Pulmonary function trajectories in rheumatoid arthritis-associated interstitial lung disease

OBJECTIVE: Interstitial lung disease (ILD) is a serious complication of rheumatoid arthritis (RA). The aim of this study was to compare pulmonary function trajectories in RA-ILD, focusing on the impact of oral corticosteroid therapy and radiographic pattern.METHOD: We used a multiple regression model with line artime trend and individual random coefficients for intercept and slope to assess forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO), allowing the description of individual linear patterns and systematic differences at a group level.RESULTS: We included 101 patients with RA-ILD retrospectively. Mean FVC and DLCO were lower in patients who received corticosteroid therapy for ILD than in untreated patients (79% vs 95% predicted, and 48% vs 58% predicted). The change in FVC per 30 days was -0.10 [95% confidence interval (95% CI) -0.18; -0.04] in the treated and -0.13 (95% 20 CI -0.19; -0.07) in the untreated group. The between-group difference was not significant (-0.03, 95% CI -0.12; 0.06, p = 0.571). For DLCO, the change per 30 days was -0.10 (95% CI -0.15; -0.04) in the treated and -0.10 (95% CI -0.14; -0.05) in the untreated group, with no significant between-group difference (0.0007, 95% CI -0.07; 0.07, p = 0.985). Inclusion of radiographic pattern did not change the results.CONCLUSION: The rate of pulmonary function decline was similar for corticosteroid-treated and untreated patients, although treated patients had significantly lower pulmonary function. This may indicate a limited disease-modifying effect in RA-ILD, but further studies are needed.</p

Clinical Course of Interstitial Lung Disease in Patients With Rheumatoid Arthritis

Interstitial lung disease (ILD) is a frequent manifestation of rheumatoid arthritis (RA) that is associated with high mortality. RA-ILD may initially be asymptomatic, and lung function may be markedly impaired by the time it is diagnosed. The course of RA-ILD is highly variable, with some patients experiencing no discernable progression or a slow decline, whereas others experience more rapid deterioration. Some patients develop progressive pulmonary fibrosis, which is associated with high mortality. Although risk factors for the progression of RA-ILD have been identified, including older age, worse lung function, and a usual interstitial pneumonia pattern on high-resolution computed tomography, it is not possible to predict the course of RA-ILD in an individual patient. The association between RA disease activity and progression of RA-ILD remains unclear. Regular monitoring is important to enable the prompt identification of progression and early intervention to preserve lung function. The management of RA-ILD requires a multidisciplinary and individualized approach, taking account of the severity and progression of articular and lung disease, risk factors for the progression of RA-ILD, and the patient's preferences, and may include immunosuppression, antifibrotic therapy, and supportive care

The diagnostic trajectories of Danish patients with autoimmune rheumatologic disease associated interstitial lung disease:an interview-based study

BACKGROUND: Autoimmune rheumatologic disease associated interstitial lung diseases (ARD-ILD) are rare conditions and the association between ARDs and respiratory symptoms often goes unrecognised by ARD patients and general practitioners (GPs). The diagnostic trajectory from the first respiratory symptoms to an ARD-ILD diagnosis is often delayed and may increase the burden of symptoms and allow further disease progression.The aim of this study was to 1) characterise the diagnostic trajectories of ARD-ILD patients and to 2) identify barriers for obtaining a timely ILD diagnosis based on the experiences and perceptions of both patients and healthcare professionals.METHOD: Semi-structured qualitative interviews were conducted with Danish ARD-ILD patients, rheumatologists, pulmonologists and ILD nurses.RESULTS: Sixteen patients, six rheumatologists, three ILD nurses and three pulmonologists participated. Five characteristics of diagnostic trajectories were identified in the patient interviews: 1) early referral to lung specialists; 2) early delay; 3) delay or shortcut depending on specific circumstances; 4) parallel diagnostic trajectories connected late in the process; 5) early identification of lung involvement without proper interpretation. With the exception of early referral to lung specialists, all of the diagnostic trajectory characteristics identified led to delayed diagnosis. Delayed diagnostic trajectories resulted in patients experiencing increased uncertainty. Inconsistent disease terminology, insufficient knowledge and lack of awareness of ARD-ILD among central healthcare professionals and delayed referral to ILD specialists were main contributors to the diagnostic delay identified by the informants.CONCLUSION: Five characteristics of the diagnostic trajectories were identified, four of which led to diagnostic delay of ARD-ILD. Improved diagnostic trajectories can shorten the diagnostic trajectory and increase early access to appropriate specialist medical care. Improved awareness and expertise in ARD-ILD across different medical specialties, especially among GPs, may contribute to more efficient and timely diagnostic trajectories and improved patient experiences.</p

Treatment of acute exacerbation in interstitial lung disease secondary to autoimmune rheumatic diseases: More questions than answers

Interstitial lung disease (ILD) is a relevant cause of morbidity and mortality in patients with autoimmune rheumatic diseases (ARDs). In the last years, an acute exacerbation (AE) – defined as an acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality - has been reported to occur in virtually all ILD types, including ARD-ILD. The aim of this review is to describe the available and investigational treatments in patients affected by AE-ARD-ILD in light of the very low quality of evidence available. Currently, management consists of efforts to identify reversible triggers of respiratory decline, such as drugs effective in ARDs and infections, including opportunistic infections, together with supportive treatments. AE-ILD, AE-ARD-ILD and acute respiratory distress syndrome share histopathologically similar findings of diffuse alveolar damage in most cases. Identification of triggers and risk factors might contribute to early diagnosis and treatment of AE-ILD, before the alveolar damage becomes irreversible. In patients with acute respiratory distress syndrome, the role of steroids and immunosuppressants remains controversial. Also, many uncertainties characterize the management of AE-ARD-ILD because of the lack of evidence and of an unquestionable effective therapy. At this time, no effective evidence-based therapeutic strategies for AE–ARD–ILD are available. In clinical practice, AE–ARD–ILD is often empirically treated with high-dose systemic steroids and antibiotics, with or without immunosuppressive drugs. Randomized controlled trials are needed to better understand the efficacy of current and future drugs for the treatment of this clinical relevant condition

Weight loss and outcomes in subjects with progressive pulmonary fibrosis: data from the INBUILD trial

BACKGROUND: Lower body mass index (BMI) and weight loss have been associated with worse outcomes in some studies in patients with pulmonary fibrosis. We analyzed outcomes in subgroups by BMI at baseline and associations between weight change and outcomes in subjects with progressive pulmonary fibrosis (PPF) in the INBUILD trial. METHODS: Subjects with PPF other than idiopathic pulmonary fibrosis were randomized to receive nintedanib or placebo. In subgroups by BMI at baseline (< 25, ≥ 25 to < 30, ≥ 30 kg/m2), we analyzed the rate of decline in FVC (mL/year) over 52 weeks and time-to-event endpoints indicating disease progression over the whole trial. We used a joint modelling approach to assess associations between change in weight and the time-to-event endpoints. RESULTS: Among 662 subjects, 28.4%, 36.6% and 35.0% had BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively. The rate of decline in FVC over 52 weeks was numerically greater in subjects with baseline BMI < 25 than ≥ 25 to < 30 or ≥ 30 kg/m2 (nintedanib: - 123.4, - 83.3, - 46.9 mL/year, respectively; placebo: - 229.5; - 176.9; - 171.2 mL/year, respectively). No heterogeneity was detected in the effect of nintedanib on reducing the rate of FVC decline among these subgroups (interaction p = 0.83). In the placebo group, in subjects with baseline BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively, 24.5%, 21.4% and 14.0% of subjects had an acute exacerbation or died, and 60.2%, 54.5% and 50.4% of subjects had ILD progression (absolute decline in FVC % predicted ≥ 10%) or died over the whole trial. The proportions of subjects with these events were similar or lower in subjects who received nintedanib versus placebo across the subgroups. Based on a joint modelling approach, over the whole trial, a 4 kg weight decrease corresponded to a 1.38-fold (95% CI 1.13, 1.68) increase in the risk of acute exacerbation or death. No association was detected between weight loss and the risk of ILD progression or the risk of ILD progression or death. CONCLUSIONS: In patients with PPF, lower BMI at baseline and weight loss may be associated with worse outcomes and measures to prevent weight loss may be required. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02999178

Acute exacerbations in patients with progressive pulmonary fibrosis

Background: Acute exacerbations of fibrosing interstitial lung diseases (ILDs) are associated with high mortality. We used prospective data from the INBUILD trial to investigate risk factors for acute exacerbations and the impact of these events in patients with progressive pulmonary fibrosis. Methods: Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF) were randomised to receive nintedanib or placebo. Associations between baseline characteristics and time to first acute exacerbation were assessed using pooled data from both treatment groups using Cox proportional hazard models, firstly univariable models and then a multivariable model using forward stepwise selection. The risk of death was estimated based on the Kaplan-Meier method. Results: Over a median follow-up of approximately 19 months, acute exacerbations were reported in 58 (8.7%) of 663 patients. In the risk factor analysis, the final model included diffusing capacity of the lung for carbon monoxide (D LCO) % predicted, treatment and age. Lower D LCO % predicted was associated with an increased risk of acute exacerbation with a hazard ratio (HR) of 1.56 (95% CI 1.21-2.02) per 10 units lower (p&lt;0.001). Age ≥65 years was associated with a numerically increased risk (HR 1.55, 95% CI 0.87-2.77; p=0.14). Treatment with nintedanib conferred a numerically reduced risk versus placebo (HR 0.60, 95% CI 0.35-1.02; p=0.06). The estimated risks of death ≤30 days and ≤90 days after an acute exacerbation were 19.0% (95% CI 8.9-29.2) and 32.0% (95% CI 19.7-44.2). Conclusions: Acute exacerbations of progressive pulmonary fibrosis may have similar risk factors and prognostic impact as acute exacerbations of IPF

Patient-reported outcomes and patient-reported outcome measures in interstitial lung disease: Where to go from here?

Patient-reported outcome measures (PROMs), tools to assess patient self-report of health status, are now increasingly used in research, care and policymaking. While there are two well-developed disease-specific PROMs for interstitial lung diseases (ILD) and idiopathic pulmonary fibrosis (IPF), many unmet and urgent needs remain. In December 2019, 64 international ILD experts convened in Erice, Italy to deliberate on many topics, including PROMs in ILD. This review summarises the history of PROMs in ILD, shortcomings of the existing tools, challenges of development, validation and implementation of their use in clinical trials, and the discussion held during the meeting. Development of disease-specific PROMs for ILD including IPF with robust methodology and validation in concordance with guidance from regulatory authorities have increased user confidence in PROMs. Minimal clinically important difference for bidirectional changes may need to be developed. Cross-cultural validation and linguistic adaptations are necessary in addition to robust psychometric properties for effective PROM use in multinational clinical trials. PROM burden of use should be reduced through appropriate use of digital technologies and computerised adaptive testing. Active patient engagement in all stages from development, testing, choosing and implementation of PROMs can help improve probability of success and further growth

The asbestos-asbestosis exposure-response relationship: a cohort study of the general working population

OBJECTIVES: The association between asbestos exposure and asbestosis in high-exposed industrial cohorts is well-known, but there is a lack of knowledge about the exposure-response relationship for asbestosis in a general working population setting. We examined the exposure-response relationship between occupational asbestos exposure and asbestosis in asbestos-exposed workers of the Danish general working population.METHODS: We followed all asbestos-exposed workers from 1979 to 2015 and identified incident cases of asbestosis using the Danish National Patient Register. Individual asbestos exposure was estimated with a quantitative job exposure matrix (SYN-JEM) from 1976 onwards and back-extrapolated to age 16 for those exposed in 1976. Exposure-response relations for cumulative exposure and other exposure metrics were analyzed using a discrete time hazard model and adjusted for potential confounders.RESULTS: The range of cumulative exposure in the population was 0.001 to 18 fibers per milliliter-year (f/ml-year). We found increasing incidence rate ratios (IRR) of asbestosis with increasing cumulative asbestos exposure with a fully adjusted IRR per 1 f/ml-years of 1.18 [95% confidence interval (CI) 1.15- -1.22]. The IRR was 1.94 (95% CI 1.53-2.47) in the highest compared to the lowest exposure tertile. We similarly observed increasing risk with increasing cumulative exposure in the inception population.CONCLUSIONS: This study found exposure-response relations between cumulative asbestos exposure and incident asbestosis in the Danish general working population with mainly low-level exposed occupations, but there is some uncertainty regarding the exposure levels.</p

The DIAMORFOSIS (DIAgnosis and Management Of lung canceR and FibrOSIS) survey: international survey and call for consensus.

Background Currently there is major lack of agreement on the diagnostic and therapeutic management of patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. Our aim was to identify variations in diagnostic and management strategies across different institutions and provide rationale for a consensus statement on this issue. Methods This was a joint-survey by European Respiratory Society (ERS) Assemblies 8, 11 and 12. The survey consisted of 25 questions. Results Four hundred and ninety-four (n=494) physicians from 68 different countries and five continents responded to the survey. Ninety-four per cent of participants were pulmonologists, 1.8% thoracic surgeons and 1.9% oncologists; 97.7% were involved in multidisciplinary team approaches on diagnosis and management. Regular low-dose high-resolution computed tomography (HRCT) scan was used by 49.5% of the respondents to screen for lung cancer in IPF. Positron emission tomography (PET) scan and endobronchial ultrasound (EBUS) is performed by 60% and 88% to diagnose nodular lesions with mediastinal lymphadenopathy in patients with advanced and mild IPF, respectively. Eighty-three per cent of respondents continue anti-fibrotics following lung cancer diagnosis; safety precautions during surgical interventions including low tidal volume are applied by 67%. Stereotactic radiotherapy is used to treat patients with advanced IPF (diffusing capacity of the lung for carbon monoxide (DLCO) &lt;35%) and otherwise operable nonsmall cell lung cancer (NSCLC) by 54% of respondents and doublet platinum regimens and immunotherapy for metastatic disease by 25% and 31.9%, respectively. Almost all participants (93%) replied that a consensus statement for the management of these patients is highly warranted. Conclusion The diagnosis and management of IPF-lung cancer (LC) is heterogeneous with most respondents calling for a consensus statement

Idiopathic pulmonary fibrosis: Best practice in monitoring and managing a relentless fibrotic disease

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease that is, by definition, progressive. Progression of IPF is reflected by a decline in lung function, worsening of dyspnea and exercise capacity, and deterioration in health-related quality of life. In the short term, the course of disease for an individual patient is impossible to predict. A period of relative stability in forced vital capacity (FVC) does not mean that FVC will remain stable in the near future. Frequent monitoring using multiple assessments, not limited to pulmonary function tests, is important to evaluate disease progression in individual patients and ensure that patients are offered appropriate care. Optimal management of IPF requires a multidimensional approach, including both pharmacological therapy to slow decline in lung function and supportive care to preserve patients' quality of life