Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871. FINDINGS: From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths. INTERPRETATION: Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials. FUNDING: Genentech.

Critically examining the experience of end of life care for people with interstitial lung disease: views of patients, families and healthcare professionals

IntroductionPeople with interstitial lung disease have a high symptom burden at the end of life and the majority die in hospital.AimsTo explore patients’ and their relatives’ experiences of end of life care in interstitial lung disease. To explore potential barriers preventing access to palliative care services and develop a theoretical framework that captures the experience of dying with interstitial lung disease.MethodsFifteen semi-structured interviews have been conducted to date with patients with interstitial lung disease, bereaved carers and healthcare professionals. Interviews are transcribed verbatim and data analysis is undertaken concurrently with data generation using Grounded Theory.ResultsData generation and analysis is ongoing but will be completed by March 2021. Candidate themes identified from the data are 1) Hidden illness, 2) Preparing for dying, 3) The important bit – final days and hours, 5) Lasting memories. These themes are likely to develop further with additional data from subsequent interviews. There is often a dichotomy between what information is wanted by relatives towards the end of life and what people with interstitial lung disease are happy to discuss. Recognition of dying is important to allow the opportunity for advance care planning for people who wish to have these discussions. Symptom control and family presence at the end of life has an impact of bereaved relatives’ lasting memories. The covid-19 pandemic has heavily influenced these factors and highlighted deficiencies in the existing services.ConclusionsThe uncertain prognosis faced by many people with interstitial lung disease leads to avoidance of advance care planning by both patients, relatives and healthcare professionals. This ongoing research project will add to the emerging body of evidence of the importance of timely end of life care in this patient group, which has many similarities to covid-19, namely respiratory symptoms, and the propensity to deteriorate suddenly.

Critically examining the experience of end of life care for people with interstitial lung disease: views of patients, families and healthcare professionals

IntroductionPeople with interstitial lung disease (ILD) have a high symptom burden at the end of life and the majority die in hospital.AimsTo explore patients’ and their relatives’ experiences of end of life care in ILD. To explore potential barriers preventing access to palliative care services and develop a theoretical framework that captures the experience of dying with ILD.MethodTwenty semi-structured interviews have been conducted to date with patients with ILD, bereaved carers and healthcare professionals. Interviews are transcribed verbatim and data analysis is undertaken concurrently with data generation using Grounded Theory.ResultsData generation and analysis is ongoing. Candidate themes identified from the data are 1) Hidden illness, 2) Preparing for dying, 3) The important bit – final days and hours, 5) Lasting memories. These themes are likely to develop further with additional data from subsequent interviews. There is often a dichotomy between what information is wanted by relatives towards the end of life and what people with ILD are happy to discuss. Recognition of dying is important to allow the opportunity for advance care planning for people who wish to have these discussions. Symptom control and family presence at the end of life has an impact of bereaved relatives’ lasting memories. The covid-19 pandemic has heavily influenced these factors and highlighted deficiencies in the existing services.ConclusionThe uncertain prognosis associated with ILD leads to avoidance of advance care planning by both patients, relatives and healthcare professionals. This ongoing research project will add to the emerging body of evidence of the importance of timely end of life care in this patient group, which has many similarities to covid-19, namely respiratory symptoms, and the propensity to deteriorate suddenly.ImpactThis research will influence the design and delivery of palliative care services for people with ILD regionally and potentially opportunity to explore this nationally.

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established.Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population.Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death.Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71).Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Respiratory follow-up of patients with COVID-19 pneumonia.

The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.