The lung as a target and as an initiator of rheumatoid arthritis-associated immunity: Implications for interstitial lung disease

Abstract

Interstitial lung disease (ILD) is a serious extra-articular co-morbidity in rheumatoid arthritis (RA) patients and accounts for a substantial part of the increased mortality in RA. In this review, we describe how environmental and lifestyle factors interact with genetic variants in the HLA genetic locus in triggering RA-specific antibodies against post-translationally modified, mainly citrullinated proteins (ACPA), which are associated with an increased risk of ILD. The same environmental risk factors, i.e. exposure to noxious agents such as smoke to the lungs contribute additionally to the emergence of RA ILD as does long-lasting high disease activity and an additional ILD-specific genetic risk variant related to mucus formation (MUC5B). Options for prevention and therapy of RA ILD resulting from this so far incomplete knowledge of its pathophysiology are expanding. The most obvious option is to address modifiable environmental risk factors, such as smoking and exposure to other noxious agents affecting the lungs. The second option is to reduce the inflammatory activity of RA; here different anti-rheumatic therapies appear to have differential effects on ILD development. The third and novel option is to use anti-fibrotic therapy which may reduce the development of RA ILD but has not yet been shown to revert existing fibrosis. The main conclusion concerning the clinical handling of RA ILD is therefore an early awareness of the risk for RA ILD combined with active measures to reduce modifiable environmental/lifestyle factors and use optimal anti-rheumatic therapies for early and sustained reduction of disease activity. These actions should be combined with a preparedness to use anti-fibrotic therapy for patients at high risk for ILD despite previous risk reduction efforts.