Predicting outcomes in rheumatoid arthritis related interstitial lung disease

Abstract

The aim of this study was to compare radiology-based prediction models in rheumatoid arthritis-related interstitial lung disease (RAILD) to identify patients with a progressive fibrosis phenotype.RAILD patients had computed tomography (CT) scans scored visually and using CALIPER and forced vital capacity (FVC) measurements. Outcomes were evaluated using three techniques, as follows. 1) Scleroderma system evaluating visual interstitial lung disease extent and FVC values; 2) Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines applied to RAILD; and 3) CALIPER scores of vessel-related structures (VRS). Outcomes were compared to IPF patients.On univariable Cox analysis, all three staging systems strongly predicted outcome (scleroderma system hazard ratio (HR) 3.78, p=9×10^-5; Fleischner system HR 1.98, p=2×10^-3; and 4.4% VRS threshold HR 3.10, p=4×10^-4). When the scleroderma and Fleischner systems were combined, termed the progressive fibrotic system (C-statistic 0.71), they identified a patient subset (n=36) with a progressive fibrotic phenotype and similar 4-year survival to IPF. On multivariable analysis, with adjustment for patient age, sex and smoking status, when analysed alongside the progressive fibrotic system, the VRS threshold of 4.4% independently predicted outcome (model C-statistic 0.77).The combination of two visual CT-based staging systems identified 23% of an RAILD cohort with an IPF-like progressive fibrotic phenotype. The addition of a computer-derived VRS threshold further improved outcome prediction and model fit, beyond that encompassed by RAILD measures of disease severity and extent.

FIGURE 1

Computed tomography (CT) images demonstrating the five groups of the modified Fleischner staging system. a) In a 55-year-old male ex-smoker, honeycombing is visible in a peripheral, basal subpleural distribution typical of a classical usual interstitial pneumonia (UIP) pattern on the axial CT image (group 1); b) a 58-year-old male ex-smoker has honeycomb cysts lying anteriorly above the horizontal fissure on a sagittal CT image with no basal subpleural honeycomb cysts in the lower lobe periphery (group 2); c) in a 57-year-old male never-smoker subtle traction bronchiectasis is visible in the peripheral basal subpleural region of the lower lobes on the axial CT image (group 3); d) a 61-year-old male ex-smoker demonstrates right mid-zone predominant traction bronchiectasis with sparing of the lung bases (group 4) on a coronal CT image; e) a 70-year-old female ex-smoker has evidence of pulmonary fibrosis in a bronchocentric distribution in the left lower lobe, with perilobular arcades of consolidation reminiscent of a fibrosing organising pneumonia pattern in the right lower lobe on the axial CT image; the bronchocentricity to the fibrosis and the organising pneumonia pattern made the CT inconsistent for a UIP pattern (group 5).

FIGURE 2

Axial computed tomography (CT) image colour maps demonstrating CALIPER-derived vessel-related structures (VRS; red). VRS represent pulmonary arteries and veins (excluding hilar vessels) and connected tubular structures, the latter primarily reflecting adjoining regions of fibrosis. a–c) axial sections in a 71-year-old female 30-pack-year ex-smoker with upper lobe emphysema and fibrosis visible in the lower lobes (VRS 2.1%); d–f) axial sections in a 62-year-old female never-smoker with upper lobe-predominant fibrosis (VRS 7.0%). Nonvascular region captures in the VRS signal are visible in the upper lobes (d) and adjacent to the right hemidiaphragm (f).

FIGURE 3

a) Kaplan–Meier curves demonstrating mortality for patients with rheumatoid arthritis-related interstitial lung disease (RAILD) subdivided according to the pattern of fibrosis on computed tomography (CT), based on the Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines. Group 1 (honeycombing occurring in an IPF-like distribution): 53% 3-year and 6-year survival, n=38; group 2 (honeycombing occurring in a non IPF-like distribution): 40% 3-year and 35% 6-year survival, n=17; group 3 (fibrosis without honeycombing, occurring in an IPF-like distribution): 75% 3-year and 69% 6-year survival, n=33; group 4 (fibrosis without honeycombing, occurring in a non IPF-like distribution): 85% 3-year and 68% 6-year survival, n=23; group 5 (patients with CT features inconsistent with a universal interstitial pneumonia (UIP) diagnosis; distribution of disease and mosaic attenuation were not considered to be inconsistent features for the purposes of this RAILD study): 92% 3-year and 75% 6-year survival, n=46. b) Combined patients from groups 1 and 2 in figure 1a: 48% 3-year and 45% 6-year survival, n=55 and patients in groups 3 and 4 in figure 1a: 76% 3-year and 58% 6-year survival, n=56 while the group of patients with inconsistent CT features in figure 1a remained unchanged. All three groups were compared to a population of IPF patients: 42% 3-year and 18% 6-year survival, n=284. c) Kaplan–Meier curves demonstrating mortality for patients with RAILD subdivided according to the scleroderma system into good-outcome and bad-outcome groups, and compared with an IPF cohort. Patients with >25% interstitial lung disease (ILD) extent on CT were given a score of 1 (bad outcome), while patients with <15% ILD extent on CT were given a score of 0 (good outcome); patients with 15–25% ILD extent on CT were adjudicated on the basis of forced vital capacity (FVC), with an FVC >70% predicted accorded a score of 0, and FVC <70% pred was accorded a score of 1. Good-outcome scleroderma system 88% 3-year and 70% 6-year survival, n=88; bad-outcome scleroderma system 50% 3-year and 40% 6-year survival, n=68. IPF patients: 42% 3-year and 18% 6-year survival, n=284. d) Kaplan–Meier curves demonstrating mortality for patients with RAILD categorised using the scleroderma system and a definite usual interstitial pneumonia (UIP) pattern on CT (disease distribution and mosaicism were not considered as being inconsistent features of a definite UIP pattern). Patients with a definite UIP pattern on CT had a score of 1 added to their scleroderma system score. Scleroderma system bad outcome with a definite UIP pattern: 35% 3-year and 35% 6-year survival, n=36; either scleroderma system bad outcome or definite UIP pattern: 78% 3-year and 58% 6-year survival, n=50; scleroderma system good outcome without definite UIP: 90% 3-year and 78% 6-year survival, n=70. IPF patients: 42% 3-year and 18% 6-year survival, n=284. e) Kaplan–Meier curves demonstrating mortality for patients with RAILD categorised using a CALIPER vessel-related structure (VRS) score of 4.4%. VRS score >4.4%: 45% 3-year and 40% 6-year survival, n=51; VRS score <4.4% 82% 3-year and 70% 6-year survival, n=106. IPF patients: 42% 3-year and 18% 6-year survival, n=284.