Effectiveness of pirfenidone in idiopathic pulmonary fibrosis according to the autoantibody status: a retrospective cohort study

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrosing interstitial pneumonia of unknown cause, characterized by a histopathological pattern of usual interstitial pneumonia (UIP) [1]. Exclusion of known causes of interstitial pneumonia, including environmental exposures, drug toxicities, and connective tissue diseases (CTDs), is important for IPF diagnosis because it affects the treatment and prognosis [2, 3].

Rheumatoid arthritis, systemic lupus erythematosus, idiopathic inflammatory myopathies, Sjögren’s syndrome, systemic sclerosis, and mixed connective tissue disease are representative CTDs that might involve the lungs and cause fibrotic lung disorders. Each CTD has its unique clinical features and presents specific autoantibody positivity that can help to distinguish it from other CTDs. An official IPF diagnostic guideline proposed by the International Consensus Statement of the American Thoracic Society and European Respiratory Society also recommends serologic autoantibody tests in all patients with newly identified interstitial lung disease to exclude CTDs [1]. However, CTDs might initially involve only the lungs, without extrathoracic features [4]. Furthermore, symptoms and signs of extrapulmonary involvement might not be present at the time of diagnosis, or they might be subtle [5]. These factors complicate the differential diagnoses of fibrotic lung disease.

The term interstitial pneumonia with autoimmune features (IPAF) was recently proposed to describe individuals with interstitial lung disease and other clinical, serologic, and morphologic features that presumably arise from an underlying autoimmune condition but do not meet the current diagnostic criteria for a CTD [6]. This group of patients demonstrates better survival than patients with IPF but markedly worse survival than those with CTD-related interstitial lung disease [7, 8]. The diagnostic criteria of IPAF include the clinical, serologic, and morphologic domains.

However, UIP is excluded from the morphologic domain because its association with CTD is weaker than that of the morphologic patterns observed in other diseases, such as non-specific interstitial pneumonia, organizing pneumonia, and lymphoid interstitial pneumonia. Therefore, patients with UIP, positive for autoantibodies, who do not meet the diagnostic criteria for CTD, are diagnosed with IPF and treated according to the IPF guidelines.

Autoantibody positivity has previously been reported in 23–41% of patients with IPF [9‐13]. To date, little is known about the clinical implications of autoantibody positivity in IPF, and the reported results are somewhat controversial. Some studies reported that autoantibody positivity was associated with a better survival outcome [10, 12], while others reported no survival difference between autoantibody-positive and autoantibody-negative patients [11, 13]. One retrospective study reported that treating autoantibody-positive IPF with immunomodulators was associated with a superior survival outcome [12]. However, it is not known if IPF with different serological autoimmune presentation respond differently to the antifibrotic treatment.

This retrospective study aimed to investigate whether pirfenidone, an antifibrotic agent currently used to treat patients with IPF, has differential effects in patients with different autoantibody statuses.

In this retrospective observational study, we show a similar slowing effect of pirfenidone on the progression of IPF irrespective of the autoantibody status. A similar change in FVC was found in autoantibody-positive and autoantibody-negative patients with IPF. The change in FVC among autoantibody-positive patients treated with pirfenidone was smaller than in those who were never treated with it. Therefore, we conclude that pirfenidone has similar efficacy in attenuating the FVC decline in patients with IPF irrespective of the autoantibody status.

Several studies have reported on the role of autoimmunity in the pathogenesis of IPF. Activated T cells, including autoreactive CD4 T cells, were found in the blood, lung tissues, hilar lymph nodes, and bronchoalveolar lavage fluid of patients with IPF [18, 19]. It was demonstrated that T cells assist B cells in proliferating and producing autoantibodies, and that this process facilitates inflammation and fibrosis in the lungs [20, 21]. However, the clinical implications of this experimentally proven evidence are uncertain.

The rate of autoantibody positivity in patients with IPF in this study was lower than that reported in other studies [12, 13, 22], but similar to that observed in healthy adults [6, 23]. This study was performed at a tertiary university hospital with a medical team specialized in interstitial lung diseases, and only respiratory specialists were authorized to prescribe pirfenidone. Patients diagnosed with IPF and prescribed pirfenidone were routinely followed up by a respiratory specialist. Therefore, although the patients were initially diagnosed with IPF, the respiratory specialist routinely examined them for evidence of alternative diagnoses. Particularly, the autoantibody-positive patients were reevaluated for alternative diagnoses if autoimmune features were observed during follow-up. This might explain the low autoantibody-positive rate in patients with IPF in this study.

Recently, a study reported that autoantibody-positive patients with IPF had a better prognosis than those negative for autoantibodies; additionally, immunomodulators, including steroids, had positive effects on mortality. The authors suggested that different treatment strategies should be enacted based on the presence of autoantibodies [12]. However, even if the autoantibody-positive patients did not meet the autoimmune disease criteria at the time of IPF diagnosis, the close follow-up of true patients with IPF to detect autoimmune diseases demonstrated attenuation of FVC decline due to pirfenidone treatment, an effect that was observed regardless of the autoantibody status. Therefore, we suggest close monitoring of patients with IPF for alternative diagnoses when pirfenidone is ineffective, especially in autoantibody-positive patients, instead of attempting different treatment strategies based on the autoantibody status.

This study has several limitations. First, not all autoantibodies in the IPAF serologic domain were tested in all patients. Therefore, patients included in the autoantibody-negative group may have actually been autoantibody-positive but were not tested for it. Second, masking of the differential effects of pirfenidone due to systemic corticosteroid use cannot be excluded. The proportion of patients using systemic corticosteroids for over 30 days was higher, and the duration of use was longer in the autoantibody-positive group than in the autoantibody-negative group. Although the differences were statistically insignificant, the efficacy difference between the groups could have been masked by the longer and higher systemic corticosteroid use in the autoantibody-positive group. Third, nintedanib, which is another anti-fibrotic approved for the treatment of IPF, was not covered by Korean health insurance until recently [24]. As a result, we were unable to evaluate the impact of autoantibody status on the efficacy of this treatment in our patient population due to small numbers of patients on this medication. Finally, as a single center study, the result of our study requires replication in larger and more diverse patient cohorts to be generalized.

The patients in this study were diagnosed with IPF after excluding other possible diagnoses. We found that pirfenidone slowed the progression of IPF, independent of the autoantibody status. We suggest that patients with IPF who do not respond to pirfenidone should be reevaluated for underlying autoimmune diseases.