Preclinical/subclinical rheumatoid arthritis-associated interstitial lung disease: misleading terms with potentially deleterious consequences

Interstitial lung disease (ILD) is a leading cause of mortality in patients with rheumatic diseases, including rheumatoid arthritis (RA).¹ The 5-year mortality rate is twice as high in RA patients with ILD than without ILD.² Moreover, a recent report demonstrated that mortality rates in patients with RA-ILD disease codes remained unchanged from 2005-2018, even though the overall RA mortality rate declined during this time period.³ Despite the evidence that ILD contributes to premature death in RA, screening for ILD in RA is not routinely performed in clinical practice, and numerous questions remain regarding the management of RA-ILD.⁴

Interstitial lung abnormalities (ILA) are sometimes incidentally observed in patients with RA who undergo imaging for other reasons. The Fleischner Society refers to ILA as specific high-resolution computed tomography (HRCT) findings that are potentially compatible with ILD in patients without clinical suspicion of the disease.⁵ A recent Fleischner Society Position Paper recommended that incidentally detected ILA in patients with autoimmune disease, such as RA, should be classified as “preclinical ILD” rather than ILA due to the presence of a strong risk factor for progressive disease.⁵ Prior literature has also referred to these radiological changes as “subclinical ILD.” One of the obstacles rheumatologists and pulmonologists face is the lack of consensus on the clinical meaning of “preclinical/subclinical” ILD in patients with RA, as these terms are also used at times to describe patients with early ILD, mild ILD, and/or ILD in an asymptomatic patient. These varying definitions not only create semantic confusion, but they also cultivate the misconception that “preclinical/subclinical” ILD is a non-worrisome feature of RA, when in fact, it is associated with 3-fold increased risk of mortality compared to those with normal lung imaging in a study among smokers with RA.⁶

The presence of symptoms related to interstitial changes on HRCT is also variable as some patients with interstitial changes have dyspnea that may or may not be due to the radiological findings. In addition, ascertaining the presence of respiratory symptoms attributable to ILD is challenging in patients with RA. The extra-pulmonary manifestations may limit exercise tolerance rendering it difficult to evaluate for exertional dyspnea. Moreover, even in patients with well controlled articular disease, many patients will modify their lifestyle to avoid joint pain and/or the sensation of breathlessness. Unless careful probing of past and current physical activity is performed, physicians may erroneously label these patients as asymptomatic. Furthermore, some RA patients may falsely attribute dyspnea to deconditioning and mobility limitations rather than underlying lung disease. Finally, ILD-related symptoms, such as cough, may be attributed to more common causes of cough, such as gastroesophageal reflux disease or post-nasal drip.

In addition to our inherent limitations in evaluating ILD-related symptoms, no evidence exists demonstrating that patients with “preclinical/subclinical” ILD and clinical ILD related to RA have different outcomes. Both RA and ILD activity were identified as independent predictors of survival in RA-ILD.⁷ Moreover, patients with less extensive ILD can still experience respiratory infections, as well as acute exacerbations, a primary contributor to hospitalizations and mortality in patients with RA-ILD. It is therefore conceivable that patients with RA diagnosed with preclinical/subclinical ILD could potentially have worse outcomes if both the RA and ILD are not monitored as closely as those diagnosed with clinical ILD.

We herein advocate that any patient with RA and ILD on HRCT, either with or without symptoms, undergoes monitoring for ILD progression. The three pillars of monitoring, derived from the recently published clinical practice guideline on progressive pulmonary fibrosis (PPF),⁸ include the following assessments: (1) symptoms; (2) physiology (e.g., declines in forced vital capacity [FVC], and when possible, diffusing capacity for carbon monoxide [DLCO]); (3) radiological changes on HRCT. The timing of the aforementioned assessments may vary based on an individual patient’s risk factors for ILD progression and suspected ILD subtype (e.g., the usual interstitial pneumonia pattern is associated with PPF in RA). Two international groups (American College of Rheumatology and the European Respiratory Society/European Alliance of Associations for Rheumatology) are currently developing clinical practice guidelines for autoimmune ILD, which will provide further guidance on how to monitor for ILD progression in patients with RA.

Future studies are needed to improve our ability to risk stratify patients with RA-ILD early in the disease course. While emerging research has augmented our understanding of which patients with RA are more likely to develop ILD,^9,10 longitudinal studies of patients with newly diagnosed RA-ILD may help uncover novel predictive biomarkers. To date, there is no evidence to recommend screening for ILD with HRCT of the chest in all RA patients, but many ILDs are incidentally diagnosed in patients with RA, so clinicians need evidence-based guidance for how to monitor and manage these patients. Future studies are needed to determine whether screening for ILD is justified in specific RA patients, such as smokers or patients with other ILD risk factors. The outcomes of these studies will help us to not only refine our ILD monitoring approach, but also identify patients who may derive the most benefit from specific ILD-targeted therapies. There is undoubtedly a future for precision medicine in RA-ILD, but first, we must ensure that all patients with RA-ILD receive appropriate ILD management.