienced acute exacerbation of ILD died within 1.5 months20   
Danish study

In a Danish study, 21% of deaths in RA-ILD were caused by acute exacerbation of ILD with the majority of these occurring in the first year of follow-up9
Japanese study

In a Japanese study, 80% of RA-ILD patients with UIP or NSIP/UIP and a history of acute exacerbation of ILD died, without first recovering12

SEVERITY OF DYSPNEA REDUCES THE DAY-TO-DAY QUALITY OF LIFE OF PATIENTS WITH RA-ILD2,3

Severity of fatigue and dyspnea was found to be most closely associated with physical health impairment in patients with RA-ILD3

Severity of cough, fatigue and dyspnea were found to be the strongest predictors of mental health impairment in patients with RA-ILD3

ILD can impact RA patients’ everyday lives3
Depression

Metal health impairment
Physical health impairment

Physical health impairment

Dyspnea significantly affects day-to-day functioning and global wellbeing* in patients with CTD-ILD including RA-ILD.2 Worsening oxygen desaturation may necessitate supplemental oxygen therapy for ILD patients.10 ILD patients requiring supplemental oxygen therapy associate it with fear of dependence, lifestyle interference and physical restriction.22 

How can you identify, monitor and manage ILD in patients with RA?
Footnotes
  • * Assessed using the MDHAQ.2
    MDHAQ CCP, cyclic citrullinated peptide; CI, confidence interval; CTD-ILD, connective tissue disease-associated interstitial lung disease; CVA, cerebrovascular accident; DLCO, diffusing capacity of the lung for carbon monoxide; HR, hazard ratio; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; MDHAQ, Multi-Dimensional Health Assessment Questionnaire; NSIP; non-specific interstitial pneumonia; PFT, pulmonary function test; RA; rheumatoid arthritis; RA-ILD, rheumatoid arthritis-associated interstitial lung disease; TLC, total lung capacity; UIP, usual interstitial pneumonia; US, United States. 

  1. Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010;62(6):1583–1591.

  2. Swigris JJ, Yorke J, Sprunger DB, et al. Assessing dyspnea and its impact on patients with connective tissue disease-related interstitial lung disease. Respir Med. 2010;104(9):1350–1355.

  3. Natalini JG, Swigris JJ, Moriset J, et al. Understanding the determinants of health related quality of life in rheumatoid arthritis-associated interstitial lung disease. Respir Med. 2017;127:1–6.

  4. Young A, Koduri G, Batley M, et al. Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology (Oxford). 2007;46(2):350–357.

  5. Hyldgaard C, Hilberg O, Pedersen AB, et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017;76(10):1700–1706.

  6. Raimundo K, Solomon JJ, Olson AL, et al. Rheumatoid arthritis – interstitial lung disease in the United States: prevalence, incidence, and healthcare costs and mortality. J Rheumatol. 2019;46(4):360–369.

  7. Cassone G, Manfredi A, Vacchi C, et al. Treatment of rheumatoid arthritis-associated interstitial lung disease: lights and shadows. J Clin Med. 2020;9(4):1082.

  8. Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease associated mortality. Am J Respir Crit Care Med. 2011;183(3):372-378.

  9. Hyldgaard C, Ellingsen T, Hilberg O, et al. Rheumatoid arthritis-associated interstitial lung disease: clinical characteristics and predictors of mortality. Respiration. 2019;98(5):455–460.

  10. Iqbal K and Kelly C. Treatment of rheumatoid arthritis-associated interstitial lung disease: a perspective review. Ther Adv Musculoskelet Dis. 2015;7(6):247–267.

  11. Kelly CA, Saravanan V, Nisar M, et al. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics – a large multicentre UK study. Rheumatology (Oxford). 2014;53(9):1676–1682.

  12. Yamakawa H, Sato S, Tsumiyama E, et al. Predictive factors of mortality in rheumatoid arthritis-associated interstitial lung disease analysed by modified HRCT classification of idiopathic pulmonary fibrosis according to the 2018 ATS/ERS/JRS/ALAT criteria. J Thorac Dis. 2019;11(12):5247–5257.

  13. Koduri G, Norton S, Young A, et al. Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology (Oxford). 2010; 49(8):1483–1489.

  14. Assayag D, Lubin M, Lee JS, King TE, Collard HR, Ryerson CJ. Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirology. 2014;19(4):493–500.

  15. Solomon JJ, Chung JH, Cosgrove GP, et al. Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2016;47(2):588–596.

  16. Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010;35(6):1322–1328.

  17. Singh N, Varghese J, England BR, et al. Impact of the pattern of interstitial lung disease on mortality in rheumatoid arthritis: A systematic literature review and meta-analysis. Semin Arthritis Rheum. 2019;49(3):358–365.

  18. Tsuchiya Y, Takayanagi N, Sugiura H, et al. Lung diseases directly associated with rheumatoid arthritis and their relationship to outcome. Eur Respir J. 2011;37(6):1411–1417.

  19. Yamakawa H, Sato S, Nishizawa T, et al. Impact of radiological honeycombing in rheumatoid arthritis-associated interstitial lung disease. BMC Pulm Med. 2020;20(1):25.

  20. Song JW, Lee HK, Lee CK, et al. Clinical course and outcome of rheumatoid arthritis-related usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30(2):103–112.

  21. Hozumi H, Nakamura Y, Johkoh T, et al. Acute exacerbation in rheumatoid arthritis associated interstitial lung disease: a retrospective case control study. BMJ Open. 2013;13(9): e003132. doi: 10.1136/bmjopen-2013-003132.

  22. Khor YH, Goh NSL, McDonald CF, Holland AE. Oxygen therapy for interstitial lung disease. A mismatch between patient expectations and experiences. Ann Am Thorac Soc. 2017;14(6):888–895.

  23. Esposito AJ, Chu SG, Madan R, et al. Thoracic manifestations of rheumatoid arthritis. Clin Chest Med. 2019;40(3):545–560.

  24. Wallace B, Vummidi D, Khanna D. Management of connective tissue diseases associated interstitial lung disease: a review of the published literature. Curr Opin Rheumatol. 2016;28(3):236–245.

  25. Kawano-Dourado L, Doyle TJ, Bonfiglioli K, et al. Baseline characteristics and progression of a spectrum of interstitial lung abnormalities and disease in rheumatoid arthritis. Chest. 2020:S0012-3692(20)31412-4. doi: 10.1016/j.chest.2020.04.061.

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