Background/Purpose: The etiology of rheumatoid arthritis (RA) is only partly understood. In addition to smoking, other airway exposures, e.g. silica dust and traffic pollution, have been positively associated with RA. Inflammatory events in the lungs may thus be of pivotal importance in the pathogenesis of RA, in particular for anti-citrullinated protein antibody (ACPA) positive RA. The potential role for respiratory tract diseases (RTD) in RA pathogenesis has not been systematically explored. We aimed to explore the hypothesis that RTD may initiate the development of RA, with a specific focus on ACPA subtype.

Methods: Cases and controls included 1996-2009 in the population-based case-control study of incident RA, EIRA (2880 cases/4069 controls), were linked to the National Patient Register to detect hospitalizations and outpatient visits listing RTDs (exposures) that occurred prior to first symptom of RA (corresponding date in matched controls). The exposures were analysed overall (any RTD), and subdivided into chronic lower (CL), acute lower (AL), chronic upper (CU) and acute upper (AU) RTD.  Asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD) were also assessed separately. Using unconditional logistic regression models with RA as the dependent variable and RTDs as the independent variables, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Models were adjusted for smoking (ever vs. never smoking). Subgroup analyses based on smoking history (never, former, non-regular, or current smoking) were performed. 

Results: Overall (irrespective of ACPA status), subjects with a history of any RTD were at increased risk of developing RA (all ORs are found in the table). Individuals with a history of CU RTDs and asthma were at significantly increased risk. ACPA positive RA was not associated with a history of any RTD. However, there was a suggestive increased risk of ACPA positive RA following a history of interstitial lung disease. For ACPA negative RA, a history of a RTD conferred significantly increased risks. This was particularly true for chronic lower RTD and for asthma. When these associations were stratified by smoking status, the increased risk was most prominent in never or non-regular smokers (data not shown). 

Conclusion: In contrast to our hypothesis, RTD seems to be associated with ACPA negative, and not ACPA positive, RA.

Table. Odds ratios (OR) and 95% confidence intervals (CI) assessing the relationship between respiratory tract diseases and rheumatoid arthritis. All models adjusted for smoking
	ACPA status	N exposed cases/controls	OR (95% CI)
Any respiratory tract disease	All	410/503	1.18 (1.02-1.36)
	Positive	251/503	1.08 (0.92-1.28)
	Negative	159/503	1.32 (1.09-1.61)
Chronic lower diseases	All	77/88	1.26 (0.92-1.71)
	Positive	43/88	1.03 (0.71-1.50)
	Negative	34/88	1.55 (1.03-2.32)
Acute lower diseases	All	99/128	1.07 (0.82-1.40)
	Positive	54/128	0.90 (0.65-1.25)
	Negative	45/128	1.40 (0.98-1.98)
Chronic upper diseases	All	190/217	1.27 (1.04-1.55)
	Positive	126/217	1.26 (1.00-1.59)
	Negative	64/217	1.23 (0.92-1.64)
Acute upper diseases	All	98/126	1.13 (0.86-1.48)
	Positive	56/126	0.98 (0.71-1.36)
	Negative	42/126	1.41 (0.98-2.02)
Asthma	All	54/57	1.46 (1.00-2.12)
	Positive	29/57	1.14 (0.72-1.80)
	Negative	25/57	1.85 (1.14-2.98)
Chronic obstructive pulmonary disease	All	11/21	0.63 (0.30-1.32)
	Positive	6/21	0.53 (0.21-1.32)
	Negative	5/21	0.86 (0.32-2.31)
Interstitial lung disease	All	5/4	1.74 (0.46-6.56)
	Positive	4/4	2.34 (0.57-9.61)
	Negative	1/4	0.92 (0.10-8.26)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/respiratory-diseases-as-risk-factors-for-rheumatoid-arthritis/