Real-world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK

Background Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting.Methods 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey.Results 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD.Conclusion We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting

Starship:Study of Telomeres and Role of Sex Hormones in Pulmonary Fibrosis

RATIONALE Pulmonary fibrosis is an interstitial lung disease (ILD) feature with no curative (other than lung transplantation) or preventative treatments. Recent evidence supports a causal role of short telomeres, and our pre-print findings suggest a potentially protective interaction between optimised sex hormone concentration (testosterone and oestrogen) in men and women and telomere maintenance pathways1. Sex hormone bioavailability is regulated by sex hormone binding globulin (SHBG) in both sexes. Supra-physiological dosing of testosterone in men causes erythrocytosis, so monitoring of haemoglobin concentration and haematocrit is required. STARSHIP set out to assess whether future therapeutic trials of sex hormone supplementation in ILD could be safe and warranted without causing supra-physiological dosing. METHODS Venepuncture was performed on 102 outpatients (age 49-89y, male n=80 [78%]) with fibrotic ILD a ta single regional centre in the UK. Age and sex-matched control samples were obtained from the Exeter 10,000 (EXTEND) biobank. Blood leukocyte telomere length (LTL; measured using high-throughput single telomere length analysis) and sex hormone/SHBG concentrations were determined in all samples. Patients consented for access to their clinical data (including routine pulmonary function). In-depth interviews were carried out by telephone with 93 self-selecting patients, using structured interviews with questions informed by clinical practice, the research team ,and patient partners. RESULTS Almost all male ILD patients (n=77/79) had haemoglobin concentrations and haematocrit below the upper reference limit. Compared to age-matched controls (AMCs) mean LTL was shorter for patients (4.57kb [95%CI: 4.46-4.69] vs 4.78kb [95%CI:4.67-4.89], p<0.006). Mean bioavailable testosterone was lower in male patients (4.95nmol/L[95%CI: 4.50-5.41] vs 6.40nmol/L [95%CI: 5.82-6.98] in AMC; p<0.0001, n=80). Oestrogen concentrations were low for both female patients and controls in keeping with their post-menopausal age, with higher SHBG concentrations for patients (mean 73.7nmol/L [95%CI: 58.6-88.9] vs 52.9nmol/L [95%CI: 42.0-63.8] in AMC; p=0.022). Mean free androgen index (FAI) was below the reference range for female patients (mean 0.51 [95%CI: 0.35-0.67] vs 1.23 [95%CI: 0.77-1.69] in AMC; p= 0.0036, N=22). Both DLCO% predicted (p=0.0005) and FVC% predicted(p=0.005) correlated with bioavailable testosterone concentration in male patients (age-adjusted analysis). FVC% predicted associated with FAI in females (p=0.013) but no association was seen between FAI and DLCO% predicted. CONCLUSIONS Interventional trials of sex hormone supplementation without causing supra-physiological dosing warrant further exploration in patients with ILD

Starship:Study of Telomeres and Role of Sex Hormones in Pulmonary Fibrosis

RATIONALE Pulmonary fibrosis is an interstitial lung disease (ILD) feature with no curative (other than lung transplantation) or preventative treatments. Recent evidence supports a causal role of short telomeres, and our pre-print findings suggest a potentially protective interaction between optimised sex hormone concentration (testosterone and oestrogen) in men and women and telomere maintenance pathways1. Sex hormone bioavailability is regulated by sex hormone binding globulin (SHBG) in both sexes. Supra-physiological dosing of testosterone in men causes erythrocytosis, so monitoring of haemoglobin concentration and haematocrit is required. STARSHIP set out to assess whether future therapeutic trials of sex hormone supplementation in ILD could be safe and warranted without causing supra-physiological dosing. METHODS Venepuncture was performed on 102 outpatients (age 49-89y, male n=80 [78%]) with fibrotic ILD a ta single regional centre in the UK. Age and sex-matched control samples were obtained from the Exeter 10,000 (EXTEND) biobank. Blood leukocyte telomere length (LTL; measured using high-throughput single telomere length analysis) and sex hormone/SHBG concentrations were determined in all samples. Patients consented for access to their clinical data (including routine pulmonary function). In-depth interviews were carried out by telephone with 93 self-selecting patients, using structured interviews with questions informed by clinical practice, the research team ,and patient partners. RESULTS Almost all male ILD patients (n=77/79) had haemoglobin concentrations and haematocrit below the upper reference limit. Compared to age-matched controls (AMCs) mean LTL was shorter for patients (4.57kb [95%CI: 4.46-4.69] vs 4.78kb [95%CI:4.67-4.89], p<0.006). Mean bioavailable testosterone was lower in male patients (4.95nmol/L[95%CI: 4.50-5.41] vs 6.40nmol/L [95%CI: 5.82-6.98] in AMC; p<0.0001, n=80). Oestrogen concentrations were low for both female patients and controls in keeping with their post-menopausal age, with higher SHBG concentrations for patients (mean 73.7nmol/L [95%CI: 58.6-88.9] vs 52.9nmol/L [95%CI: 42.0-63.8] in AMC; p=0.022). Mean free androgen index (FAI) was below the reference range for female patients (mean 0.51 [95%CI: 0.35-0.67] vs 1.23 [95%CI: 0.77-1.69] in AMC; p= 0.0036, N=22). Both DLCO% predicted (p=0.0005) and FVC% predicted(p=0.005) correlated with bioavailable testosterone concentration in male patients (age-adjusted analysis). FVC% predicted associated with FAI in females (p=0.013) but no association was seen between FAI and DLCO% predicted. CONCLUSIONS Interventional trials of sex hormone supplementation without causing supra-physiological dosing warrant further exploration in patients with ILD

Real world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK

Background Nintedanib slows progression of lung function decline in patients with progressive fibrosing interstitial lung disease (PF-ILD) and was recommended for this indication within the NHS in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting. Methods Twenty-six UK centres were invited to take part in a national service evaluation between 17/11/21 and 30/09/22. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability was collected via electronic survey. Results Twenty-four UK prescribing centres responded to the service evaluation invitation. Between 17/11/2021 and 30/09/2022, 1120 patients received a multi-disciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298/1120,26.6%), connective tissue disease associated interstitial lung disease (197/1120,17.6%), rheumatoid arthritis associated ILD (180/1120,16.0%), idiopathic non-specific interstitial pneumonia (125/1120,11.1%) and unclassifiable ILD (100/1120,8.9%). Of these, 54.4% (609/1120) were receiving concomitant corticosteroids, 355/1120 (31.7%) were receiving concomitant mycophenolate mofetil and 340/1120 (30.3%) were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD. Conclusion We have demonstrated the use of nintedanib for the treatment of PFILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting

Age and frailty are independently associated with increased COVID-19 mortality and increased care needs in survivors: results of an international multi-centre study

Introduction: Increased mortality has been demonstrated in older adults with coronavirus disease 2019 (COVID-19), but the effect of frailty has been unclear. Methods: This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS) and delirium on risk of increased care requirements on discharge, adjusting for the same variables. Results: Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, interquartile range [IQR] 54–83; 55.2% male). The risk of death increased independently with increasing age (>80 versus 18–49: hazard ratio [HR] 3.57, confidence interval [CI] 2.54–5.02), frailty (CFS 8 versus 1–3: HR 3.03, CI 2.29–4.00) inflammation, renal disease, cardiovascular disease and cancer, but not delirium. Age, frailty (CFS 7 versus 1–3: odds ratio 7.00, CI 5.27–9.32), delirium, dementia and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. Conclusion: Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.</p