Rheumatoid Arthritis (RA) associated interstitial lung disease (ILD)

Highlights

• The lifetime risk of RA–ILD is significant and associated mortality is high.

• The UIP subtype has a poor prognosis similar to classical IPF.

• The management of ILD in RA requires a multidisciplinary approach.

Abstract

Rheumatoid Arthritis (RA) is the most common Connective Tissue Disease (CTD) and represents an increasing burden on global health resources. Interstitial lung disease (ILD) has been recognised as a complication of RA but its potential for mortality and morbidity has arguably been under appreciated for decades. New studies have underscored a significant lifetime risk of ILD development in RA. Contemporary work has identified an increased risk of mortality associated with the Usual Interstitial Pneumonia (UIP) pattern which shares similarity with the most devastating of the interstitial pulmonary diseases, namely Idiopathic Pulmonary Fibrosis (IPF). In this paper, we discuss recent studies highlighting the associated increase in mortality in RA–UIP. We explore associations between radiological and histopathological features of RA–ILD and the prognostic implications of same. We emphasise the need for translational research in this area given the growing burden of RA–ILD. We highlight the importance of the respiratory physician as a key stakeholder in the multidisciplinary management of this disorder. RA–ILD focused research offers the opportunity to identify early asymptomatic disease and define the natural history of this extra articular manifestation. This may provide a unique opportunity to define key regulatory fibrotic events driving progressive disease. We also discuss some of the more challenging and novel aspects of therapy for RA–ILD.

Introduction

Rheumatoid Arthritis (RA) is a systemic inflammatory disorder characterised by the targeted progressive destruction of joints in the body. The disorder likely results from specific environmental exposures in a genetically susceptible individual with a resultant abnormal immune response. RA affects approximately 1% of the population and it is estimated that 2 million adults in the United States are burdened by this disease [1]. The total RA related economic cost to society in Europe is estimated at €45.3 billion annually [2]. Women are three times more likely to be affected than men [3]. Survival in RA patients is lower than that of the normal population and there has been no fundamental change in the last 40 years [4], [5].

Pulmonary pathology is common and contributes significantly to morbidity and to a mortality of 10 to 20% [6]. Pulmonary manifestations can affect all components of the lungs with varying degrees of inflammation and fibrosis. Airway diseases, pleural complications and nodules have been described [7], [8], [9], [10]. The presence of radiographic and clinical bronchiectasis is notable particularly in severe RA [11]. The commonly coined term “rheumatoid lung disease” is evidently a misnomer and represents a multitude of varying pleural and pulmonary pathologies.

However, ILD is the most common and potentially most devastating extra-articular manifestation of RA in the lung [12]. ILD is heterogeneous in RA but the majority of cases mimic the two idiopathic interstitial pneumonia patterns of nonspecific interstitial pneumonia (NSIP) and Usual Interstitial Pneumonia (UIP). Recent work has indicated that ILD may be a feature of early RA, that the prevalence increases with advancing age and the diagnosis of ILD in RA carries a poor prognosis, oftentimes similar to Idiopathic Pulmonary Fibrosis (IPF) [13], [14]. The presence of ILD has received poor emphasis in the management of Connective Tissue Diseases and RA patients in particular [15]. The prognostic value of these patterns has been unclear to date and the treatment of RA–ILD has generally recommended the use of anti-inflammatory and immunosuppressive agents regardless of interstitial pneumonia pattern present [16]. However, the presence of the UIP pattern on High Resolution Computed Tomography (HRCT) in RA patients may be associated with a significantly shorter survival compared to other forms of interstitial disease [17].

ILD may precede articular disease and the presence of interstitial lung changes in asymptomatic patients has been reported [18], [19]. A number of clinical and genetic factors have now been proposed to allow for identification of RA patients at risk of ILD [20]. The study of early RA–ILD provides an opportunity for research and the potential development of screening programmes.

The management of ILD in RA patients is a challenge. Interstitial pulmonary pathology may be a manifestation of the chronic immune activation and cellular inflammatory processes that occur in RA and subsequently promote aberrant fibroproliferation [1]. It is too early to speculate on a potential pathogenic overlap with IPF [21]. Furthermore, drug related and infectious complications may result in ILD development in RA [22]. Novel biological treatments and their reported potential association with an increased risk of pulmonary interstitial disease and a higher risk of death have further confounded many clinicians [23]. Several agents have been described in the literature for the treatment of RA–ILD but no large randomised controlled trials exist to date to guide clinicians in the complex management of RA–ILD.