Improving risk-stratification of rheumatoid arthritis patients for interstitial lung disease.

Jérôme Avouac,Alexia Steelandt,Yuichiro Shirai,Yannick Allanore,Anne Cauvet,Muriel Elhai,Oliver Distler,Masataka Kuwana,Gernot Zissel

doi:10.1371/journal.pone.0232978

Abstract

ObjectiveTo determine the performance of 3 circulating markers for the diagnosis and the progression of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA).MethodsSerum concentrations of 3 circulating markers, lung epithelial-derived surfactant protein D (SPD), chemokine CCL-18 and Krebs von den Lungen-6 glycoprotein (KL-6), were measured by ELISA in consecutive patients with established RA. These patients were recruited from 3 tertiary centers and they all had been investigated by chest high-resolution computed tomography (HRCT). For a subset of French patients, a follow-up HRCT was available (mean interval between HRCT: 3±1.5 years).ResultsAmong the 147 included patients (age: 66 ± 12 years, 69% women, disease duration 11 ± 10 years), 40 (27%) had RA-ILD on chest HRCT. SPD, CCL18 and KL-6 concentrations were significantly higher in patients with RA-ILD. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72–0.86) compared to SPD (AUC: 0.66 95% CI 0.58–0.74) and CCL18 (AUC: 0.62, 95% CI 0.53–0.70). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. The combination of KL-6 with SPD and CCL18 improved its diagnostic ability, with increased sensitivity from 68% to 77%, specificity from 83% to 97%. Increased KL-6 levels were independently associated with the presence of RA-ILD after the adjustment on other RA-ILD risk factors. In the French subset with longitudinal data, baseline KL-6 serum levels were predictive of ILD progression and the degree of ILD progression on HRCT was proportional to baseline KL-6 concentrations.ConclusionThese results show that KL-6 is a relevant circulating marker for the diagnosis and might be an interesting marker for the progression of RA-ILD.

Highlights

Interstitial lung disease (ILD) is the most common pulmonary manifestation of rheumatoid arthritis (RA), occurring in *10% of patients
Diagnostic and prognostic value of KL6 in rheumatoid arthritis-associated interstitial lung disease. These results show that Krebs von den Lungen-6 glycoprotein (KL-6) is a relevant circulating marker for the diagnosis and might be an interesting marker for the progression of RA-ILD
Patients with RA-ILD (n = 40, age at onset: 56 ± 16 years) were more likely to be older than RA patient without ILD, with a higher proportion of males, smokers, and higher frequency of positive anti-citrullinated protein antibodies (ACPA)

Summary

Introduction

Interstitial lung disease (ILD) is the most common pulmonary manifestation of rheumatoid arthritis (RA), occurring in *10% of patients. It has emerged in recent series as a key prognostic factor including survival [1]. RA-ILD shares some genetic and phenotypic similarities with other fibrotic diseases including idiopathic pulmonary fibrosis, supporting the use of the same drugs in these conditions [2, 3]. Circulating biomarkers could aid in this risk-stratification, as recently reported in systemic sclerosis (SSc)-associated ILD [4,5,6]. Circulating lung epithelial-derived surfactant protein D (SPD), CCL-18 and Krebs von den Lungen-6 glycoprotein (KL-6) were identified as relevant diagnostic and prognostic markers of SSc-ILD. Our objective was to evaluate the merit of these 3 circulating markers for the diagnosis and the progression of RA-ILD

Methods

Results

Conclusion