George A. Margaritopoulos

Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement

The connective tissue disorders (CTDs), also called collagen vascular diseases (CVDs), represent a heterogeneous group of immunologically mediated inflammatory disorders with a large variety of affected organs. Individuals with a CTD (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögrens syndrome, polymyositis/dermatomyositis and mixed connective tissue disease) are susceptible to respiratory involvement. When the lungs are affected, an increasing mortality and morbidity in CVDs occurs. Interstitial lung disease (ILD) is established as a clinical corollary across the spectrum of CTDs, with an overall incidence estimated at 15%. Therefore, pivotal clinical dilemmas remain in the evaluation and management of ILD involvement in CVDs. Critical questions are the presence of fibrosis and whether the disease is clinically significant. Moreover, the clinician has to decide if treatment is warranted and which is the best therapeutic approach. The use of additional tests, such as pulmonary function tests, high-resolution computed tomography scan, bronchoalveolar lavage fluid and surgical lung biopsy, deserves better discussion. The present review focuses on establishing the diagnosis of ILD in CTD, and on evaluating disease activity and prognosis. This will provide the basis for therapeutic decisions that will be discussed, including an overview of recent advances.

Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future

During the past decade important progress has been made regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF), which is the most devastating form of idiopathic interstitial pneumonia with a median survival of 3 years. The knowledge gained has been used to design multicentre, randomised, placebo-controlled trials in order to investigate agents with different mechanisms of action. Encouraging results have led to licensing of the first IPF-specific drug, pirfenidone. However, the road to successful treatment is still long. The main aim for the future should be the careful design of clinical trials, by choosing the most clinically meaningful end-point and keeping in mind that combination of various agents may be more effective. This approach has been used in the treatment of lung cancer with which IPF presents many similarities.

Recent advances in the pathogenesis and clinical evaluation of pulmonary fibrosis

Interstitial lung diseases (ILDs) are a group of heterogeneous disorders, either idiopathic or associated with injurious or inflammatory causes, in which the major site of damage is the lung interstitium. For a long time, knowledge regarding pathogenesis was trivial and there were difficulties in diagnosing and subsequently treating these diseases. During the past decade, however, there has been an impressive development in the field of ILDs. Idiopathic pulmonary fibrosis, the most common and fatal form of ILD, was initially believed to be due to an inflammatory response to unknown lung injury, whereas nowadays it is believed to be the result of multiple injuries at different sites of the lung followed by aberrant repair. The integration of clinical, radiological and histological data, namely a multidisciplinary team (MDT) approach, has provided grounds for a more accurate diagnosis of ILDs, and helped the identification of different entities and development of different therapeutic approaches. However, because of the complexity of ILDs, even this approach may fail to establish a confident diagnosis. How should the clinician behave in this case and what are the pitfalls of the MDT approach? In addition, since diagnosis is the major predictor of prognosis, are there any other tools available to predict prognosis?

Smoking and Pulmonary Fibrosis: Novel Insights

The relationship between smoking and pulmonary fibrosis is under debate and intense investigation. The aim of this paper is to review the existing literature and identify further areas of research interest. Recently the negative influence of cigarette smoking on IPF outcome was highlighted, as non-smokers exhibit a better survival than ex-smokers and combined current- and ex-smokers. In patients with non-specific interstitial pneumonia (NSIP), a high prevalence of emphysema was recently demonstrated, providing an indirect support for a smoking pathogenetic hypothesis in NSIP. The coexistence of pulmonary fibrosis and emphysema has been extensively described in a syndrome termed combined pulmonary fibrosis and emphysema (CPFE). Connective tissue disorders (CTDs) are a group of autoimmune diseases which affect the lung, as one of the most common and severe manifestations. However, the relationship between smoking and autoimmune disorders is still conflicting. Rheumatoid arthritis results from the interaction between genetic and environmental factors, while the best established environmental factor is tobacco smoking. Smoking has also a negative impact on the response of the RA patients to treatment. The aforementioned smoking-related implications give rise to further research questions and certainly provide one more important reason for physicians to advocate smoking cessation and smoke-free environment.

Expression analysis of Akt and MAPK signaling pathways in lung tissue of patients with idiopathic pulmonary fibrosis (IPF)

Purpose of the study: Several studies in patients with lung cancer have shown that epidermal growth factor receptor regulates various tumorigenic processes through the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin and Ras/Raf/Mek/Erk (mitogen-activated protein kinase (MAPK)) signalling pathways. The aim of our study is to evaluate whether these pathways are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and to seek indirect evidence of a common pathogenetic pathway with lung cancer. m-RNA expression of oncogenes participating in these two signaling pathways, as well as the combined m-RNA expression of the suppressor genes R-kip and p53 in lung tissue of patients with IPF were evaluated. Basic procedures: The study population was composed by two distinct groups. Patients with IPF (n = 25) and control subjects who underwent thoracic surgery for reasons other than interstitial lung disease (n = 10). Expression analysis of the aforementioned oncogenes and suppressor genes was performed using real-time reverse transcription polymerase chain reaction. Main findings: We found no difference in the overall m- RNA expression between controls and IPF in both investigated pathways. However, Braf has been overexpressed in IPF samples (P = 0.01) in contrast with K-ras that has been found downregulated (P < 0.001) in comparison with controls. Principal conclusions: These findings cannot exclude the hypothesis of involvement of Akt and MAPK signalling pathways in pathogenesis of IPF. However, further investigation is needed in order to verify these data.

NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung.

In this study we investigated the implication of NLRP3 inflammasomes in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis–usual interstitial pneumonia (RA-UIP). NLRP3 inflammasome activation at baseline and following stimulation with lipopolysaccharide/ATP was evaluated by measuring interleukin (IL)-1β and IL-18 levels released in the bronchoalveolar lavage fluid (BALF) fluid and by cultures of BALF cells. IL-1β and IL-18 levels were significantly elevated in the BALF and BALF macrophage cultures from RA-UIP patients, consistent with pre-existing inflammasome activation in these patients. In contrast, in IPF, BALF levels of IL-1β were significantly less elevated relative to RA-UIP and IL-18 was lower than controls. Furthermore, upon inflammasome stimulation, IPF BALF macrophage cultures failed to upregulate IL-1β and partly IL-18 secretion, in contrast to controls, which showed robust IL-1β and IL-18 upregulation. Interestingly, RA-UIP BALF cell cultures treated with lipopolysaccharide/ATP showed a potent stimulation of IL-18 secretion but not IL-1β, the latter being already elevated in the unstimulated cultures, while examination of the intracellular IL-1β levels in RA-UIP BALF cells upon NLRP3 inflammasome stimulation showed a significant upregulation of IL-1β suggesting the NLRP3 pathway could be further activated. Taken together, our results suggest distinct inflammasome activation profiles between autoimmune and idiopathic lung fibrosis. Distinct NLRP3 inflammasome activation profiles between autoimmune and IPF lung macrophages compared with controls http://ow.ly/UKYlp

Idiopathic pulmonary fibrosis and sleep disorders: No longer strangers in the night

The prevalence of obstructive sleep apnoea (OSA) is continuously increasing in patients with idiopathic pulmonary fibrosis (IPF) and, for the first time, the recent IPF guidelines recognise OSA as an important associated comorbidity that can affect patients survival. Thus, it becomes conceivable that clinicians should refer patients with newly diagnosed IPF to sleep centres for the diagnosis and treatment of OSA as well as for addressing issues regarding the reduced compliance of patients with continuous positive airway pressure therapy. The discovery of biomarkers common to both disorders may help early diagnosis, institution of the most appropriate treatment and follow-up of patients. Better understanding of epigenetic changes may provide useful information about pathogenesis and, possibly, development of new drugs for a dismal disease like IPF. It is now believed that IPF and sleep disorders can coexist in the same patient http://ow.ly/LXPSL

Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: an international case–cohort study

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (κw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53–0.72, p<0.0001) than academic physicians (κw=0.56, IQR 0.45–0.65, p<0.0001) or physicians with access to multidisciplinary team (MDT) meetings (κw=0.54, IQR 0.45–0.64, p<0.0001). The prognostic accuracy of academic physicians with >20 years of experience (C-index=0.72, IQR 0.0–0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70–0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72–0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts. Academic status, access to MDT meetings and clinician experience predict accuracy of a clinical diagnosis of IPF http://ow.ly/k43W30cTMg1

Self-Eating: Friend or Foe? The Emerging Role of Autophagy in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is the most common and severe form of idiopathic interstitial pneumonias. Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the pathogenesis remains elusive, and little therapeutic progress has been made in the last few years. Mortality in 3–5 years is still 50%. Autophagy, a highly conserved homeostatic mechanism necessary for cell survival, has been recently implicated in the pathogenesis of pulmonary disorders. In this paper we aim to highlight some key issues regarding the process of autophagy and its possible association with the pathogenesis of idiopathic pulmonary fibrosis.

Smoking-related idiopathic interstitial pneumonia: A review.

For many years, cigarette smoking has been considered as the leading cause of chronic obstructive pulmonary disease and lung cancer. Recently, however, it has also been associated with the development of diffuse interstitial lung diseases. In the latest classification of the major idiopathic interstitial pneumonias (IIP), the term smoking‐related IIP has been introduced, including two entities, namely desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis‐interstitial lung disease (RB‐ILD). Other entities in which smoking has a definite or suggested role include pulmonary Langerhans cell histiocytosis, smoking‐related interstitial fibrosis, combined pulmonary fibrosis and emphysema syndrome and idiopathic pulmonary fibrosis. In this review, we will focus on the mechanisms of smoking‐related lung damage and on the clinical aspects of these disorders with the exception of idiopathic pulmonary fibrosis, which will be reviewed elsewhere in this review series.