Serum C-reactive protein is associated with earlier mortality across different interstitial lung diseases

Background and Objective: The acute-phase protein C-reactive protein (CRP) is known to be associated with poor outcomes in cancer and cardiovascular disease, but there is limited evidence of its prognostic implications in interstitial lung diseases (ILDs). We therefore set out to test whether baseline serum CRP levels are associated with mortality in four different ILDs. Methods: In this retrospective study, clinically measured CRP levels, as well as baseline demographics and lung function measures, were collected for ILD patients first presenting to the Royal Brompton Hospital between January 2010 and December 2019. Cox regression analysis was used to determine the relationship with 5-year mortality. Results: Patients included in the study were: idiopathic pulmonary fibrosis (IPF) n = 422, fibrotic hypersensitivity pneumonitis (fHP) n = 233, rheumatoid arthritis associated ILD (RA-ILD) n = 111 and Systemic Sclerosis associated ILD (SSc-ILD) n = 86. Patients with a recent history of infection were excluded. Higher CRP levels were associated with shorter 5-year survival in all four disease groups on both univariable analyses, and after adjusting for age, gender, smoking history, immunosuppressive therapy and baseline disease severity (IPF: HR (95% CI): 1.3 (1.1–1.5), p = 0.003, fHP: 1.5 (1.2–1.9), p = 0.001, RA-ILD: 1.4 (1.1–1.84), p = 0.01 and SSc-ILD: 2.7 (1.6–4.5), p < 0.001). Conclusion: Higher CRP levels are independently associated with reduced 5-year survival in IPF, fHP, RA-ILD and SSc-ILD

Prevalence and effects of emphysema in never-smokers with rheumatoid arthritis interstitial lung disease

AIMS: Autoimmune conditions such as rheumatoid arthritis-related interstitial lung disease (RA-ILD) have been linked to the existence of emphysema in never-smokers. We aimed to quantify emphysema prevalence in RA-ILD never-smokers and investigate whether combined pulmonary fibrosis and emphysema (CPFE) results in a worsened prognosis independent of baseline disease extent. METHODS: RA-ILD patients presenting to the Royal Brompton Hospital (n=90) and Asan Medical Center (n=155) had CT's evaluated for a definite usual interstitial pneumonia (UIP) pattern, and visual extents of emphysema and ILD. RESULTS: Emphysema, identified in 31/116 (27%) RA-ILD never-smokers, was associated with obstructive functional indices and conformed to a CPFE phenotype: disproportionate reduction in gas transfer (DLco), relative preservation of lung volumes. Using multivariate logistic regression, adjusted for patient age, gender and ILD extent, emphysema presence independently associated with a CT-UIP pattern in never-smokers (0.009) and smokers (0.02). On multivariate Cox analysis, following adjustment for patient age, gender, DLco, and a CT-UIP pattern, emphysema presence (representing the CPFE phenotype) independently associated with mortality in never-smokers (p=0.04) and smokers (p<0.05). CONCLUSION: 27% of RA-ILD never-smokers demonstrate emphysema on CT. Emphysema presence in never-smokers independently associates with a definite CT-UIP pattern and a worsened outcome following adjustment for baseline disease severity

Mortality prediction in idiopathic pulmonary fibrosis: evaluation of computer-based CT analysis with conventional severity measures

Computer-based computed tomography (CT) analysis can provide objective quantitation of disease in idiopathic pulmonary fibrosis (IPF). A computer algorithm, CALIPER, was compared with conventional CT and pulmonary function measures of disease severity for mortality prediction.CT and pulmonary function variables (forced expiratory volume in 1 s, forced vital capacity, diffusion capacity of the lung for carbon monoxide, transfer coefficient of the lung for carbon monoxide and composite physiologic index (CPI)) of 283 consecutive patients with a multidisciplinary diagnosis of IPF were evaluated against mortality. Visual and CALIPER CT features included total extent of interstitial lung disease, honeycombing, reticular pattern, ground glass opacities and emphysema. In addition, CALIPER scored pulmonary vessel volume (PVV) while traction bronchiectasis and consolidation were only scored visually. A combination of mortality predictors was compared with the Gender, Age, Physiology model.On univariate analyses, all visual and CALIPER-derived interstitial features and functional indices were predictive of mortality to a 0.01 level of significance. On multivariate analysis, visual CT parameters were discarded. Independent predictors of mortality were CPI (hazard ratio (95% CI) 1.05 (1.02-1.07), p<0.001) and two CALIPER parameters: PVV (1.23 (1.08-1.40), p=0.001) and honeycombing (1.18 (1.06-1.32), p=0.002). A three-group staging system derived from this model was powerfully predictive of mortality (2.23 (1.85-2.69), p<0.0001).CALIPER-derived parameters, in particular PVV, are more accurate prognostically than traditional visual CT scores. Quantitative tools such as CALIPER have the potential to improve staging systems in IPF

Evaluation of computer-based computer tomography stratification against outcome models in connective tissue disease-related interstitial lung disease: a patient outcome study

Table S1. Lobar visual scores were adjusted using scintigraphic and gas dilution measures of the physiological contribution of each lobe to the total lung volume in health (top row). The figure was divided by the proportion of each lung representing a lobe (16.7%), or in the case of the left upper lobe, which included the lingula, two lobes (33.3%). Table S2. Single determination standard deviation values of visual CT scores for connective tissue disease-related interstitial lung disease cases. Table S3. Patient age, gender, smoking status and measures of pulmonary function indices, CALIPER and visually scored CT parameters and echocardiography data for the four groups of the ILD-GAP index. Data represent mean values with standard deviations. CTD, connective tissue disease; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; DLco, diffusing capacity for carbon monoxide; Kco, carbon monoxide transfer coefficient; TLC, total lung capacity; CPI, composite physiologic index; ILD, interstitial lung disease; GGO, ground glass opacity; PVV, pulmonary vessel volume; TxBx, traction bronchiectasis; PA, pulmonary artery; AAo, ascending aorta; RVSP, right ventricular systolic pressure. Table S4. P values demonstrating differences between automated stratified groups calculated using one-way ANOVA with Bonferroni correction for continuous variables and t-test with Bonferroni correction for categorical variables. ILD, interstitial lung disease; PA, pulmonary artery; Ao, ascending aorta; HC, honeycombing; DLco, diffusing capacity for carbon monoxide; Kco, carbon monoxide transfer coefficient; CPI, composite physiologic index; RVSP, right ventricular systolic pressure. * not significant. Figure S1. CONSORT diagram illustrating the selection of patients for the final study population. ILD, interstitial lung disease; CTD, connective tissue disease; IPAF, interstitial pneumonia with autoimmune features; LCH, Langerhans cell histiocytosis; LAM, lymphangioleiomyomatosis; CT, computed tomography. (DOCX 67 kb

Evaluation of visual and computer-based CT analysis for the identification of functional patterns of obstruction and restriction in hypersensitivity pneumonitis

BACKGROUND AND OBJECTIVE: To determine whether computer-based quantification (CALIPER software) is superior to visual computed tomography (CT) scoring in the identification of CT patterns indicative of restrictive and obstructive functional indices in hypersensitivity pneumonitis (HP). METHODS: A total of 135 consecutive HP patients had CT parenchymal patterns evaluated quantitatively by both visual scoring and CALIPER. Results were evaluated against: forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity for carbon monoxide (DLCO ) and a composite physiological index (CPI) to identify which CT scoring method better correlated with functional indices. RESULTS: CALIPER-derived scores of total interstitial lung disease extent correlated more strongly than visual scores: FVC (CALIPER R = 0.73, visual R = 0.51); DLCO (CALIPER R = 0.61, visual R = 0.48); and CPI (CALIPER R = 0·70, visual R = 0·55). The CT variable that correlated most strongly with restrictive functional indices was CALIPER pulmonary vessel volume (PVV): FVC R = 0.75, DLCO R = 0.68 and CPI R = 0.76. Ground-glass opacity quantified by CALIPER alone demonstrated strong associations with restrictive functional indices: CALIPER FVC R = 0.65; DLCO R = 0.59; CPI R = 0.64; and visual = not significant. Decreased attenuation lung quantified by CALIPER was a better morphological measure of obstructive lung disease than equivalent visual scores as judged by relationships with TLC (CALIPER R = 0.63 and visual R = 0.12). All results were maintained on multivariate analysis. CONCLUSION: CALIPER improved on visual scoring in HP as judged by restrictive and obstructive functional correlations. Decreased attenuation regions of the lung quantified by CALIPER demonstrated better linkages to obstructive lung physiology than visually quantified CT scores. A novel CALIPER variable, the PVV, demonstrated the strongest linkages with restrictive functional indices and could represent a new automated index of disease severity in HP

Serial automated quantitative CT analysis in idiopathic pulmonary fibrosis: functional correlations and comparison with changes in visual CT scores

OBJECTIVES: To determine whether computer-based CT quantitation of change can improve on visual change quantification of parenchymal features in IPF. METHODS: Sixty-six IPF patients with serial CT imaging (6-24 months apart) had CT features scored visually and with a computer software tool: ground glass opacity, reticulation and honeycombing (all three variables summed as interstitial lung disease extent [ILD]) and emphysema. Pulmonary vessel volume (PVV) was estimated by computer only. Relationships between changes in CT features and forced vital capacity (FVC) were examined using univariate and multivariate linear regression analyses. RESULTS: On univariate analysis, changes in computer variables demonstrated stronger linkages to FVC change than changes in visual scores (CALIPER ILD:R2=0.53, p<0.0001; Visual ILD:R2=0.16, p=0.001). PVV increase correlated most strongly with relative FVC change (R2=0.57). When PVV constituents (vessel size and location) were examined, an increase in middle zone vessels linked most strongly to FVC decline (R2=0.57) and was independent of baseline disease severity (characterised by CT fibrosis extent, FVC, or DLco). CONCLUSIONS: An increase in PVV, specifically an increase in middle zone lung vessels, was the strongest CT determinant of FVC decline in IPF and was independent of baseline disease severity. KEY POINTS: • Computer analysis improves on visual CT scoring in evaluating deterioration on CT • Increasing pulmonary vessel volume is the strongest CT predictor of functional deterioration • Increasing pulmonary vessel volume predicts functional decline independent of baseline disease severity

Serial CT analysis in idiopathic pulmonary fibrosis: comparison of visual features that determine patient outcome

Aims: Patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotic medication and patients with non-IPF fibrosing lung disease often demonstrate rates of annualised forced vital capacity (FVC) decline within the range of measurement variation (5.0%–9.9%). We examined whether change in visual CT variables could help confirm whether marginal FVC declines represented genuine clinical deterioration rather than measurement noise. Methods: In two IPF cohorts (cohort 1: n=103, cohort 2: n=108), separate pairs of radiologists scored paired volumetric CTs (acquired between 6 and 24 months from baseline). Change in interstitial lung disease, honeycombing, reticulation, ground-glass opacity extents and traction bronchiectasis severity was evaluated using a 5-point scale, with mortality prediction analysed using univariable and multivariable Cox regression analyses. Both IPF populations were then combined to determine whether change in CT variables could predict mortality in patients with marginal FVC declines. Results: On univariate analysis, change in all CT variables except ground-glass opacity predicted mortality in both cohorts. On multivariate analysis adjusted for patient age, gender, antifibrotic use and baseline disease severity (diffusing capacity for carbon monoxide), change in traction bronchiectasis severity predicted mortality independent of FVC decline. Change in traction bronchiectasis severity demonstrated good interobserver agreement among both scorer pairs. Across all study patients with marginal FVC declines, change in traction bronchiectasis severity independently predicted mortality and identified more patients with deterioration than change in honeycombing extent. Conclusions: Change in traction bronchiectasis severity is a measure of disease progression that could be used to help resolve the clinical importance of marginal FVC declines

Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial

BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group. INTERPRETATION: Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy. FUNDING: Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK)

Defining genetic risk factors for scleroderma-associated interstitial lung disease

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10–1.54), p^{corr} = 0.015) and rs10488631 (OR 1.48 (1.14–1.92), p^{corr} = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18–1.73), p^{corr} = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24–2.39), p^{corr} = 0.0098), and rs2004640 (OR 1.39 (1.11–1.75), p^{corr} = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45–2.38), p^{corr} = 6.6 × 10^{-6}). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51–0.85), p^{corr} = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD