Impact of radiological honeycombing in rheumatoid arthritis-associated interstitial lung disease

Interstitial lung disease (ILD) is a progressive fibrotic disease of the lung parenchyma. Occurring in association with several connective tissue diseases, it is the most common and important pulmonary manifestation of rheumatoid arthritis (RA) [1]. The poor prognostic factors of RA-ILD include male sex, older age, a wide range of fibrotic changes on computed tomography (CT), usual interstitial pneumonia (UIP) pattern, and acute exacerbation [2‐5]. In particular, radiological analysis by high-resolution CT (HRCT) is often used in clinical practice, and for clinicians determining the management of RA-ILD, it is important to know whether each patient has UIP [5‐7]. However, an unclassifiable pattern on HRCT is present to some extent in the RA-ILD population because RA-ILD exhibits a diversity of patterns [6, 8]. Recent reports including our study showed that the major HRCT pattern in RA-ILD was mixed nonspecific interstitial pneumonia (NSIP) and UIP [9, 10]. However, radiological honeycomb pattern is a poorer prognostic factor than a UIP pattern on HRCT [10]. Adegunsoye et al. recently noted that honeycomb represents a progressive fibrotic ILD phenotype of underlying disease such as RA and chronic hypersensitive pneumonia [11]. Therefore, we highlight radiological honeycomb as the most important radiological finding. Further, the radiological course of honeycomb formation over long-term follow-up is not well known. Thus, the aims of the present study were to assess the sequential radiological changes (i.e., whether honeycombing formed) in patients with RA-ILD and to evaluate whether this impacts their survival.

Radiological honeycombing has been described in diverse forms of ILD, but its prevalence and association with mortality across the spectrum of ILD remain unclear [11]. The present study aimed to assess the time course over which radiological honeycombing could evolve and whether its formation would influence survival in patients with RA-ILD.

First, in terms of radiological changes occurring during the follow-up period (median duration: 4.7 years), 40% of the RA-ILD patients formed honeycombing. Yamauchi et al. reported that in IPF, 53.3% of the patients developed honeycombing over a mean follow-up period of 5.9 years [15]. Giacomi et al. also reported the development of honeycombing in 32% of their patients over a median follow-up period of 4.8 years [16]. The present study is, to our knowledge, the first to focus on the development of honeycombing during follow-up for RA-ILD. In our cohort, 36% of patients with probable UIP and 50% of patients with mixed NSIP/UIP developed honeycombing, and to some extent, patients with RA-ILD developed honeycombing during long-term follow-up as a component of IPF. Importantly, over the long term, honeycomb also arose in a quarter of the RA-ILD patients with NSIP. In 28% of idiopathic ILD patients with initial findings suggestive of NSIP, follow-up CT scans were interpreted as more suggestive of IPF [17]. Taken together, we observed that a certain number of chronic ILD patients developed honeycombing over the long term, regardless of their underlying disease (i.e., RA or idiopathic) and CT pattern (i.e., probable UIP, mixed NSIP/UIP, or NSIP).

Second, we found no significant difference in the prognoses of the RA-ILD patients who did or did not eventually develop honeycombing. In IPF, it is controversial whether having honeycomb is a poor prognostic factor [11, 15]. However, recent reports indicated that the development of honeycombing in RA-ILD was a poorer prognostic factor than CT pattern (e.g., UIP, NSIP) [9, 11]. Similarly, our recent study also showed having honeycomb to be a poor prognostic factor in RA-ILD [10]. Therefore, we speculated that the small sample size in our study probably induced this result. In fact, the Kaplan-Meier survival curve for the time from the date of honeycomb formation to death in the Honeycomb group showed a poor median survival time of 3.2 years. In comparison with this survival time, surprisingly, our previous study showed a median survival time of 6.4 years in the RA-ILD patients with honeycomb. Therefore, it appears that survival is poorer in RA-ILD patients who develop a honeycomb pattern over the disease course than in those with honeycomb found at the initial diagnosis [10]. Thus, the possibility that patients with the characteristics of both progressive ILD and honeycomb development must be considered to have a poor prognosis. However, both our previous and present studies present the possibility that the disease course in some RA-ILD patients with honeycomb at the initial diagnosis might stabilize as burnt out. A minority of patients, even those with a UIP pattern, experience significant improvement or stabilization in pulmonary function over the disease course [18]. Taken together, the disease behavior of RA-ILD accompanied by honeycombing is heterogeneous, and the most important thing is to evaluate the disease, including radiological changes, over the entire clinical course rather than only at specific points.

There are limitations in the current study. First, it is a retrospective study with a relatively small number of patients. Second, selection bias may be present because this study was performed in a single center, and some of the patients were excluded from the long-term analysis due to insufficient follow-up data. Third, we could not determine whether the clinical diagnosis of RA-ILD impacted treatment decisions and, as such, the natural disease course.

The present study confirmed that radiological findings over the disease course and clinical disease behavior in RA-ILD are heterogenous. A certain number of RA-ILD patients developed a honeycomb pattern over long-term follow-up, regardless of whether they had UIP or NSIP. A progressive disease course and radiological honeycombing could be useful predictors of poor prognosis in patients with RA-ILD. This may help in assessing appropriate strategies to treat the RA itself and the combination of RA and ILD.