[Show abstract][Hide abstract] ABSTRACT: Background Idiopathic Pulmonary Fibrosis (IPF) is an increasingly important respiratory illness in the UK. Rising prevalence of disease, emerging treatments, development of clinical guidelines for diagnosis and management and a NHS England service specification1 increase demands on healthcare providers who are required to enhance capacity or reconfigure services to manage patients.
Aims Estimate the patient care pathways across service providers in England compared with pathways recommended by NICE guidelines2 and the NHS England Service Specification; in terms of time and cost per patient by ‘diagnosis’, ‘management’ and ‘monitoring’, and then levels of reimbursement to providers for current levels of care and those recommended.
Methods Structured interviews with clinicians and coders ascertained current levels of service provision, excluding drug costs, by 14 NHS specialist ILD providers. Data were analysed utilising a bottom-up costing approach to estimate the total pathway costs. Comparison with services and costs as recommended by NICE guidelines and service specification allowed estimation of NHS providers’ profit or loss.
Results The estimated mean cost per patient for the first year of diagnosis, management and monitoring was £1,414, which is approximately £418 (42%) more than is reimbursed by the PBR tariff.3 By comparison, the equivalent cost of the NICE/service specification pathway is approximately £477 (41%) more than reimbursed by the tariff. In particular, it was noted that significant staff time is required for MDT discussion, but that this is not reimbursed.
Conclusions Results suggest that current NHS tariffs for ILD are insufficient to support current service provision. This is true for current levels of care as well as for the levels of care recommended by NICE. The risks of failure to amend the NHS tariff are:
[Show abstract][Hide abstract] ABSTRACT: Introduction and objectives From September 2011 to May 2013, pirfenidone was available in the UK in a named patient programme (NPP). We present results from an extension to a previous real-world study (Parfrey et al. Abstract S98, BTS Winter Conference 2012) now including longer follow-up and all patients enrolled in the pirfenidone NPP from 4 centres.
Methods Four centre, retrospective, cohort review of patient outcomes in the 24 months following pirfenidone initiation in the NPP. Discontinuation data were separately collected for all patients prescribed pirfenidone at the Brompton between Sept 2011 and May 2014.
Results Two hundred and eighteen eligible patients have been identified. Demographic data have been collected for 124 patients (78% male) and outcome data at 12 months from 58 patients. Mean (±S. D.) age at diagnosis was 67.1(± 8.1) years. Mean time from diagnosis to pirfenidone initiation was 27.7(± 30.6) months. At pirfenidone initiation, mean FVC was 69.3(±18.9)% predicted (with 27 (22.0%) patients having FVC >80% predicted); DLco was 40.3(± 13.8)% predicted. Following a 14-day titration period, 53 (93%) patients were receiving the recommended dose of 2403 mg/day pirfenidone. At 6 and 12 months; 47 (81%) and 44 (76%) patients continued to receive pirfenidone.
187 patients have been prescribed pirfenidone at the Brompton since Sept 2011. At 10 months following initiation 18.5% of these have discontinued pirfenidone with no further discontinuations beyond this time. For patients in the NPP with available paired baseline and 6 or 12 month FVC, mean decline in FVC% predicted over first 6 months of pirfenidone treatment was 3.2(± 7.9)%; over first 12 months 1.6(±12.0)%. One patient’s FVC% predicted declined >10% in the first 12 months of treatment. Mean decline in DLco% predicted over first 6 months from pirfenidone initiation was 9.1(± 14.7)%; over first 12 months’ treatment, 7.0(± 17.2)%.
Conclusions The high proportion of patients remaining on pirfenidone at 12 months suggests it is well tolerated and any tolerability issues tend to occur early in treatment. Lung function is largely preserved at 12 months following pirfenidone initiation. Longer-term observation of lung function and clinical outcomes will continue to determine the real-world benefits of pirfenidone.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) are forms of idiopathic interstitial pneumonias that have distinct histopathological features and outcomes. It is unknown if these idiopathic interstitial pneumonias have common mechanisms of fibrosis. Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of sporadic and familial idiopathic pulmonary fibrosis. In response to endoplasmic reticulum (ER) stress, cells trigger the unfolded protein response (UPR) with upregulation of chaperones, such as BiP, and the phosphatase growth arrest and DNA damage 34 (GADD34). However, this may have profound effects on cell proliferation and survival. We hypothesised that ER stress may also be involved in the pathogenesis of NSIP.
Paraffin embedded lung biopsy sections from 4 patients with sporadic idiopathic pulmonary fibrosis (IPF) (UIP histopathology) and 4 non-specific interstitial pneumonia (NSIP) (NSIP histopathology) were evaluated for the ER stress markers BiP and GADD34 using immunohistochemistry. For each biopsy sample, six high power fields (x 200 magnification) were scored for fibrosis and inflammation as well as BiP and GADD34 using semi-quantitative analysis by 2 blinded, independent investigators.
BiP and GADD34 were expressed in areas of fibrosis, localised to reactive type II pneumocytes and endothelial cells. No staining was detected in fibroblasts or fibroblastic foci. In sporadic IPF (UIP), levels of BiP within the epithelium correlated with fibrosis (r2 0.56, p = 0.0001, Figure 1a) more than inflammation (r2 0.38, p = 0.0013). In contrast, epithelial GADD34 was more strongly associated with NSIP fibrosis (r2 0.56, p < 0.0001, Figure 1b). There was no association between the ER stress markers and inflammation in NSIP.
These data suggest that ER stress and the unfolded protein response are features of NSIP as well as IPF and may play a role in determining the severity of the fibrotic response.
[Show abstract][Hide abstract] ABSTRACT: Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.
The Journal of Rheumatology 02/2014; 41(4). DOI:10.3899/jrheum.131251 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities.
The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF).
A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed.
Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary fibrosis is the end stage of many diffuse parenchymal lung diseases. It is characterised by excessive matrix formation leading to destruction of the normal lung architecture and finally death. Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the delineation of primary pathways has proven to be elusive.In this paper susceptibility and injurious agents such as viruses and gastroesophageal reflux and their likely role in initiating disease are discussed. Further topics that are elaborated are candidate ancillary pathways, including immune mechanisms, oxidative and endoplasmic reticulum stress, activation of the coagulation cascade and the potential role of stem cells. The paper will try to provide the reader with an integrated view on the current knowledge and attempts to provide a road map for future research.It is important to explore robust models of overall pathogenesis, reconciling a large number of clinical and scientific observations. We believe that the integration of current data into a "big picture" overview of fibrogenesis is essential for the development of effective antifibrotic strategies. The latter will likely consist of a combination of agents targeting a number of key pathways.
European Respiratory Journal 05/2013; 41(5):1207-18. DOI:10.1183/09031936.00073012 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of the lungs of unknown origin with a poor prognosis. A small trial of co-trimoxazole demonstrated improvements in symptoms and functional parameters over a 3-month period. We therefore conducted a larger trial with a concurrent economic evaluation to investigate this antibiotic further.
We report an economic evaluation alongside a multi-centre, randomised, placebo-controlled, double-blind trial of 12 months therapy with 960 mg co-trimoxazole daily in 181 patients with fibrotic idiopathic interstitial pneumonia (IIP). Patients were recruited from 28 university and district hospitals in the UK and were aged over 40 years with fibrotic IIP. We report costs to the National Health Service (NHS) and society, change in forced vital capacity (primary endpoint) and quality-adjusted life-years (QALYs) gained, incremental cost effectiveness and cost utility ratios over 12 months.
From the perspective of society, mean cost per patient in the co-trimoxazole arm was approximately £1177 higher than in the placebo arm, but mean QALYs were 0.053 higher yielding an incremental cost-effectiveness ratio of £22,012 per QALY gained with a 54.44 % probability of being below £30,000. The cost of IPF to UK society in 2011 is tentatively estimated at £124 million, of which 13 % is NHS costs, 1 % social services, 2 % patient out-of-pocket costs and 84 % lost productivity.
Given commonly employed thresholds in the UK NHS, on balance co-trimoxazole may be a cost-effective treatment for IPF, although there is substantial decision uncertainty. However, recent guidance on the use of immunosuppressive therapy in IPF patients should be taken into account prior to any policy decision.
[Show abstract][Hide abstract] ABSTRACT: Lung biopsy is the last option to obtain lung tissue for a precise diagnosis in patients with interstitial lung disease (ILD). Several surgical techniques have been reported. The successful application of a hybrid approach is herein reported. The procedure utilizes a single-trocar video-assisted thoracoscopic surgery technique to localize and withdraw the tip of the lingula outside the chest to perform a biopsy in the diagnosis of ILDs. The advantages of this technique over other commonly used methods have also been discussed.
[Show abstract][Hide abstract] ABSTRACT: Pleuroparenchymal fibroelastosis (PPFE) is a rare condition characterised by predominantly upper lobe pleural and subjacent parenchymal fibrosis, the latter being intra-alveolar with accompanying elastosis of the alveolar walls. The aim of this study was to review cases fulfilling published imaging and histological criteria, and identify any common clinical features that may suggest an underlying aetiology for a condition that has previously been regarded as idiopathic. Of 12 patients (seven females, median age 57 yrs), the presenting symptoms were shortness of breath (11 out of 12 patients) and dry cough (six out of 12 patients). Seven patients reported recurrent infections during the course of their disease. Five demonstrated nonspecific autoantibody positivity. Two patients had a family history of interstitial lung disease (ILD). High-resolution computed tomography features of lung disease remote from the pleuroparenchymal changes were present in six out of 12 patients (coexistent fibrosis, n=5; bronchiectasis, n=1). Of seven patients with tissue sampled from the lower lobes, four patients showed less intense PPFE changes (one with additional features of hypersensitivity pneumonitis) and three showed usual interstitial pneumonia. PPFE is a distinct clinicopathological entity, with clinical data suggesting a link to recurrent pulmonary infection. Genetic and autoimmune mechanisms may also contribute to the development of these changes. PPFE may also present with more diffuse involvement than previously reported, and coexist with different patterns of ILD.
European Respiratory Journal 03/2012; 40(2):377-85. DOI:10.1183/09031936.00165111 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rituximab (RTX), a B-cell depleting mAb, has been reported to cause pulmonary toxicity in many patients. As the use of this biologic is increasing, we have undertaken a systematic review of the literature to gauge the nature and extent of non-infection-related RTX-induced lung disease.
A systematic literature review was undertaken to document all reported cases of RTX-associated interstitial lung disease (RTX-ILD), evaluating the epidemiological, clinical, radiological, histopathological, laboratory and management data from the available primary sources. The search was conducted using PubMed, the Cochrane Library and EMBASE up to June 2010 using the terms RTX in the advanced search option without limitations and all relevant publications reviewed manually. In addition, unpublished data from the Food and Drug Administration, the European Medicines Agency and the manufacturer (Roche) were evaluated to complement this search. Identified articles were included if they displayed a potential relationship between the administration of RTX and ILD following exclusion of other likely causes.
A total of 121 cases of potential RTX-ILD were identified from 21 clinical studies/trials, 30 case reports and 10 case series. The most common indication for RTX was diffuse large B-cell lymphoma. RTX-ILD occurred more frequently in male patients and was most common during the fifth and sixth decades of life. In most cases, RTX was part of combination chemotherapy, but in 30 (24.7%) cases it was given as monotherapy. The mean and median number of cycles of RTX before disease onset was four, but cases following the first cycle or as late as the 12th cycle were also identified. The mean time of onset, from the last RTX infusion until symptom development or relevant abnormal radiological change was 30 days (range 0-158 days). Abnormal radiological findings were similar in all patients, with diffuse bilateral lung infiltrates apparent on chest radiographs and/or thoracic CT. Hypoxaemia was seen in all cases and pulmonary function tests were uniformly abnormal with a characteristic diffusion capacity deficit and restrictive ventilatory pattern. RTX-ILD was fatal in 18 cases.
ILD is a rare but potentially fatal complication of RTX therapy. This diagnosis should be considered in any patient who develops respiratory symptoms or new radiographic changes while receiving this biologic agent.
[Show abstract][Hide abstract] ABSTRACT: Lung disease is commonly encountered in rheumatological practice either as a manifestation of the underlying condition or as a consequence of using disease-modifying therapies. This has been particularly apparent with the TNF-α antagonists and exacerbations of interstitial lung disease (ILD). In view of this, we undertook a review of the current literature to identify non-infectious pulmonary complications associated with the newer biologic agents used for the treatment of rheumatic conditions.
A systematic literature review (SLR) was conducted using PubMed, the Cochrane Library and EMBASE for reviews, meta-analyses, clinical studies and randomized controlled trials, case studies and series, published up to June 2010 using the terms rituximab (RTX), certolizumab, golimumab (GOL), tocilizumab (TCZ) and abatacept in the advanced search option without limitations. In addition, abstracts from International Rheumatology conferences and unpublished data from the Food and Drug Administration, the European Medicines Agency and drug manufacturers were used to complement our search. References were reviewed manually and only those articles that suggested a potential relationship between the biological agent and lung toxicity, following exclusion of other causes, were included.
Reported non-infectious pulmonary adverse events with TCZ included a fatal exacerbation of RA-associated ILD, new-onset ILD, idiopathic pulmonary fibrosis and allergic pneumonitis, as well as three cases of microbiological culture-negative pneumonia. Although RTX had a higher incidence of pulmonary toxicity, only 7 of the 121 cases reported involved rheumatological diseases. GOL treatment was associated with four cases of non-infectious pulmonary toxicity and two cases of pneumonia with negative microbiological studies. There were no episodes of pulmonary toxicity identified for either certolizumab or abatacept.
Our results highlight an association between the use of newer biologic agents (TCZ, RTX and GOL) and the development of non-infectious parenchymal lung disease in patients with RA. Post-marketing surveillance and biologic registries will be critical for detecting further cases of ILD and improving our understanding of the pathophysiology of this process. As the use of these drugs increases, clinicians must remain vigilant for potential pulmonary complications and exercise caution in prescribing biologic therapies, particularly to rheumatological patients with pre-existing ILD.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown aetiology. It has a very poor prognosis and no effective treatment. There are two major barriers to the development of novel treatments in IPF: an incomplete understanding of its pathogenesis and the fact that current models of the disease are poorly predictive of therapeutic response. Recent studies suggest an important role for the alveolar epithelium in the pathogenesis of IPF. However, practical limitations associated with isolation and culture of primary alveolar epithelial cells have hampered progress towards further elucidating their role in the pathogenesis of the disease or developing disease models that accurately reflect the epithelial contribution. The practical limitations of primary alveolar epithelial cell culture can be divided into technical, logistical and regulatory hurdles that need to be overcome to ensure rapid progress towards improved treatment for patients with IPF. To develop a strategy to facilitate alveolar epithelial cell harvest, retrieval and sharing between IPF research groups and to determine how these cells contribute to IPF, a workshop was organised to discuss the central issues surrounding epithelial cells in IPF (ECIPF). The central themes discussed in the workshop have been compiled as the proceedings of the ECIPF.