Factors Associated with Airway Disease and Interstitial Lung Disease in Rheumatoid Arthritis

Ji-Won Kim; Hwajeong Lee; Jung-Yoon Choe; Jun Hyun Hwang; Sung-Hoon Park; Hye-Sun Lee; Seong-Kyu Kim

doi:10.4078/jrd.2016.23.2.101

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Kim, Lee, Choe, Hwang, Park, Lee, and Kim: Factors Associated with Airway Disease and Interstitial Lung Disease in Rheumatoid Arthritis

Original Article

J Rheum Dis 2016;23(2):101-108.

Published online: 31 October 2016

DOI: https://doi.org/10.4078/jrd.2016.23.2.101

Factors Associated with Airway Disease and Interstitial Lung Disease in Rheumatoid Arthritis

Ji-Won Kim¹, Hwajeong Lee¹, Jung-Yoon Choe¹, Jun Hyun Hwang², Sung-Hoon Park¹, Hye-Sun Lee¹, Seong-Kyu Kim¹

¹Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea

²Department of Preventive Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea

Corresponding to: Jung-Yoon Choe, Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, 33 Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472, Korea. E-mail: jychoe@cu.ac.kr

Received 10 September 2015 Revised 14 October 2015 Accepted 15 October 2015

This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

This study examined lung involvement in patients with rheumatoid arthritis (RA) and identified factors associated with airway disease (AD) and interstitial lung disease (ILD).

Methods

A total of 507 RA patients were enrolled in a cross-sectional study. Lung involvement was assessed by high-resolution computed tomography scan. The patient groups were classified according to normal, AD, and ILD. Multinomial logistic regression analysis was performed to identify factors associated with AD and ILD.

Results

The most frequent lung involvement was AD (38.3%) followed by ILD (12.6%). Old age (adjust odds ratio [aOR] 2.58, 95% confidence interval [CI] 1.70 to 3.90 for AD; aOR 4.38, 95% CI 2.30 to 8.35 for ILD), male gender (aOR 2.57, 95% CI 1.22 to 5.42 for AD; aOR 5.48, 95% CI 2.20 to 13.65 for ILD) were factors associated with AD and ILD in RA patients. ILD was associated with short disease duration (aOR 0.30, 95% CI 0.14 to 0.62), AD was associated with high titers of anticyclic citrullinated peptides antibodies (anti-CCP; aOR 1.61, 95% CI 1.07 to 2.44).

Conclusion

AD was the most frequent lung involvement in patients with RA. Old age and male gender were both associated with AD and ILD. Short disease duration was associated with ILD. High titers of anti-CCP was associated with AD.

Keywords: Rheumatoid arthritis, Obstructive lung diseases, Interstitial lung diseases, X-ray computed tomography, Risk factors

REFERENCES

1. Carmona L, González-Alvaro I, Balsa A, Angel Belmonte M, Tena X, Sanmartí R. Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity. Ann Rheum Dis. 2003; 62:897–900.

2. Cimmino MA, Salvarani C, Macchioni P, Montecucco C, Fossaluzza V, Mascia MT, et al. Extraarticular manifestations in 587 Italian patients with rheumatoid arthritis. Rheumatol Int. 2000; 19:213–7.

3. Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extraarticular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003; 62:722–7.

4. Demoruelle MK, Solomon JJ, Fischer A, Deane KD. The lung may play a role in the pathogenesis of rheumatoid arthritis. Int J Clin Rheumtol. 2014; 9:295–309.

5. Yunt ZX, Solomon JJ. Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am. 2015; 41:225–36.

6. England BR, Sayles H, Michaud K, Caplan L, Davis LA, Cannon GW, et al. Cause-specific mortality in male US veterans with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016; 68:36–45.

7. Alexiou I, Germenis A, Koutroumpas A, Kontogianni A, Theodoridou K, Sakkas LI. Anti-cyclic citrullinated peptide-2 (CCP2) autoantibodies and extra-articular manifestations in Greek patients with rheumatoid arthritis. Clin Rheumatol. 2008; 27:511–3.

8. Bilgici A, Ulusoy H, Kuru O, Celenk C, Unsal M, Danaci M. Pulmonary involvement in rheumatoid arthritis. Rheumatol Int. 2005; 25:429–35.

9. Gabbay E, Tarala R, Will R, Carroll G, Adler B, Cameron D, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med. 1997; 156:528–35.

10. Gochuico BR, Avila NA, Chow CK, Novero LJ, Wu HP, Ren P, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med. 2008; 168:159–66.

11. Mori S, Koga Y, Sugimoto M. Small airway obstruction in patients with rheumatoid arthritis. Mod Rheumatol. 2011; 21:164–73.

12. Mori S, Koga Y, Sugimoto M. Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis. Respir Med. 2012; 106:1591–9.

13. Saag KG, Kolluri S, Koehnke RK, Georgou TA, Rachow JW, Hunninghake GW, et al. Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum. 1996; 39:1711–9.

14. Sakaida H. IgG rheumatoid factor in rheumatoid arthritis with interstitial lung disease. Ryumachi. 1995; 35:671–7.

15. Shidara K, Hoshi D, Inoue E, Yamada T, Nakajima A, Taniguchi A, et al. Incidence of and risk factors for interstitial pneumonia in patients with rheumatoid arthritis in a large Japanese observational cohort, IORRA. Mod Rheumatol. 2010; 20:280–6.

16. Aubart F, Crestani B, Nicaise-Roland P, Tubach F, Bollet C, Dawidowicz K, et al. High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J Rheumatol. 2011; 38:979–82.

17. Inui N, Enomoto N, Suda T, Kageyama Y, Watanabe H, Chida K. Anti-cyclic citrullinated peptide antibodies in lung diseases associated with rheumatoid arthritis. Clin Biochem. 2008; 41:1074–7.

18. Kelly CA, Saravanan V, Nisar M, Arthanari S, Woodhead FA, Price-Forbes AN, et al. British Rheumatoid Interstitial Lung (BRILL) Network. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics-a large multicentre UK study. Rheumatology (Oxford). 2014; 53:1676–82.

19. Reynisdottir G, Karimi R, Joshua V, Olsen H, Hensvold AH, Harju A, et al. Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol. 2014; 66:31–9.

20. Rocha-Muñoz AD, Ponce-Guarneros M, Gamez-Nava JI, Olivas-Flores EM, Mejía M, Juárez-Contreras P, et al. Anti-cyclic citrullinated peptide antibodies and severity of interstitial lung disease in women with rheumatoid arthritis. J Immunol Res. 2015; 2015; 151626.

21. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31:315–24.

22. Tanaka N, Kim JS, Newell JD, Brown KK, Cool CD, Meehan R, et al. Rheumatoid arthritis-related lung diseases: CT findings. Radiology. 2004; 232:81–91.

23. Dawson JK, Fewins HE, Desmond J, Lynch MP, Graham DR. Fibrosing alveolitis in patients with rheumatoid arthritis as assessed by high resolution computed tomography, chest radiography, and pulmonary function tests. Thorax. 2001; 56:622–7.

24. Bongartz T, Nannini C, Medina-Velasquez YF, Achenbach SJ, Crowson CS, Ryu JH, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010; 62:1583–91.

25. Wilsher M, Voight L, Milne D, Teh M, Good N, Kolbe J, et al. Prevalence of airway and parenchymal abnormalities in newly diagnosed rheumatoid arthritis. Respir Med. 2012; 106:1441–6.

26. Perez T, Remy-Jardin M, Cortet B. Airways involvement in rheumatoid arthritis: clinical, functional, and HRCT findings. Am J Respir Crit Care Med. 1998; 157:1658–65.

27. Mori S, Cho I, Koga Y, Sugimoto M. Comparison of pulmonary abnormalities on high-resolution computed tomography in patients with early versus longstanding rheumatoid arthritis. J Rheumatol. 2008; 35:1513–21.

28. Kim EJ, Collard HR, King TE Jr. Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest. 2009; 136:1397–405.

29. Lee HK, Kim DS, Yoo B, Seo JB, Rho JY, Colby TV, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005; 127:2019–27.

30. Tansey D, Wells AU, Colby TV, Ip S, Nikolakoupolou A, du Bois RM, et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology. 2004; 44:585–96.

31. Chen J, Shi Y, Wang X, Huang H, Ascherman D. Asymptomatic preclinical rheumatoid arthritis-associated interstitial lung disease. Clin Dev Immunol. 2013; 2013; 406927.

32. Rangel-Moreno J, Hartson L, Navarro C, Gaxiola M, Selman M, Randall TD. Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J Clin Invest. 2006; 116:3183–94.

33. Demoruelle MK, Weisman MH, Simonian PL, Lynch DA, Sachs PB, Pedraza IF, et al. Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? Arthritis Rheum. 2012; 64:1756–61.

34. Fischer A, Solomon JJ, du Bois RM, Deane KD, Olson AL, Fernandez-Perez ER, et al. Lung disease with anti-CCP anti-bodies but not rheumatoid arthritis or connective tissue disease. Respir Med. 2012; 106:1040–7.

35. Gizinski AM, Mascolo M, Loucks JL, Kervitsky A, Meehan RT, Brown KK, et al. Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA. Clin Rheumatol. 2009; 28:611–3.

36. Geddes DM, Webley M, Emerson PA. Airways obstruction in rheumatoid arthritis. Ann Rheum Dis. 1979; 38:222–5.

Table 1.

Generalized characteristics of enrolled patients

Characteristic	Total (n=507)
Age (yr)	62.0 (54.0∼70.0)
At diagnosis	48.0 (39.0∼57.0)
≥65	209 (41.2)
Disease duration (yr)	14.0 (10.0∼17.0)
≥10	398 (78.5)
Male	81 (16.0)
Smoking history	51 (10.1)
ESR (mm/h)	35.0 (18.0∼60.0)
CRP (mg/L) RF (IU/mL)	1.8 (0.5∼6.6) 113.6 (48.0∼241.5)
Anti-CCP (U/mL)	100 (21.8∼500.0)

Values are presented as median (interquartile range) or number (%). Anti-CCP: anti-cyclic citrullinated peptide anti bodies, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, RF: rheumatoid factor.

Table 2.

Distribution of lung involvement in enrolled patients

Pulmonary involvement	Data
No lung disease	249
Airway disease^*	194
Bronchiectasis	145 (74.7)
Bronchiolitis	47 (24.2)
Emphysema	26 (13.4)
Small airway disease	10 (5.2)
Interstitial lung disease	64
UIP	20 (31.3)
NSIP	11 (17.2)
Unspecified	33 (51.5)
Pleural involvement	9
Pleural effusion	5 (55.6)
Pleural thickening	4 (44.4)
Vascular involvement	0

Values are presented as number only or number (%). NSIP: nonspecific interstitial pneumonia, UIP: usual interstitial pneumonia.

^* Twenty-nine patients were accompanied by bronchiectasis and bronchiolitis. Four patients were accompanied by bronchiectasis and emphysema. One patient was accompanied by bronchiolitis and emphysema.

Table 3.

Comparison of clinical parameters between no lung disease, airway disease, and interstitial lung disease

Characteristic	No lung disease (n=249)	Airway disease (n=194)	Interstitial lung disease (n=64)	p-value
Age (yr)	58.0 (51.0∼65.0)	65.0 (58.0∼72.0)	68.0 (61.0∼75.0)	＜0.001^*
≥65	70 (28.1)	98 (50.5)	41 (64.1)	＜0.001^†
At diagnosis	44.0 (35.0∼52.0)	51.0 (44.0∼59.0)	58.0 (48.5∼64.0)	＜0.001^*
Disease duration (yr)	14.0 (11.0∼17.0)	14.0 (10.0∼17.0)	11.0 (5.5∼16.5)	＜0.001^*
≥10	211 (84.7)	152 (78.4)	35 (54.7)	＜0.001^†
Male	18 (7.2)	39 (20.1)	24 (37.5)	＜0.001^†
Smoking history	15 (6.0)	23 (11.9)	13 (20.3)	0.002^†
ESR (mm/h)	32.0 (16.0∼56.0)	33.5 (17.0∼59.0)	44.5 (30.0∼76.0)	0.003^*
Low tertile (≤23)	85 (34.1)	72 (37.1)	12 (18.8)
Middle tertile (24∼49)	92 (36.9)	61 (31.4)	24 (37.5)	0.048^†
High tertile (≥50)	72 (28.9)	61 (31.4)	28 (43.8)
CRP (mg/L)	1.3 (0.3∼4.0)	1.9 (0.5∼6.6)	6.1 (1.1∼26.1)	＜0.001^*
Low tertile (≤0.8)	100 (40.2)	67 (34.5)	12 (18.8)
Middle tertile (0.9∼4.0)	87 (34.9)	63 (32.5)	16 (25.0)	＜0.001^†
High tertile (≥4.1)	62 (24.9)	64 (33.0)	36 (56.3)
RF (IU/mL)	86.1 (33.7∼211.4)	125.8 (60.7∼272.4)	180.4 (76.4∼331.0)	＜0.001^*
High-titer (≥110)	105 (42.2)	111 (57.2)	42 (65.6)	＜0.001^†
Anti-CCP (U/mL)	76.4 (14.2∼500.0)	121.2 (35.2∼500.0)	267.5 (64.2∼500.0)	＜0.001^*
High-titer (≥100)	119 (47.8)	122 (62.9)	46 (71.9)	＜0.001^†
TNF-α inhibitors	23 (9.2)	16 (8.2)	3 (4.7)	0.500^†
Abatacept	2 (0.8)	2 (1)	0 (0)	0.721^†
Methotrexate	204 (81.9)	152 (78.4)	45 (70.3)	0.119^†
Bucillamine	13 (5.2)	8 (4.1)	5 (7.8)	0.508^†
Sulfasalazine	43 (17.3)	38 (19.6)	16 (25.0)	0.366^†
Leflunomide	24 (9.6)	25 (12.9)	3 (4.7)	0.156^†

Values are presented as median (interquartile range) or number (%). Anti-CCP: anti-cyclic citrullinated peptide antibodies, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, RF: rheumatoid factor, TNF-α, tumor necrosis factor alpha.

^* Analysis was done Kruskal-Wallis test or

^† earson chi-square test.

Table 4.

Determination of factors associated with lung involvement in univariate analysis

Characteristic		Airway disease vs. no lung disease		Interstitial lung disease vs. no lung disease
Characteristic		cOR (95% CI)	p-value^*	cOR (95% CI)	p-value^*
Age (yr)	<65	1		1
	≥65	2.61 (1.76∼3.87)	＜0.001	4.56 (2.55∼8.15)	＜0.001
Disease duration (yr)	＜10	1		1
	≥10	0.65 (0.40∼1.06)	0.084	0.22 (0.12∼0.40)	＜0.001
Gender	Female	1		1
	Male	3.23 (1.78∼5.85)	＜0.001	7.70 (3.83∼15.46)	＜0.001
Smoking history	No	1		1
	Yes	2.10 (1.06∼4.14)	0.033	3.98 (1.78∼8.87)	0.001
ESR (mm/h)	Low tertile (≤23)	1		1
	Middle tertile (24∼49)	0.78 (0.50∼1.23)	0.287	1.85 (0.87∼3.92)	0.110
	High tertile (≥50)	1.00 (0.63∼1.59)	0.999	2.76 (1.31∼5.81)	0.008
CRP (mg/L)	Low tertile (≤0.8)	1		1
	Middle tertile (0.9∼4.0)	1.08 (0.69∼1.69)	0.734	1.53 (0.69∼3.42)	0.297
	High tertile (≥4.1)	1.54 (0.97∼2.46)	0.690	4.84 (2.34∼10.00)	＜0.001
RF (IU/mL)	Low-titer (＜110)	1		1
	High-titer (≥110)	1.83 (1.26∼2.68)	0.002	2.62 (1.48∼4.65)	0.001
Anti-CCP (U/mL)	Low-titer (＜100)	1		1
	High-titer (≥100)	1.85 (1.26∼2.72)	0.002	2.79 (1.53∼5.08)	0.001

Analysis was done by univariate multinomial logistic regression analysis. Anti-CCP: anti-cyclic citrullinated peptide antibodies, CI confidence interval, cOR: crude odds ratio, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, RF: rheumatoid factor

^* p-values were obtained by comparison with patients with no lung disease.

Table 5.

Determination of factors associated with lung involvement in multivariate analysis

Characteristic		Airway disease vs. no lung disease		Interstitial lung disease vs. no lung disease
Characteristic		aOR (95% CI)	p-value^*	aOR (95% CI)	p-value^*
Age (yr)	＜65	1		1
	≥65	2.58 (1.70∼3.90)	＜0.001	4.38 (2.30∼8.35)	＜0.001
Disease duration (yr)	＜10	1		1
	≥10	0.73 (0.42∼1.28)	0.274	0.30 (0.14∼0.62)	0.001
Gender	Female	1		1
	Male	2.57 (1.22∼5.42)	0.013	5.48 (2.20∼13.65)	＜0.001
Smoking history	No	1		1
	Yes	0.88 (0.36∼2.15)	0.782	0.76 (0.25∼2.30)	0.630
ESR (mm/h)	Low tertile (≤23)	1		1
	Middle tertile (24∼49)	0.72 (0.44∼1.17)	0.182	1.47 (0.63∼3.42)	0.374
	High tertile (≥50)	0.77 (0.44∼1.36)	0.373	1.52 (0.60∼3.83)	0.373
CRP (mg/L)	Low tertile (≤0.8)	1		1
	Middle tertile (0.9∼4.0)	0.94 (0.57∼1.55)	0.800	0.92 (0.38∼2.21)	0.854
	High tertile (≥4.1)	1.20 (0.66∼2.16)	0.553	1.60 (0.63∼4.09)	0.327
RF (IU/mL)	Low-titer (＜110)	1		1
	High-titer (≥110)	1.45 (0.97∼2.17)	0.073	1.62 (0.85∼3.01)	0.142
Anti-CCP (U/mL)	Low-titer (＜100)	1		1
	High-titer (≥100)	1.61 (1.07∼2.44)	0.023	1.68 (0.85∼3.31)	0.135

Analysis was done by multivariate multinomial logistic regression analysis. Anti-CCP: anti-cyclic citrullinated peptide antibodies, aOR: adjusted odds ratio, CI: confidence interval, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, RF: rheumatoid factor.

^* p-values were obtained by comparison with patients with no lung disease.

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