South-West of England's Experience of the Safety and Tolerability Pirfenidone and Nintedanib for the Treatment of Idiopathic Pulmonary Fibrosis (IPF).

Purpose: Pirfenidone and nintedanib are two novel antifibrotic agents licensed for the treatment IPF. Prior to being approved for use in England for patients with FVC >50% and <80%, these were made available for all IPF patients under the Mild Patient Program (MPP) and Patient In Need Scheme (PIN). Prescribing of these medications is restricted to specialist centers. We sought to characterize the population of patients prescribed antifibrotics and determine the drug tolerability of these medications in the Northern hub of the Southwest of England regional ILD network. Methods: A retrospective analysis of all patients treated with antifibrotics between August 2012 and July 2017 was undertaken. Baseline characteristics including patient demographics and pulmonary physiology, in addition to drug tolerability and reasons for treatment cessation were collated. Data were compared using unpaired student's t-test, Chi-squared, Mann-Whitney rank sum or ANOVA as appropriate. Logistic regression analysis evaluated clinical characteristics associated with discontinuation of pirfenidone therapy. P < 0.05 was considered statistically significant. Findings: A total of 164 patients, all with consensus diagnoses of IPF, were identified. Of these, 70.1% (115/164) received pirfenidone as their initial therapy. Baseline age, gender and pulmonary physiology did not differ significantly between groups. Drug discontinuation occurred most commonly due to adverse drug reactions events (ADRs) for both pirfenidone [40.0% (46/115)] and nintedanib [16.3% (8/49)]. Anorexia, rash and gastrointestinal disturbance were reported most commonly as the reason for cessation of pirfenidone; anorexia, nausea and weight loss for nintedanib. Duration of therapy prior to discontinuation because of ADRs did not differ significantly between medication groups but patients with a baseline FVC < 65% predicted, had a significantly shorter duration of pirfenidone prior to discontinuation due to ADRs, compared to those with a FVC 65-80% predicted. Multivariate logistic regression did not identify any independent baseline characteristics that predicted discontinuation of pirfenidone therapy prior to 52 weeks. Implications: Idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib had comparable treatment emergent adverse event (TEAE) profiles in clinical practice to those reported in clinical trials. The TEAE profile of pirfenidone was higher than clinical trial data would suggest, although comparable to real-world datasets. Further work is required to explore the possible reasons underpinning this finding, including whether this is related to population co-morbidities or center threshold. No new safety concerns were identified.

Pulmonary Langerhans cell histiocytosis (PLCH): a new UK register.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease of unknown aetiology. We aimed to characterise a UK-wide cohort of patients with PLCH and compare diagnostic and management methods in specialist and non-specialist centres. 106 cases (53 hospitals) identified. Complete data received in 67 cases (53.7% female, age 37.1±14.4 years). 96% current or ex-smokers. Treatment; smoking cessation (79%), corticosteroids (30.6%), cytotoxic therapy (26.9%) and lung transplant (6%). Patients at specialist centres received cytotoxic drugs more often (p=0.0001) and survival appeared higher. This dataset indicates a more even gender distribution than previously documented. It suggests variation in clinical management and outcomes achieved dependent on clinical experience.

A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma.

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.