Nintedanib for non-IPF progressive pulmonary fibrosis: 12-month outcome data from a real-world multicentre observational study

Background Nintedanib slows lung function decline for patients with non-idiopathic pulmonary fibrosis progressive pulmonary fibrosis (PPF) in clinical trials, but the real-world safety and efficacy are not known. Methods In this retrospective cohort study, standardised data were collected from patients in whom nintedanib was initiated for PPF between 2019 and 2020 through an early-access programme across eight centres in the United Kingdom. Rate of lung function change in the 12 months pre- and post-nintedanib initiation was the primary analysis. Symptoms, drug safety, tolerability and stratification by interstitial lung disease subtype and computed tomography pattern were secondary analyses. Results 126 patients were included; 67 (53%) females; mean±sd age 60±13 years. At initiation of nintedanib, mean forced vital capacity (FVC) was 1.87 L (58% predicted) and diffusing capacity of the lung for carbon monoxide (DLCO) was 32.7% predicted. 68% of patients were prescribed prednisolone (median dose 10 mg) and 69% were prescribed a steroid-sparing agent. In the 12 months after nintedanib initiation, lung function decline was significantly lower than in the preceding 12 months: FVC −88.8 mL versus −239.9 mL (p=0.004), and absolute decline in DLCO −2.1% versus −6.1% (p=0.004). Response to nintedanib was consistent in sensitivity and secondary analyses. 89 (71%) out of 126 patients reported side-effects, but 86 (80%) of the surviving 108 patients were still taking nintedanib at 12 months with patients reporting a reduced perception of symptom decline. There were no serious adverse events. Conclusion In PPF, the real-world efficacy of nintedanib replicated that of clinical trials, significantly attenuating lung function decline. Despite the severity of disease, nintedanib was safe and well tolerated in this real-world multicentre study

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

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

Monocyte profile and function in sarcoidosis

Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology. The immune pathology is characterised by dysregulated T cell (TH1) activity, macrophage activation and granuloma formation, resulting in systemic inflammation, and organ dysfunction. I hypothesised that, as the systemic precursor to the macrophage, altered monocyte activity in sarcoidosis may contribute to the early immune pathology of the disease. In this thesis, I examined their phenotype, four key monocytic functions: cytokine production, suppression of T cell proliferation, phagocytosis and fusion (as a precursor to granulomagenesis); and their gene expression profile compared to monocytes from healthy controls. My data show that the expanded monocyte compartment comprise a greater proportion of the inflammatory (CD14++CD16+) and patrolling (CD14+CD16++) subsets, increased TNFα and IL-12 and decreased IL-10 and IL-4 production in sarcoidosis compared with healthy controls. The IL-10 deficit renders the monocytes less able to regulate T cell proliferation or their own fusion to multinucleate giant cells, potentially contributing to T cell expansion and granuloma formation respectively. Additionally, sarcoidosis monocytes are less able to phagocytose inert material. I also showed that previously reported deficiency in invariant NKT cells and low serum vitamin D levels in sarcoidosis may be linked to reduced IL-10 production by monocytes. Vitamin D treatment in vitro restored most of these deficiencies and provides a potential therapeutic method for manipulating monocyte function and disease genesis in sarcoidosis.</p

Monocyte profile and function in sarcoidosis

Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology. The immune pathology is characterised by dysregulated T cell (TH1) activity, macrophage activation and granuloma formation, resulting in systemic inflammation, and organ dysfunction. I hypothesised that, as the systemic precursor to the macrophage, altered monocyte activity in sarcoidosis may contribute to the early immune pathology of the disease. In this thesis, I examined their phenotype, four key monocytic functions: cytokine production, suppression of T cell proliferation, phagocytosis and fusion (as a precursor to granulomagenesis); and their gene expression profile compared to monocytes from healthy controls. My data show that the expanded monocyte compartment comprise a greater proportion of the inflammatory (CD14++CD16+) and patrolling (CD14+CD16++) subsets, increased TNFα and IL-12 and decreased IL-10 and IL-4 production in sarcoidosis compared with healthy controls. The IL-10 deficit renders the monocytes less able to regulate T cell proliferation or their own fusion to multinucleate giant cells, potentially contributing to T cell expansion and granuloma formation respectively. Additionally, sarcoidosis monocytes are less able to phagocytose inert material. I also showed that previously reported deficiency in invariant NKT cells and low serum vitamin D levels in sarcoidosis may be linked to reduced IL-10 production by monocytes. Vitamin D treatment in vitro restored most of these deficiencies and provides a potential therapeutic method for manipulating monocyte function and disease genesis in sarcoidosis.This thesis is not currently available on ORA

Real-world retrospective observational study exploring the effectiveness and safety of antifibrotics in idiopathic pulmonary fibrosis.

BACKGROUND Pirfenidone and nintedanib are the only disease-modifying treatments available for idiopathic pulmonary fibrosis (IPF). Our aim was to test their effectiveness and safety in clinical practice. METHODS This is a single-centre retrospective observational study undertaken at a specialised interstitial lung disease centre in England. Data including progression-free survival (PFS), mortality and drug tolerability were compared between patients with IPF on antifibrotic therapies and an untreated control group who had a forced vital capacity percentage (FVC %) predicted within the licensed antifibrotic treatment range. RESULTS 104 patients received antifibrotic therapies and 64 control patients were identified. PFS at 6 months was significantly greater in the antifibrotic group (75.0%) compared with the control group (56.3%) (p=0.012). PFS was not significant at 12 or 18 months when comparing the antifibrotic group with the control group. The 12-month post-treatment mean decline in FVC % predicted (-4.6±6.2%) was significantly less than the 12-month pretreatment decline (-10.4±11.8%) (p=0.039). The 12-month mortality rate was not significantly different between the antifibrotic group (25.3%) and the control group (35.5%) (p=0.132). Baseline Body Mass Index of≤25, baseline diffusion capacity for carbon monoxide percentage predicted of ≤35 and antifibrotic discontinuation within 3 months were independent predictors of 12-month mortality. Antifibrotic discontinuation was significantly higher by 3 and 6 months for patients on pirfenidone than those on nintedanib (p=0.006 and p=0.044, respectively). Discontinuation at 12 months was not significantly different (p=0.381). CONCLUSIONS This real-world study revealed that antifibrotics are having promising effects on PFS, lung function and mortality. These findings may favour commencement of nintedanib as first-line antifibrotic therapy, given the lower rates of early treatment discontinuation, although further studies are required to investigate this

BTS clinical statement on pulmonary sarcoidosis

This British Thoracic Society (BTS) Clinical Statement addresses the diagnosis, evaluation and management of pulmonary sarcoidosis, with each section summarised with key clinical practice points. In an era in which medical practice is increasingly determined by evidence-based guidelines, it must be acknowledged from the outset that current evidence in sarcoidosis, especially with regard to treatment, is weak. Thus, a number of the conclusions in this Statement are based on expert opinion and accumulated clinical experience. The diagnosis of pulmonary sarcoidosis is often challenging, with ongoing evolution in clinician views on the need for a tissue diagnosis. Historically, a biopsy diagnosis was considered mandatory and we provide guidance on when to offer bronchoscopy and which bronchoscopic procedure to perform. We also stress that decisions made by individual patients to decline bronchoscopy, when there is a highly probable but not definite clinical diagnosis, should be supported in most cases, with careful subsequent monitoring. The document includes sections on the diagnosis of cardiac sarcoidosis and pulmonary hypertension as either disorder may present to respiratory physicians as ‘symptomatic pulmonary sarcoidosis’. Traditional treatment algorithms and their reported application in the medical literature tend to be based on a ‘one size fits all’ approach and this has often led to over-treatment and major steroid-related comorbidity. However, a great many patients do not need to be treated: the broad indications for initiating therapy are a) a high risk of mortality or disability due to major organ involvement; and b) unacceptable loss of quality of life. In this statement, we focus on the management of pulmonary disease; the management of concurrent cardiac sarcoidosis or pulmonary hypertension requires referral to expert sub-specialist teams. Key pulmonary management considerations are discussed in this statement. Whilst higher dose treatment regimens may be required in high-risk disease, a highly flexible patient-centred approach is essential when treatment is introduced solely for quality of life reasons. In this context, sustained high-dose therapy is usually inappropriate. Patients should be asked to weigh-up treatment benefits against adverse effects before longer-term treatment decisions are made, with the danger of important comorbidities arising from long-term treatment kept carefully in mind. Monitoring must be tailored to specific goals. Fatigue, a highly prevalent and often disabling symptom in sarcoidosis, requires a systematic approach. Above all, we highlight the need for active patient involvement in decision-making and this, in turn, requires attention to clear communication, discussed in the final part of this statement. Finally, it is important to note that in a few areas of diagnosis and management where there was a non-unanimous consensus amongst the statement authors, this is clearly indicated. Scope The Statement covers diagnosis and management of pulmonary sarcoidosis. Reference is also made to diagnosis of cardiac sarcoidosis and pulmonary hypertension as either disorder may present to respiratory physicians as ‘symptomatic pulmonary sarcoidosis’. Other extra pulmonary sarcoidosis diagnoses are not covered by this Statement and it is recommended that specialists with specific sarcoidosis knowledge be consulted when the disease is present outside the chest. Importantly, it may be difficult to identify the true extent of organ involvement leading to underestimation of disease outside the chest

The burden of Progressive Fibrotic Interstitial lung disease across the UK

The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted version (12 month embargo), submitted versio

Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages:similarities and differences

<p>The molecular repertoire of macrophages in health and disease can provide novel biomarkers for diagnosis, prognosis, and treatment. Th2-IL-4-activated macrophages (M2) have been associated with important diseases in mice, yet no specific markers are available for their detection in human tissues. Although mouse models are widely used for macrophage research, translation to the human can be problematic and the human macrophage system remains poorly described. In the present study, we analyzed and compared the transcriptome and proteome of human and murine macrophages under resting conditions (M0) and after IL-4 activation (M2). We provide a resource for tools enabling macrophage detection in human tissues by identifying a set of 87 macrophage-related genes. Furthermore, we extend current understanding of M2 activation in different species and identify Transglutaminase 2 as a conserved M2 marker that is highly expressed by human macrophages and monocytes in the prototypic Th2 pathology asthma.</p>