Helen Parfrey

Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes

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.

Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomised controlled trial

Background Idiopathic pulmonary fibrosis (IPF) is a fatal condition with limited treatment options. However, in a previous small study, co-trimoxazole was found to be beneficial. Methods In a double-blind multicentre study, 181 patients with fibrotic idiopathic interstitial pneumonia (89% diagnosed as definite/probable IPF) were randomised to receive co-trimoxazole 960 mg twice daily or placebo for 12 months in addition to usual care. Measurements were made of forced vital capacity (FVC) (primary endpoint), diffusing capacity of carbon monoxide (Dlco) and EuroQol (EQ5D)-based utility, 6-minute walk test (6MWT) and Medical Research Council (MRC) dyspnoea score (secondary endpoints). All-cause mortality and adverse events were recorded (tertiary endpoints). Results Co-trimoxazole had no effect on FVC (mean difference 15.5 ml (95% CI −93.6 to 124.6)), Dlco (mean difference −0.12 mmol/min/kPa (95% CI 0.41 to 0.17)), 6MWT or MRC dyspnoea score (intention-to-treat analysis). The findings of the per-protocol analysis were the same except that co-trimoxazole treatment resulted in a significant improvement in EQ5D-based utility (mean difference 0.12 (95% CI 0.01 to 0.22)), a reduction in the percentage of patients requiring an increase in oxygen therapy (OR 0.05 (95% CI 0.00 to 0.61)) and a significant reduction in all-cause mortality (co-trimoxazole 3/53, placebo 14/65, HR 0.21 (95% CI 0.06 to 0.78), p=0.02)) compared with placebo. The use of co-trimoxazole reduced respiratory tract infections but increased the incidence of nausea and rash. Conclusions The addition of co-trimoxazole therapy to standard treatment for fibrotic idiopathic interstitial pneumonia had no effect on lung function but resulted in improved quality of life and a reduction in mortality in those adhering to treatment. ISRCTN22201583

Non-infectious pulmonary toxicity of rituximab: a systematic review

OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSION 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.

The pathogenesis of pulmonary fibrosis: a moving target

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 review susceptibility and injurious agents, such as viruses and gastro-oesophageal reflux, and their probable role in initiating disease will be 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. This review 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 probably consist of a combination of agents targeting a number of key pathways.

Non-infectious pulmonary complications of newer biological agents for rheumatic diseases—a systematic literature review

OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSION 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.

α1-Antitrypsin deficiency, liver disease and emphysema

alpha(1)-Antitrypsin is a member of the serine proteinase inhibitor (serpin) superfamily and a potent inhibitor of neutrophil elastase. The most important deficiency variant of alpha(1)-antitrypsin arises from the Z mutation (Glu342Lys). This mutation perturbs the proteins tertiary structure to promote a precise, sequential intermolecular linkage that results in polymer formation. These polymers accumulate within the endoplasmic reticulum of the hepatocyte forming inclusion bodies that are associated with neonatal hepatitis, juvenile cirrhosis and adult hepatocellular carcinoma. The resultant secretory defect leads to plasma deficiency of alpha(1)-antitrypsin. This exposes lung tissue to uncontrolled proteolytic attack from neutrophil elastase, culminating in alveolar destruction. Thus, the Z alpha(1)-antitrypsin homozygote is predisposed to developing early onset basal, panacinar emphysema. In this review, we summarise the current understanding of the pathobiology of alpha(1)-antitrypsin deficiency and the associated liver cirrhosis and emphysema. We show how this knowledge has led to the development of novel therapeutic approaches to treat this condition.

Targeting a Surface Cavity of α1-Antitrypsin to Prevent Conformational Disease

Conformational diseases are caused by a structural rearrangement within a protein that results in aberrant intermolecular linkage and tissue deposition. This is typified by the polymers that form with the Z deficiency variant of α1-antitrypsin (Glu-342 → Lys). These polymers are retained within hepatocytes to form inclusions that are associated with hepatitis, cirrhosis, and hepatocellular carcinoma. We have assessed a surface hydrophobic cavity in α1-antitrypsin as a potential target for rational drug design in order to prevent polymer formation and the associated liver disease. The introduction of either Thr-114 → Phe or Gly-117 → Phe on strand 2 of β-sheet A within this cavity significantly raised the melting temperature and retarded polymer formation. Conversely, Leu-100 → Phe on helix D accelerated polymer formation, but this effect was abrogated by the addition of Thr-114 → Phe. None of these mutations affected the inhibitory activity of α1-antitrypsin. The importance of these observations was underscored by the finding that the Thr-114 → Phe mutation reduced polymer formation and increased the secretion of Z α1-antitrypsin from a Xenopus oocyte expression system. Moreover cysteine mutants within the hydrophobic pocket were able to bind a range of fluorophores illustrating the accessibility of the cavity to external agents. These results demonstrate the importance of this cavity as a site for drug design to ameliorate polymerization and prevent the associated conformational disease.

In search of the fibrotic epithelial cell: opportunities for a collaborative network

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.

Amplification of TGFβ Induced ITGB6 Gene Transcription May Promote Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease with poor survival rates and limited treatment options. Upregulation of αvβ6 integrins within the alveolar epithelial cells is a characteristic feature of IPF and correlates with poor patient survival. The pro-fibrotic cytokine TGFβ1 can upregulate αvβ6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous TGFβ1 increases expression of the integrin β6 subunit gene (ITGB6) and αvβ6 integrin cell surface expression in a time- and concentration-dependent manner. TGFβ1-induced ITGB6 expression occurs via transcriptional activation of the ITGB6 gene, but does not result from effects on ITGB6 mRNA stability. Basal expression of ITGB6 in, and αvβ6 integrins on, lung epithelial cells occurs via homeostatic αvβ6-mediated TGFβ1 activation in the absence of exogenous stimulation, and can be amplified by TGFβ1 activation. Fundamentally, we show for the first time that TGFβ1-induced ITGB6 expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit ITGB6 transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the ITGB6 promoter abolishes TGFβ1-induced ITGB6 transcriptional activity. Using chromatin immunoprecipitation we demonstrate that TGFβ1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the ITGB6 gene promoter within this region. Finally, using an adenoviral TGFβ1 over-expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for TGFβ1-induced αvβ6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of αvβ6 integrin activated TGFβ1-induced ITGB6 gene expression regulates epithelial basal αvβ6 integrin expression, and demonstrates that this occurs via Smad-dependent transcriptional regulation at a single Smad binding site in the promoter of the β6 subunit gene. Active TGFβ1 amplifies this pathway both in vitro and in vivo, which may promote fibrosis.

TNF Receptor-1 (TNF-R1) Ubiquitous Scaffolding and Signaling Protein Interacts with TNF-R1 and TRAF2 via an N-Terminal Docking Interface

TNF receptor-1 (TNF-R1) signal transduction is mediated through the assembly of scaffolding proteins, adaptors, and kinases. TNF receptor ubiquitous scaffolding and signaling protein (TRUSS), a 90.1 kDa TNF-R1-associated scaffolding protein, also interacts with TRAF2 and IKK and contributes to TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) and c-Jun-NH(2)-terminal kinase (JNK) activation. Little is known about the mechanism of interaction among TRUSS, TNF-R1, and TRAF2. To address this issue, we used deletional and site-directed mutagenesis approaches to systematically investigate (i) the regions of TRUSS that interact with TNF-R1 and TRAF2 and (ii) the ability of TRUSS to self-associate to form higher-order complexes. Here we show that sequences located in the N-terminal (residues 1-248) and central (residues 249-440) regions of TRUSS are required to form a docking interface that supports binding to both TNF-R1 and TRAF2. While the C-terminal region (residues 441-797) did not directly interact with TNF-R1 or TRAF2, sequences located in this region were capable of self-association. Collectively, these data suggest that (i) the interaction between TNF-R1 and TRAF2 requires sequences located in the entire N-terminal half (residues 1-440) of TRUSS, (ii) the binding interface for TNF-R1 is closely linked with the TRAF2 binding interface, and (iii) the assembly of homomeric TRUSS complexes may contribute to its role in TNF-R1 signaling.