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Erschienen in: Clinical Rheumatology 4/2017

12.02.2017 | Original Article

Retrospective study of the clinical characteristics and risk factors of rheumatoid arthritis-associated interstitial lung disease

verfasst von: Yongfeng Zhang, Hongbin Li, Nawei Wu, Xin Dong, Yi Zheng

Erschienen in: Clinical Rheumatology | Ausgabe 4/2017

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Abstract

This study aims to explore the clinical characteristics and risk factors of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). This is a retrospective study of 550 patients with RA. All patients underwent chest high-resolution computed tomography (HRCT) scanning. (1) Two hundred thirty-seven out of five hundred fifty (43.1%) patients with RA were diagnose with ILD. 13.5% ILD occurred before RA onset, 69.6% ILD occurred within 10 years of RA onset, and 16.9% ILD occurred more than 10 years after RA onset. (2) The most common chest CT characteristics of RA-ILD included reticular patterns (57.8%), pleural thickening (57%), ground-glass attenuation (53.2%), followed by interlobular septum thickening, nodules, emphysematous bullae, honeycombing, and bronchiectasis. The proportion of the UIP pattern and NSIP on HRCT was 18.6% and 57.8%. (3) RA-ILD was often associated with other lung lesions, including pleural disease, bronchiectasis, and pulmonary hypertension. (4) the comparisons between RA with ILD and RA without ILD showed that male, smoking, age, disease duration, number of swelling joints, globulin levels, erythrocyte sedimentation rate, C-reactive protein levels, lactate dehydrogenase, the positive rate of rheumatoid factor (RF) and the absolute value of RF, forced vital capacity, forced expiratory volume in 1 s, and carbon monoxide diffusion rate, were statistically different (P < 0.05). Logistic regression analysis showed that age, smoking, elevated lactate dehydrogenase, and RF positive were closely correlated to RA-ILD. RA-ILD occurs more often within 10 years of RA onset and coexists with other lung lesions. The elevated lactate dehydrogenase, RF positive, smoking, and advanced age are closely correlated with RA-ILD.
Literatur
1.
Zurück zum Zitat Gabriel SE (2001) The epidemiology of rheumatoid arthritis. Rheum Dis Clin N Am 27(2):269–281CrossRef Gabriel SE (2001) The epidemiology of rheumatoid arthritis. Rheum Dis Clin N Am 27(2):269–281CrossRef
2.
Zurück zum Zitat Kapetanovic MC, Lindqvist E, Geborek P, Saxne T, Eberhard K (2011) Long-term mortality rate in rheumatoid arthritis patients with disease onset in the 1980s. Scand J Rheumatol 40(6):433–438CrossRefPubMed Kapetanovic MC, Lindqvist E, Geborek P, Saxne T, Eberhard K (2011) Long-term mortality rate in rheumatoid arthritis patients with disease onset in the 1980s. Scand J Rheumatol 40(6):433–438CrossRefPubMed
3.
Zurück zum Zitat Kuo CF, Luo SF, See LC, Chou IJ, Chang HC, Yu KH (2013) Rheumatoid arthritis prevalence, incidence, and mortality rates: a nationwide population study in Taiwan. Rheumatol Int 33(2):355–360CrossRefPubMed Kuo CF, Luo SF, See LC, Chou IJ, Chang HC, Yu KH (2013) Rheumatoid arthritis prevalence, incidence, and mortality rates: a nationwide population study in Taiwan. Rheumatol Int 33(2):355–360CrossRefPubMed
4.
Zurück zum Zitat Zayeni H, Haji-Abbasi A, Foumani SA et al (2016) Pulmonary involvement in rheumatoid arthritis: a cross-sectional study in Iran. Lung India 33(1):49–52CrossRefPubMedPubMedCentral Zayeni H, Haji-Abbasi A, Foumani SA et al (2016) Pulmonary involvement in rheumatoid arthritis: a cross-sectional study in Iran. Lung India 33(1):49–52CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Koduri G, Norton S, Young A et al (2010) Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology (Oxford) 49(8):1483–1489CrossRef Koduri G, Norton S, Young A et al (2010) Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology (Oxford) 49(8):1483–1489CrossRef
6.
Zurück zum Zitat Bongartz T, Nannini C, Medina-Velasquez YF et al (2010) Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum 62(6):1583–1591CrossRefPubMedPubMedCentral Bongartz T, Nannini C, Medina-Velasquez YF et al (2010) Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum 62(6):1583–1591CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Assayag D, Lee JS, King TE Jr (2014) Rheumatoid arthritis associated interstitial lung disease: a review. Medicina (B Aires) 74(2):158–165 Assayag D, Lee JS, King TE Jr (2014) Rheumatoid arthritis associated interstitial lung disease: a review. Medicina (B Aires) 74(2):158–165
8.
Zurück zum Zitat Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324CrossRefPubMed Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324CrossRefPubMed
9.
Zurück zum Zitat Aletaha D, Neogi T, Silman AJ et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581CrossRefPubMed Aletaha D, Neogi T, Silman AJ et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581CrossRefPubMed
10.
Zurück zum Zitat Furukawa H, Oka S, Shimada K et al (2012) Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. PLoS One 7(5):e33133CrossRefPubMedPubMedCentral Furukawa H, Oka S, Shimada K et al (2012) Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. PLoS One 7(5):e33133CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat C J (2013) Exploration of the MUC5B polymorphism frequency in rheumatoid arthritis interstitial lung disease. Am J Respir Crit Care Med 187:A5982 C J (2013) Exploration of the MUC5B polymorphism frequency in rheumatoid arthritis interstitial lung disease. Am J Respir Crit Care Med 187:A5982
12.
Zurück zum Zitat Perez-Dorame R, Mejia M, Mateos-Toledo H, Rojas-Serrano J (2015) Rheumatoid arthritis-associated interstitial lung disease: lung inflammation evaluated with high resolution computed tomography scan is correlated to rheumatoid arthritis disease activity. Reumatol Clin 11(1):12–16CrossRefPubMed Perez-Dorame R, Mejia M, Mateos-Toledo H, Rojas-Serrano J (2015) Rheumatoid arthritis-associated interstitial lung disease: lung inflammation evaluated with high resolution computed tomography scan is correlated to rheumatoid arthritis disease activity. Reumatol Clin 11(1):12–16CrossRefPubMed
13.
Zurück zum Zitat Gabbay E, Tarala R, Will R et al (1997) Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med 156(2 Pt 1):528–535CrossRefPubMed Gabbay E, Tarala R, Will R et al (1997) Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med 156(2 Pt 1):528–535CrossRefPubMed
14.
Zurück zum Zitat Ayhan-Ardie FFOO, Yorgancioglu ZR, Ustun N, Gokharman FD (2006) Pulmonary involvement in life long non-smoking patients with rheumatoid arthritis and ankylosing spondylitis without respiratory symptoms. Clin Rheumatol 25(2):213–218CrossRef Ayhan-Ardie FFOO, Yorgancioglu ZR, Ustun N, Gokharman FD (2006) Pulmonary involvement in life long non-smoking patients with rheumatoid arthritis and ankylosing spondylitis without respiratory symptoms. Clin Rheumatol 25(2):213–218CrossRef
15.
Zurück zum Zitat Sebastiani M, Manfredi A, Cerri S, Della Casa G, Luppi F, Ferri C (2016) Radiologic classification of usual interstitial pneumonia in rheumatoid arthritis-related interstitial lung disease: correlations with clinical, serological and demographic features of disease. Clin Exp Rheumatol 34(3):564–565PubMed Sebastiani M, Manfredi A, Cerri S, Della Casa G, Luppi F, Ferri C (2016) Radiologic classification of usual interstitial pneumonia in rheumatoid arthritis-related interstitial lung disease: correlations with clinical, serological and demographic features of disease. Clin Exp Rheumatol 34(3):564–565PubMed
16.
Zurück zum Zitat Wang JX, Du CG (2015) A retrospective study of clinical characteristics of interstitial lung disease associated with rheumatoid arthritis in Chinese patients. Med Sci Monit 21:708–715CrossRefPubMedPubMedCentral Wang JX, Du CG (2015) A retrospective study of clinical characteristics of interstitial lung disease associated with rheumatoid arthritis in Chinese patients. Med Sci Monit 21:708–715CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Turesson C, Jacobsson LT, Sturfelt G, Matteson EL, Mathsson L, Ronnelid J (2007) Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis 66(1):59–64CrossRefPubMed Turesson C, Jacobsson LT, Sturfelt G, Matteson EL, Mathsson L, Ronnelid J (2007) Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis 66(1):59–64CrossRefPubMed
18.
Zurück zum Zitat Zrour SH, Touzi M, Bejia I et al (2005) Correlations between high-resolution computed tomography of the chest and clinical function in patients with rheumatoid arthritis. Prospective study in 75 patients. Joint Bone Spine 72(1):41–47CrossRefPubMed Zrour SH, Touzi M, Bejia I et al (2005) Correlations between high-resolution computed tomography of the chest and clinical function in patients with rheumatoid arthritis. Prospective study in 75 patients. Joint Bone Spine 72(1):41–47CrossRefPubMed
19.
Zurück zum Zitat Saag KG, Kolluri S, Koehnke RK et al (1996) Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum 39(10):1711–1719CrossRefPubMed Saag KG, Kolluri S, Koehnke RK et al (1996) Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum 39(10):1711–1719CrossRefPubMed
20.
Zurück zum Zitat Hoovestol RA, Mikuls TR (2011) Environmental exposures and rheumatoid arthritis risk. Curr Rheumatol Rep 13(5):431–439CrossRefPubMed Hoovestol RA, Mikuls TR (2011) Environmental exposures and rheumatoid arthritis risk. Curr Rheumatol Rep 13(5):431–439CrossRefPubMed
21.
Zurück zum Zitat Mori S, Koga Y, Sugimoto M (2012) Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis. Respir Med 106(11):1591–1599CrossRefPubMed Mori S, Koga Y, Sugimoto M (2012) Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis. Respir Med 106(11):1591–1599CrossRefPubMed
22.
Zurück zum Zitat Zou J, Guo Q, Chi J, Wu H, Bao C (2015) HRCT score and serum ferritin level are factors associated to the 1-year mortality of acute interstitial lung disease in clinically amyopathic dermatomyositis patients. Clin Rheumatol 34(4):707–714CrossRefPubMed Zou J, Guo Q, Chi J, Wu H, Bao C (2015) HRCT score and serum ferritin level are factors associated to the 1-year mortality of acute interstitial lung disease in clinically amyopathic dermatomyositis patients. Clin Rheumatol 34(4):707–714CrossRefPubMed
23.
Zurück zum Zitat Kobayashi N, Takezaki S, Kobayashi I et al (2015) Clinical and laboratory features of fatal rapidly progressive interstitial lung disease associated with juvenile dermatomyositis. Rheumatology (Oxford) 54(5):784–791CrossRef Kobayashi N, Takezaki S, Kobayashi I et al (2015) Clinical and laboratory features of fatal rapidly progressive interstitial lung disease associated with juvenile dermatomyositis. Rheumatology (Oxford) 54(5):784–791CrossRef
24.
Zurück zum Zitat Aggarwal BD (2014) Lactate dehydrogenase as a biomarker for silica exposure-induced toxicity in agate workers. Occup Environ Med 71(8):578–582CrossRefPubMed Aggarwal BD (2014) Lactate dehydrogenase as a biomarker for silica exposure-induced toxicity in agate workers. Occup Environ Med 71(8):578–582CrossRefPubMed
25.
Zurück zum Zitat Frank ST, Weg JG, Harkleroad LE, Fitch RF (1973) Pulmonary dysfunction in rheumatoid disease. Chest 63(1):27–34CrossRefPubMed Frank ST, Weg JG, Harkleroad LE, Fitch RF (1973) Pulmonary dysfunction in rheumatoid disease. Chest 63(1):27–34CrossRefPubMed
26.
Zurück zum Zitat Olson AL, Swigris JJ, Sprunger DB et al (2011) Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 183(3):372–378CrossRefPubMed Olson AL, Swigris JJ, Sprunger DB et al (2011) Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 183(3):372–378CrossRefPubMed
27.
Zurück zum Zitat Norton S, Koduri G, Nikiphorou E, Dixey J, Williams P, Young A (2013) A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular manifestations in RA and their impact on outcome. Rheumatology (Oxford) 52(1):99–110CrossRef Norton S, Koduri G, Nikiphorou E, Dixey J, Williams P, Young A (2013) A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular manifestations in RA and their impact on outcome. Rheumatology (Oxford) 52(1):99–110CrossRef
28.
Zurück zum Zitat Richman NC, Yazdany J, Graf J, Chernitskiy V, Imboden JB (2013) Extraarticular manifestations of rheumatoid arthritis in a multiethnic cohort of predominantly Hispanic and Asian patients. Medicine (Baltimore) 92(2):92–97CrossRef Richman NC, Yazdany J, Graf J, Chernitskiy V, Imboden JB (2013) Extraarticular manifestations of rheumatoid arthritis in a multiethnic cohort of predominantly Hispanic and Asian patients. Medicine (Baltimore) 92(2):92–97CrossRef
29.
Zurück zum Zitat Kelly CA, Saravanan V, Nisar M, Arthanari S, Woodhead FA, Price-Forbes AN, Dawson J, Sathi N, Ahmad Y, Koduri G, Young A (2014) Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiologicaland radiological characteristics—a large multicentre UK study. Rheumatology (Oxford) 53(9):1676–1682CrossRef Kelly CA, Saravanan V, Nisar M, Arthanari S, Woodhead FA, Price-Forbes AN, Dawson J, Sathi N, Ahmad Y, Koduri G, Young A (2014) Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiologicaland radiological characteristics—a large multicentre UK study. Rheumatology (Oxford) 53(9):1676–1682CrossRef
30.
Zurück zum Zitat Solomon JJ, Ryu JH, Tazelaar HD, Myers JL, Tuder R, Cool CD, Curran-Everett D, Fischer A, Swigris JJ, Brown KK. Fibrosing interstitial pneumonia predicts survival in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Respir Med 107(8):1247–1252. Solomon JJ, Ryu JH, Tazelaar HD, Myers JL, Tuder R, Cool CD, Curran-Everett D, Fischer A, Swigris JJ, Brown KK. Fibrosing interstitial pneumonia predicts survival in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Respir Med 107(8):1247–1252.
31.
Zurück zum Zitat Kim EJ, Elicker BM, Maldonado F, Webb WR, Ryu JH, Van Uden JH, Lee JS, King TE Jr, Collard HR (2010) Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J 35(6):1322–1328CrossRefPubMed Kim EJ, Elicker BM, Maldonado F, Webb WR, Ryu JH, Van Uden JH, Lee JS, King TE Jr, Collard HR (2010) Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J 35(6):1322–1328CrossRefPubMed
32.
Zurück zum Zitat McDonagh J, Greaves M, Wright AR, Heycock C, Owen JP, Kelly C (1994) High resolution computed tomography of the lungs in patients with rheumatoid arthritis and interstitial lung disease. Br J Rheumatol 33(2):118–122CrossRefPubMed McDonagh J, Greaves M, Wright AR, Heycock C, Owen JP, Kelly C (1994) High resolution computed tomography of the lungs in patients with rheumatoid arthritis and interstitial lung disease. Br J Rheumatol 33(2):118–122CrossRefPubMed
33.
Zurück zum Zitat Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR (2001) Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax 56(8):622–627CrossRefPubMedPubMedCentral Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR (2001) Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax 56(8):622–627CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Youssef AA, Machaly SA, El-Dosoky ME, El-Maghraby NM (2012) Respiratory symptoms in rheumatoid arthritis: relation to pulmonary abnormalities detected by high-resolution CT and pulmonary functional testing. Rheumatol Int 32(7):1985–1995CrossRefPubMed Youssef AA, Machaly SA, El-Dosoky ME, El-Maghraby NM (2012) Respiratory symptoms in rheumatoid arthritis: relation to pulmonary abnormalities detected by high-resolution CT and pulmonary functional testing. Rheumatol Int 32(7):1985–1995CrossRefPubMed
35.
Zurück zum Zitat Yilmazer B, Gumustas S, Cosan F et al (2016) High-resolution computed tomography and rheumatoid arthritis: semi-quantitative evaluation of lung damage and its correlation with clinical and functional abnormalities. Radiol Med 121(3):181–189CrossRefPubMed Yilmazer B, Gumustas S, Cosan F et al (2016) High-resolution computed tomography and rheumatoid arthritis: semi-quantitative evaluation of lung damage and its correlation with clinical and functional abnormalities. Radiol Med 121(3):181–189CrossRefPubMed
36.
Zurück zum Zitat Karazincir S, Akoglu S, Guler H, Balci A, Babayigit C, Egilmez E (2009) The evaluation of early pulmonary involvement with high resolution computerized tomography in asymptomatic and non-smoker patients with rheumatoid arthritis. Tuberk Toraks 57(1):14–21PubMed Karazincir S, Akoglu S, Guler H, Balci A, Babayigit C, Egilmez E (2009) The evaluation of early pulmonary involvement with high resolution computerized tomography in asymptomatic and non-smoker patients with rheumatoid arthritis. Tuberk Toraks 57(1):14–21PubMed
37.
Zurück zum Zitat Bilgici A, Ulusoy H, Kuru O, Celenk C, Unsal M, Danaci M (2005) Pulmonary involvement in rheumatoid arthritis. Rheumatol Int 25(6):429–435CrossRefPubMed Bilgici A, Ulusoy H, Kuru O, Celenk C, Unsal M, Danaci M (2005) Pulmonary involvement in rheumatoid arthritis. Rheumatol Int 25(6):429–435CrossRefPubMed
38.
Zurück zum Zitat Akira MSM, Hara H (1999) Thin-section CT findings in rheumatoid arthritis-associated lung disease: CT patterns and their courses. J Comput Assist Tomogr 23(6):941–948CrossRefPubMed Akira MSM, Hara H (1999) Thin-section CT findings in rheumatoid arthritis-associated lung disease: CT patterns and their courses. J Comput Assist Tomogr 23(6):941–948CrossRefPubMed
39.
Zurück zum Zitat Lee JS, Im JG, Ahn JM, Kim YM, Han MC (1992) Fibrosing alveolitis: prognostic implication of ground-glass attenuation at high-resolution CT. Radiology 184(2):451–454CrossRefPubMed Lee JS, Im JG, Ahn JM, Kim YM, Han MC (1992) Fibrosing alveolitis: prognostic implication of ground-glass attenuation at high-resolution CT. Radiology 184(2):451–454CrossRefPubMed
Metadaten
Titel
Retrospective study of the clinical characteristics and risk factors of rheumatoid arthritis-associated interstitial lung disease
verfasst von
Yongfeng Zhang
Hongbin Li
Nawei Wu
Xin Dong
Yi Zheng
Publikationsdatum
12.02.2017
Verlag
Springer London
Erschienen in
Clinical Rheumatology / Ausgabe 4/2017
Print ISSN: 0770-3198
Elektronische ISSN: 1434-9949
DOI
https://doi.org/10.1007/s10067-017-3561-5

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