An older age at the time of diagnosis and treatment with methotrexate were significantly associated with an increased risk of developing "acute exacerbation" of rheumatoid arthritis–associated interstitial lung disease in a retrospective cohort study of 51 patients.
The other risk factor associated with the development of acute exacerbation (AE) was a specific pattern on high-resolution CT scan, which was also associated with poorer survival, reported Dr. Hironao Hozumi, of Hamamatsu (Japan) University, and associates.
Overall, survival was also significantly lower among those who developed AE, according to the study. As far as the authors know, this is the first study to investigate the risk factors and prognosis associated with AE in patients who have been diagnosed with rheumatoid arthritis–associated interstitial lung disease (RA-ILD). Until this study, risk factors and prognosis for AEs in patients with RA-ILD have been unclear, they said.
AE is "a recently established and an increasingly recognized occurrence" in people with idiopathic pulmonary fibrosis, and it also affects people with other types of interstitial lung diseases, including those associated with collagen vascular disease, the authors noted. It was defined in the study as "acute deterioration in respiratory status, with newly developed bilateral ground-glass opacities and/or consolidations" visible on chest x-ray or CT scans.
The retrospective case-control study evaluated medical records and images of 51 patients consecutively diagnosed with RA-ILD at Hamamatsu University Hospital between 1995 and 2012. The median ages at the time of the RA and ILD diagnoses were 61 and 62 years, respectively. A majority (57%) of the patients were men. The patients had been followed for a median of 8.5 years (range, 1-17 years) before being diagnosed with AE (BMJ Open 2013;3:e003132).
During the observation period of 1-11 years, 11 of the 51 patients (22%) developed AE at a median age of 72 years (range, 60-86 years). In a univariate Cox hazard analysis, an older age at ILD diagnosis was associated with an 11% increased risk for AE occurrence.
Of the 11 patients who developed AE, 7 (64%) died of respiratory failure during the initial episode of AE, compared with 2 (5%) of the 40 patients who did not develop AE.
There was a usual interstitial pneumonia (UIP) pattern on high-resolution CT in 14 (27%) of the 51 patients. This pattern was found in 6 (55%) of the patients who had AE, compared with 8 (20%) of the 40 patients with no AE, a significant difference. This comparison gave a hazard ratio of 1.95 in a univariate Cox hazard analysis. For AE occurrence, a UIP pattern on high-resolution CT had a positive predictive value of 43% and a negative predictive value of 87%. The 1-year incidence of AE was 6.5% among those with a UIP pattern on high-resolution CT, compared with an overall rate of 2.8% in the study.
The overall 5-year survival was 90% for all the patients, but there was a significant difference among those with or without the UIP pattern (70% vs. 97%). Patients’ risk of death more than doubled with an AE occurrence (hazard ratio, 2.47).
The use of methotrexate was associated with a threefold increased risk of developing AE (HR, 3.04) in a univariate Cox hazard analysis. Of 10 patients treated with methotrexate, 6 (55%) in the AE group used the drug (including 5 who had been treated for at least 3 years and 1 treated for 1 year), compared with 4 (10%) in the non-AE group, a significant difference. Although methotrexate was discontinued, the respiratory condition of all six patients in the AE group continued to deteriorate and they had poor responses to corticosteroid therapy.
The authors found no associations with disease activity and the development of AE, so RA activity may not be related to the development of AE, the authors wrote. However, they noted that methotrexate "possibly accelerates the fibroproliferative process of RA-ILD."
There also were no significant differences in factors that included sex, age at the time of diagnosis of RA or RA-ILD, smoking habits, and other factors between those who did and did not develop an AE.
The investigators said that the limitations of the study included the retrospective design and the small sample size, and that "larger prospective studies investigating AEs in RA-ILD are indicated."
The authors had no disclosures to report. The study was partly funded by a grant from Japan’s Ministry of Health, Labor, and Welfare to the Diffuse Lung Diseases Research Group.