Detection of Rheumatoid Arthritis–Interstitial Lung Disease Is Enhanced by Serum Biomarkers

Abstract

Rationale: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized.Objectives: To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD.Methods: Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. Measurements and Main Results:A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD.Conclusions: Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.Keywords: interstitial lung disease; rheumatoid arthritis; subclinical; biomarkers; risk prediction

Role of Autoantibodies in the Diagnosis of Connective-Tissue Disease ILD (CTD-ILD) and Interstitial Pneumonia with Autoimmune Features (IPAF)

“…RA-ILD occurs in 10%–30% of patients, and is the only complication of RA increasing in prevalence [33,82]. Prognosis is poor, with a mean survival from diagnosis of 3–8 years, accounting for approximately 6% of all RA deaths [82,83,84].…”

The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis

“…Preclinical pulmonary processes may also further subset patients with RA who later develop ILD which has known excess mortality in RA [97]. Identifying RA patients early in the development of ILD may similarly have major prevention or treatment implications and many of these processes likely are initiated in the preclinical RA phases [98]. …”

Variation in serum biomarkers with sex and female hormonal status: implications for clinical tests

“…They have been investigated for autoimmune disease and arthritis12, cancer345, cardiovascular disease6, mental and neurological disorders789101112, kidney function13, and other applications. Despite the increasing number of published serum biomarker studies (Supplementary Fig.…”