Rationale: Mycophenolate (MMF) and azathioprine (AZA) are two immunosuppressive medications commonly used in patients with fibrotic interstitial lung diseases (ILDs).We sought to determine the prescribing patterns and tolerability of MMF and AZA using a real-world cohort of patients with fibrotic ILD.Methods: Patients with connective tissue disease ILD (CTD-ILD), fibrotic hypersensitivity pneumonitis (HP), and unclassifiable ILD were identified from the 8-center prospective CAnadian REgistry for Pulmonary Fibrosis (CARE-PF).Medication data were obtained through a standardized chart review and included medication start date, dose, adverse effects and actions taken, and medication stop date.Adverse effects were comprehensively collected for the first 6 months after medication start with a grace period of an additional 3 months to maximize inclusion of available data.Results: There were 1217 patients who received MMF or AZA (mean age 59±13 years and 37% males), of whom 161 had HP, 844 CTD-ILD, and 212 unclassifiable ILD (Table 1).Mean FVC was 69±19% predicted and DLCO was 53±18% predicted.Median time from ILD diagnosis to initiation of MMF or AZA was 9 months (interquartile range [IQR] 1-30) for HP, 4 months (IQR 0-17) for CTD-ILD, and 7 months (IQR 1-24) for unclassifiable ILD.The prescribing patterns for the total cohort were as follows: 64% received MMF only, 16% received AZA only, 4% switched from MMF to AZA, and 16% switched from AZA to MMF.The median time to discontinuation was 55 days for MMF and 54 days (IQR 30-91) for AZA in those discontinuing medication.Among patients taking MMF, the most common adverse effects were gastrointestinal (18%) and constitutional symptoms (5%), which were also the most common reasons for medication discontinuation (60% and 14% of those who stopped MMF).Among patients taking AZA, the most common adverse effects were gastrointestinal (14%), transaminitis (11%), and hematologic (8%), which were also the most likely reasons for discontinuation (44%, 30%, and 20% of patients who stopped AZA).Conclusion: Patients with fibrotic ILD in this large prospective registry were more likely to be prescribed MMF compared to AZA.A similar percentage of patients discontinued either medication in the first 6 months.Gastrointestinal and constitutional symptoms were the most common reasons for discontinuing MMF, while gastrointestinal, transaminitis, and hematologic abnormalities were the most common reasons for AZA.These findings could be used to support management decisions in fibrotic ILD.
Lung imaging findings vary among subtypes of connective tissue disease-associated interstitial lung disease (CTD-ILD), leading to both diagnostic and therapeutic challenges.
Objectives
We performed a comprehensive assessment of ILD morphology across CTD-ILD subtypes by examining the presence of overall imaging patterns and specific morphological features.
Methods
High-resolution chest computed tomography (HRCT) of patients with CTD-ILD enrolled in the multicentre Canadian Registry for Pulmonary Fibrosis from their first ILD clinic visit were re-reviewed in standardized multidisciplinary discussion. All CTD diagnoses were rheumatologist-confirmed. An experienced chest radiologist blinded to clinical data quantified the percentage of lung parenchyma affected by honeycombing, reticulation, ground glass opacity (GGO), hypoattenuating lobules, consolidation, and emphysema. Gas trapping was evaluated on expiratory CT. Each case was categorized into an overall disease pattern including usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), fibrotic hypersensitivity pneumonitis (fHP), lymphocytic interstitial pneumonia (LIP), and unclassifiable.
Results
615 patients with CTD-ILD were assessed with 215 (33%) having systemic sclerosis (SSc), 127 (20%) rheumatoid arthritis (RA), 100 (16%) idiopathic inflammatory myopathy (IIM), 61 (9%) mixed connective tissue disease (MCTD), 40 (6%) Sjogren's syndrome (SS), 19 (3%) lupus (SLE), and 83 (13%) undifferentiated connective tissue disease (UCTD). NISP was most predominant in SSc (76%), IIM (62%), and MCTD (66%), while UIP was most common in RA (47%) and SS (33%). A fHP pattern was most common in RA (15%), SLE (21%), and MCTD (12%) (Figure 1a). There was substantial variability in the extent of fibrotic (honeycombing, reticulations) and non-fibrotic (pure GGO, consolidation) parenchymal features within and across each CTD (Figure 1b).
Conclusion
There is considerable variation in imaging features across subtypes of CTD-ILD, with NSIP generally most common, UIP most frequent in RA and SS, and fHP less frequent but most common in RA, SLE, and MCTD. This variability highlights the need for additional data on management of CTD-ILD that considers the potential for variable treatment responses across major CTD-ILD subtypes and phenotypes.
Progressive fibrosing interstitial lung disease (PF-ILD) is characterised by progressive physiological, symptomatic and/or radiographic worsening. The real-world prevalence and characteristics of PF-ILD remain uncertain.Patients were enrolled from the Canadian Registry for Pulmonary Fibrosis between 2015 and 2020. PF-ILD was defined as a relative forced vital capacity (FVC) decline ≥10%, death, lung transplantation or any two of: relative FVC decline ≥5% and <10%, worsening respiratory symptoms or worsening fibrosis on computed tomography of the chest, all within 24 months of diagnosis. Time-to-event analysis compared progression between key diagnostic subgroups. Characteristics associated with progression were determined by multivariable regression.Of 2746 patients with fibrotic ILD (mean±sd age 65±12 years; 51% female), 1376 (50%) met PF-ILD criteria in the first 24 months of follow-up. PF-ILD occurred in 427 (59%) patients with idiopathic pulmonary fibrosis (IPF), 125 (58%) with fibrotic hypersensitivity pneumonitis (HP), 281 (51%) with unclassifiable ILD (U-ILD) and 402 (45%) with connective tissue disease-associated ILD (CTD-ILD). Compared with IPF, time to progression was similar in patients with HP (hazard ratio (HR) 0.96, 95% CI 0.79-1.17), but was delayed in patients with U-ILD (HR 0.82, 95% CI 0.71-0.96) and CTD-ILD (HR 0.65, 95% CI 0.56-0.74). Background treatment varied across diagnostic subtypes, with 66% of IPF patients receiving antifibrotic therapy, while immunomodulatory therapy was utilised in 49%, 61% and 37% of patients with CHP, CTD-ILD and U-ILD, respectively. Increasing age, male sex, gastro-oesophageal reflux disease and lower baseline pulmonary function were independently associated with progression.Progression is common in patients with fibrotic ILD, and is similarly prevalent in HP and IPF. Routinely collected variables help identify patients at risk for progression and may guide therapeutic strategies.
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is challenging to manage, with a paucity of robust data to guide treatment. Our aim was to characterize the pharmacologic treatment of RA-ILD utilizing a retrospective design in a national multi-center prospective cohort, and to identify associations between treatment and change in lung function and survival.Patients with RA-ILD and a radiological pattern of non-specific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) were included. Unadjusted and adjusted linear mixed models and Cox proportional hazards models were used to compare lung function change and risk of death or lung transplant by radiologic patterns and treatment.Of 161 patients with RA-ILD, UIP pattern was more common than NSIP (55.9% vs. 44.1%). Only 44/161 (27%) patients were treated over median follow-up of 4 years with medication choice appearing unrelated to patient-specific variables. Decline in forced vital capacity (FVC) was not associated with treatment. Patients with NSIP had lower risk of death or transplant, compared to UIP (P=0.0042). In patients with NSIP, there was no difference in time to death or transplant comparing treated to untreated in adjusted models [hazard ratio (HR) =0.73; 95% confidence interval (CI): 0.15-3.62; P=0.70]. Similarly, in patients with UIP, there was no difference in time to death or lung transplant between treated and untreated in adjusted models (HR =1.06; 95% CI: 0.49-2.28; P=0.89).Treatment of RA-ILD is heterogeneous, with most patients in this cohort not receiving treatment. Patients with UIP had worse outcomes compared to NSIP, similar to other cohorts. Randomized clinical trials are needed to inform pharmacologic therapy in this patient population.
Rationale: Hypoxemia in fibrotic interstitial lung disease (ILD) indicates disease progression and is of prognostic significance. The onset of hypoxemia signifies disease progression and predicts mortality in fibrotic ILD. Accurately predicting new-onset exertional and resting hypoxemia prompts appropriate patient discussion and timely consideration of home oxygen. Objectives: We derived and externally validated a risk prediction tool for both new-onset exertional and new-onset resting hypoxemia. Methods: This study used ILD registries from Canada for the derivation cohort and from Australia and the United States for the validation cohort. New-onset exertional and resting hypoxemia were defined as nadir oxyhemoglobin saturation < 88% during 6-minute-walk tests, resting oxyhemoglobin saturation < 88%, or the initiation of ambulatory or continuous oxygen. Candidate predictors included patient demographics, ILD subtypes, and pulmonary function. Time-varying Cox regression was used to identify the top-performing prediction model according to Akaike information criterion and clinical usability. Model performance was assessed using Harrell's C-index and goodness-of-fit (GoF) likelihood ratio test. A categorized risk prediction tool was developed. Results: The best-performing prediction model for both new-onset exertional and new-onset resting hypoxemia included age, body mass index, a diagnosis of idiopathic pulmonary fibrosis, and percent predicted forced vital capacity and diffusing capacity of carbon monoxide. The risk prediction tool exhibited good performance for exertional hypoxemia (C-index, 0.70; GoF, P = 0.85) and resting hypoxemia (C-index, 0.77; GoF, P = 0.27) in the derivation cohort, with similar performance in the validation cohort except calibration for resting hypoxemia (GoF, P = 0.001). Conclusions: This clinically applicable risk prediction tool predicted new-onset exertional and resting hypoxemia at 6 months in the derivation cohort and a diverse validation cohort. Suboptimal GoF in the validation cohort likely reflected overestimation of hypoxemia risk and indicated that the model is not flawed because of underestimation of hypoxemia.
