Clinical review: Idiopathic pulmonary fibrosis—Past, present and future

ARTICLE IN PRESS Respiratory Medicine (2006) 100, 1871–1885

HISTORICAL REVIEW

Clinical review: Idiopathic pulmonary fibrosis—Past, present and future Owen J. Dempsey Interstitial Lung Disease Clinic, Department of Respiratory Medicine, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, UK Received 10 August 2006; accepted 16 August 2006

KEYWORDS Interstitial lung disease; Usual interstitial pneumonitis; Fibroblastic focus

Summary Idiopathic pulmonary fibrosis (IPF) is an important, and devastating, interstitial lung disease. It has a median mortality of only 3 years, worse than many cancers, and its incidence continues to rise. In this article, an overview of key developments in our understanding and clinical management of IPF will be provided. & 2006 Elsevier Ltd. All rights reserved.

Introduction In 1868, Flint described a condition called ‘‘chronic pneumonitis’’ and noticed that the fingertips of one patient assumed a bulbous appearance.1,2 This was probably the first recorded case of the condition we now recognise as idiopathic pulmonary fibrosis (IPF), formerly known as cryptogenic fibrosing alveolitis. IPF has continued to puzzle and frustrate clinicians in equal measures over the years, and remains an enigma. It is an important, and devastating, disease, with a median mortality of 3 years, worse than many cancers,3 and its incidence continues to rise, doubling in just over a decade.4 We will begin in the past, highlighting lessons from the last century that are still having relevance Tel.: +44 1224 552320; fax: + 44 1224 551210.

E-mail address: [email protected].

today. Key papers, some of which have been published in Respiratory Medicine, and its forerunners, will be cited, in this Centennial issue. Thereafter, we will turn to the present day, assessing how much we know about IPF and the role of current therapies and management. Finally, an overview of exciting potential therapies that are beginning to emerge in well-designed trials will be provided, and we will try and predict what the future holds for this group of patients who continue to have great clinical need.

Methods A comprehensive literature search using Medline, Clinical Evidence, Cochrane library and EMBASE was performed. In addition, issues of Respiratory Medicine and its forerunners since 1907 (British

0954-6111/$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2006.08.017

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Journal of Tuberculosis, British Journal of Tuberculosis and Diseases of the Chest, British Journal of Diseases of the Chest) were also reviewed. Published articles, and articles in press, available up to July 2006, were then selected and extracted, along with papers which the author felt to be topical, and of interest to clinicians.

Definitions and classification The interstitium is the microscopic space between the basement membranes of the alveolar epithelium and capillary endothelium, and forms part of the blood–gas barrier. Idiopathic interstitial pneumonias (IIPs) are characterised by expansion of the interstitial compartment by inflammatory cells, with associated fibrosis in many cases.5 The most recent international classification, published in 2002, divides IIPs into seven distinct groups—IPF, nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), cryptogenic organising pneumonia (COP) and lymphoid interstitial pneumonia (LIP).6 IPF is the most common form, accounting for approximately 60% of cases and is associated with a classic pathologic pattern called usual interstitial pneumonia (UIP).7 It is important to be aware that in UIP, ‘‘pneumonia’’ is used to describe inflammation (rather than infection), while ‘‘usual’’ indicates that the histological pattern is that most commonly observed. A UIP pattern can be seen in patients with other conditions (asbestosis, connective tissue diseases, chronic hypersensitivity pneumonitis, and certain drug-induced lung diseases) and is not unique to IPF, although often the terms are used synonymously.7

Pathology Key features include lower lobe and subpleural predominance, geographical and temporal heterogeneity, relatively mild interstitial inflammation with fibrosis, typically with normal or only mildly affected intervening lung.8 Ultimately this results in chronic scarring with architectural distortion and honeycombing. The distinctive fibroblastic focus, a hallmark lesion that is the site of active fibrosis, is not unique to UIP but is seen at the interface between dense peripheral fibrosis and more normal lung centrally in the lobule (Fig. 1). Ground glass opacification is seen, but seldom extensive. Acute exacerbations of IPF are associated with signs of

Figure 1 The photograph shows a large fibroblastic focus (arrow) in an area of interstitial chronic inflammation, located beneath epithelial cells that line the luminal surface (magnification
200).

diffuse alveolar damage, notably hyaline membrane formation, hyperplastic type II alveolar cells, and interstitial thickening secondary to oedema and inflammatory/fibroblastic cell infiltration.8,9

Pathogenesis The cause of IPF is unknown. Following Hamman and Rich’s description in 1944 of what we would now describe as AIP, the ‘‘inflammatory/alveolitis’’ hypothesis prevailed for several decades, the assumption being that IPF was a chronic inflammatory disease, occurring in response to an unknown stimulus, and if left untreated, led to progressive lung injury and ultimately fibrosis.10,11 As discussed later in this review, it is now clear that antiinflammatory agents have been disappointingly ineffective in the management of IPF.12,13 The current ‘‘epithelial/mesenchymal’’ hypothesis suggests that IPF results from multiple episodes of epithelial cell activation from, as yet unidentified, exogenous and endogenous stimuli.14 The initial insult to the lungs is still unclear, and results in disruption of the alveolar epithelium.15 Consequently, migration, proliferation and activation of mesenchymal cells occurs, resulting in the formation of fibroblastic/myofibroblastic foci (Fig. 1), with excessive accumulation of extra-cellular matrix, mirroring abnormal wound repair.14 The origin of the fibroblasts, key cells in the pathogenesis of IPF, is still unclear, and is possible that extrapulmonary, as well as pulmonary progenitor cells are involved in the aberrant repair/remodelling process.16–19 This complex process is well-described elsewhere and offers potential targets for therapeutic intervention.14

ARTICLE IN PRESS Idiopathic pulmonary fibrosis

Epidemiology A comprehensive epidemiological overview has recently been published, and it is clear that robust data is largely lacking for IPF.20 Diagnostic imprecision, changing disease classification and heterogeneous study design have been responsible for significant variation in estimated incidence and prevalence. In one of the best population-based studies, from Bernalillo County in New Mexico, Coultas et al.21 recorded all new cases of interstitial lung disease registered over a 2-year period in a population of nearly half a million inhabitants. Coultas et al.21 reported an incidence/prevalence (male/female) per 105 population of 11/7 and 20/13, respectively. A Norwegian study reported an incidence/prevalence for hospitalised IPF of 4.3 and 20 per 1000 000.22 In the UK, data has been analysed from a primary care database of approximately 4 million patients, with 962 cases of IPF identified between 1991 and 2003, excluding patients with connective tissue diseases and adjusting for age and gender.4 The incidence of IPF has been reported as rising by 11% annually between 1991 and 2003, suggesting the number of recorded diagnoses of IPF is doubling every 8 years.4 Most studies suggest IPF is more common in men,21,23,24 and is a disease predominantly of the elderly, with a mean age of onset typically 67–69.21 Many potential risk factors have been suggested as being linked with IPF,7 notably cigarette smoking,25 medication (anti-depressants),26 chronic aspiration,27–29 metal and wood dusts 24,30,31 and infectious agents.7,20,21 Viral infections suggested to be linked with IPF include hepatitis C, adenovirus and Epstein– Barr virus.32 In vivo, Epstein–Barr replication has been reported to be significantly increased within type II alveolar epithelial cells in lung biopsies from patients with IPF, compared to controls.33 Several studies have suggested that IPF may be related to repeated aspiration of gastric contents over long periods of time and a recent study suggests that abnormal gastro-oesophageal reflux is highly prevalent, but often clinically occult, in patients with IPF.27–29 Familial IPF is rare, with a recent UK study reporting a prevalence of 1.34 cases per million, accounting for only 0.5–2.2% of all cases.34 A Finnish study reported similar findings, with familial IPF accounting for 3.3–3.7% of cases.35 Clustering within families has been widely reported, and a group of 111 families, with 309 affected individuals, has recently been described36 Interestingly, phenotypic heterogeneity was seen in almost half the families, with several subtypes of IIP reported, suggesting that environmental factors are also

1873 relevant. Older age, male sex and having ever smoked cigarettes were associated with developing IPF.36 Associations between IPF and specific polymorphisms in genes encoding interleukin-1 receptor antagonist, tumour necrosis factor-a and complement receptor 1 have been reported.37 Furthermore, two mutations in the gene encoding surfactant protein C have been identified, resulting in protein misfolding, causing type II epithelial cell injury.38,39 Susceptibility to IPF probably involves a combination of genetic polymorphisms related to epithelial cell injury and abnormal wound healing. Gene expression profile is now also being used to identify target genes involved in tissue remodelling and epithelial/mesenchymal differentiation.40,41

Natural history and acute exacerbations A diagnosis of IPF is associated with a median mortality of approximately 3 years.3 Early studies generally overestimated survival rates, and often included patients with other forms of IIP such as NSIP, which typically is associated with better survival and more response to corticosteroids and other therapies. The perception of IPF has, until recently, been one of a disease that progresses at a steady rate, but it is clear that many patients experience a much more rapid decline, often punctuated by precipitous, and often terminal episodes, now termed ‘‘acute exacerbations’’.42 Indeed, acute exacerbations were found to precede death in as many as 47% of patients in a recent study of patients from the placebo arm of a large trial.43 The specific diagnostic criteria defining an acute exacerbation are not yet agreed, but loosely based on the criteria suggested by Kondoh et al.9 and include worsening dyspnoea or cough within the last month, new ground-glass opacities or consolidation on chest imaging studies, worsening hypoxaemia and rapid development of respiratory failure in the absence of infection, pulmonary embolism, congestive heart failure, pneumothorax or other obvious alternative diagnosis.9,44,45 Lung biopsies usually show diffuse alveolar damage, as described earlier.8 High flow oxygen and empirical intravenous methylprednisolone are often tried, although evidence for the latter is limited to case reports.46 One study has suggested that anticoagulation may also significantly improve survival, although the mechanism is unclear.47 The study had significant methodological flaws and further studies are needed before anti-coagulation is recommended.45 Acute exacerbations are associated with high mortality, with several studies reporting poor

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outcome if patients are admitted to an intensive care unit.48,49 In one study, 92% of hospital survivors died a median of 2 months after discharge.48

Diagnosis It is important to make a confident diagnosis of IPF (Table 1), since this has implications for prognosis, and allows the creation of a logical management plan. Many other IIPs, notably NSIP, present identically to IPF, yet behave completely differently in terms of steroid responsiveness and prognosis. There is evidence to suggest that a dynamic, multidisciplinary approach results in better diagnostic outcomes, and patients with IPF are increasingly being managed in specialist clinics.50,51 This allows clinical, physiological, radiological and histopathological data to be viewed in context.

Clinical features Patients typically present with gradual onset, progressive exertional dyspnoea, often initially attributed erroneously to the ageing process, or misdiagnosed as respiratory tract infection or pulmonary oedema. Cough, often non-productive, is also commonly a symptom. Alternatively, IPF is detected incidentally in an asymptomatic patient, when a chest radiograph is performed for other medical problems. Clinical examination often, but not always, reveals digital clubbing, with coarse ‘‘Velcro-’’ like crackles audible on auscultation over lower lobes particularly. More advanced disease is associated with signs of pulmonary hypertension and cor pulmonale.

Table 1

Radiological features In early IPF, a chest radiograph is often normal.52 With disease progression, features such as reduced lung volumes and predominantly peripheral and basal fibrotic changes become apparent. Highresolution CT scanning is much more sensitive, and is the major diagnostic advance in interstitial lung disease over the last two decades. It allows optimal visualisation of small structures such as nodules, bronchial and cyst walls and inter/intralobular septa and, if typical of UIP/IPF, often obviates the need for surgical lung biopsies. Typical features include a basal, peripheral predominance and patchy reticular abnormality, with honeycombing.53 A normal HRCT scan virtually excludes the diagnosis. Features such as significant mediastinal lymphadenopathy, ground-glass attenuation, cysts, upper-lobe predominance, pleural plaques and effusion, should raise the possibility of alternative diagnosis. Inter-observer variability in reporting HRCTs, between practising thoracic radiologists has been assessed.54 Good agreement was found, with weighted k values quantifying the likelihood of specific diseases, moderate to good (mean 0.57, range 0.49–0.70), but cases diagnosed with low confidence, particularly when NSIP was considered as a differential diagnosis, were felt to benefit from the expertise of a reference panel.54

Physiological features Spirometry is classically restrictive in pattern, although in early IPF may be deceptively normal. Many patients have co-existing emphysema, which further complicates interpretation of spirometry

Diagnostic criteria for IPF in absence of surgical lung biopsy.7

Major criteria (all four features require to be present)  Exclusion of other known causes of interstitial lung disease, such as drug toxicities, environmental exposures, and collagen vascular diseases  Abnormal pulmonary function studies that include evidence of restriction with or without impaired gas exchange  Bibasal reticular abnormalities with minimal ground glass opacities on high resolution computed tomographic scan  Transbronchial lung biopsy or bronchoalveolar lavage showing no features to support an alternative diagnosis Minor criteria (three out of four features must be present)  Age 450 years  Insidious onset of otherwise unexplained dyspnoea on exertion  Duration of illness 3 months  Bibasal inspiratory crackles (dry or ‘‘Velcro-’’ type in quality)

ARTICLE IN PRESS Idiopathic pulmonary fibrosis alone.55 Gas transfer is more sensitive, and is typically reduced, before spirometry has become abnormal. Desaturation during exercise during a 6min walk is another important finding, and is relevant not only to grading disease severity, but also in terms of predicting prognosis, as discussed later in this review.56

Other tests Bronchoscopy with transbronchial biopsies and lavage are of limited diagnostic value, but can suggest alternative diagnoses, such as sarcoidosis, infection, malignancy or organising pneumonia.57 Blood tests are generally non-specific, although can suggest alternative diagnoses, such as sarcoidosis (angiotensin converting enzyme) and vasculitis/connective tissue disorders (strongly positive anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, extractable nuclear antigens). Serum biomarkers in interstitial lung disease, while still a research tool, may have a role as prognostic and diagnostic tools, and an excellent overview is provided elsewhere.58 For example, circulating levels of KL-6, a lung epithelium-specific protein, have been shown to predict the efficacy of corticosteroids at an earlier time point than other studied non-specific markers, when overall clinical effect may not yet be evident.59 Furthermore, KL-6 has been compared to other serum biomarkers, such as surfactant protein-A, surfactant protein-D and monocyte chemoattractant protein-1, with receiver operating characteristic curves suggesting KL-6’s superiority as a biomarker.60

Diagnostic criteria and the role of surgical lung biopsy Surgical lung biopsy is not necessary in all patients, particularly if key HRCT, clinical and physiology diagnostic criteria are present.7 (Table 1) If biopsies are required, a video-assisted thoracoscopic approach is usually sufficient.61,62 It is important that biopsies are taken from several lobes, given UIP and NSIP can co-exist in the same lung and the disease is often patchy.3,63 General and pulmonary pathologists often differ in their interpretation of the histopathology and this has clinical implications for care.64 Patients with IPF generally tolerate surgical lung biopsy well, although risk factors for those likely to do poorly include, unsurprisingly, those requiring mechanical ventilation or who are im-

1875 munosuppressed.65 There is a small (2%) risk of postoperative acute exacerbations occurring.66

Prognosis Overall, the prognosis of IPF is poor, with a median mortality typically of 3 years in several studies.67–70 The prognosis of an individual patient, however, is more difficult to define, with some patients experiencing a precipitous decline after long periods of relative stability.43 Advanced age and male gender are associated with higher mortality. Several prognostic physiological markers have been suggested, either alone or in combination.71,72 The clinically useful concept of ‘‘limited’’ (gas transfer 440%) and ‘‘advanced’’ (gas transfer o39%) disease has been suggested, with the latter group likely to do poorly, and ideally referred for transplant if otherwise a suitable candidate (Fig. 2).56 In the ‘‘limited’’ disease group, serial changes in pulmonary function appear to be predictive of prognosis, with a fall in forced vital capacity of 410% and gas transfer 415% being associated with a poorer outcome, over relatively short periods of assessment e.g. 6–12 months.56,73–77 It is interesting to note that similar observations about the utility of longitudinal pulmonary function assessment were being made as long ago as 1972 by Benson and Hughes78 in the British Journal of Diseases of the Chest. Desaturation during a 6-min walk to o88% is also another clinically useful marker of poor prognosis, and adds to the predictive ability of serial changes in physiology.79 Others have suggested that a novel measure, the ‘‘distance-saturation product’’ i.e. product of the distance walked and lowest oxygen saturation during the 6-min walk test, is slightly more accurate that either parameter alone, in predicting mortality.80 Desaturation on exercise should also prompt an echocardiogram, looking for evidence of co-existing secondary pulmonary arterial hypertension.81 This is highly relevant, given a systolic pulmonary artery pressure on cardiac echocardiogram of 450 mmHg is associated with a 1-year survival rate of 45%, compared to a pulmonary artery pressure of o50 mmHg which has a 1-year survival rate of 83%.82 The pattern of features seen on HRCT is also useful in assessing prognosis, patients with a scan typical of UIP/IPF experiencing the highest mortality.75 HRCT findings also add prognostic information to the histological diagnosis of UIP/IPF; survival is worse in patients with histological UIP if they also have a HRCT pattern felt by an expert radiologist to

ARTICLE IN PRESS 1876

O.J. Dempsey IPF confirmed7

Stratify disease severity

Gas transfer < 40% predicted

Clinical trial appropriate?

Single lung transplant appropriate?

Yes

No

Refer + “standard” therapy 7

Listed

Gas transfer > 40% predicted

Yes

Trial

No

“Standard” therapy (6 month trial) 7

≥ 3 monthly clinic review (symptoms, CXR, PFTs)

Not listed

Stop treatment or consider alternative7 Worse

Stable

Better

Continue Other general issues Smoking cessation Osteoporosis prophylaxis / bone densitometry Vaccinations (influenza, pneumococcal) Oxygen (including ambulatory assessment) Pulmonary rehabilitation Screen for depression and coexisting cardiac disease, including pulmonary hypertension Palliative care if deteriorating and no surgical / trial options

Figure 2 Simple management algorithm for IPF. Refer to text for details.

be ‘‘definite’’ or ‘‘probable’’ UIP, compared with patients with histological UIP, but an atypical HRCT pattern for UIP.75

Management This is comprehensively reviewed in current ERS/ ATS guidelines.7 A simple overview is provided in Fig. 2.56 If patients are clinically stable, with ‘‘limited’’ disease i.e. gas transfer 440% predicted, many clinicians would suggest that it is reasonable to adopt a ‘‘watch-and-wait’’ policy, assessing patients frequently over the next 6–12 months and only considering potentially toxic drug

therapy if there was evidence of clinical, radiological or physiological deterioration. If, during this initial assessment phase, patients demonstrate disease progression i.e. FVC fall 410% over 6 months and/or desaturation o88% during a 6-min walk, then referral for single lung transplant assessment should be considered, assuming otherwise medically appropriate.56,83 If patients have advanced disease i.e. gas transfer o39% predicted, they should similarly be referred for single lung transplant assessment.56,83 Ideally, all patients should be considered for participation in a placebo-controlled trial, and some current phase II/III trials are summarised in Tables 2 and 3. Treatment with combination immunosuppressant therapy (prednisolone plus

ARTICLE IN PRESS Idiopathic pulmonary fibrosis azathioprine) +/ anti-oxidant therapy i.e. N-acetylcysteine, can be considered at any stage,7 although as discussed later in this review, evidence for corticosteroid and immunosuppressant therapy is not persuasive, and patients should be aware of this.12,13 Other areas of management that should not be neglected include oxygen therapy (domiciliary and ambulatory),84,85 pulmonary rehabilitation,86 nutrition, osteoporosis prophylaxis,87,88 smoking cessation, assessment and treatment of common co-morbidities such as cardiovascular disease, psychological support for impaired quality of life 89 and ultimately palliative care. Space precludes a more detailed discussion, but key references are cited above.

Role of oral corticosteroids This is a question that has been comprehensively examined in the medical literature, and the short answer is ‘‘probably not’’.12,90 In 1944, Hamman and Rich10 described four cases of a previously unrecognised fatal pulmonary disease, characterised by increasing breathlessness, which they called ‘‘acute diffuse interstitial fibrosis’’ of the lungs. With the introduction of cortisone 4 years later, in 1948, it is perhaps not surprising that clinicians enthusiastically embraced this new therapy, given the dismal prognosis associated with the newly describe ‘‘Hamman–Rich’’ syndrome (which would now be classified as AIP). Early experience with cortisone, however, was disappointing. This is highlighted in a review article from 1959, published in the British Journal of Diseases of the Chest (a forerunner of Respiratory Medicine).91 One would have hoped and anticipated that steroid therapy would halt and reverse the interstitial fibrotic changes in the lungs which produce such a distressing illness with ultimate death from asphyxia and right heart failure, but experience has shown them to be of little value. Despite this initial pessimism, over the next few decades corticosteroids became increasingly accepted as standard therapy, with small case series and uncontrolled studies suggesting a useful subjective and objective response.90 These early studies were, in retrospect, poorly designed, and the favourable response to oral corticosteroid likely reflected inclusion of patients with more steroid responsive interstitial disease, such as NSIP. The importance of careful histological classification, and its impact on response to corticosteroid

1877 therapy, is now well recognised. In a recent Cochrane review, the efficacy of corticosteroids in adult patients with IPF was examined. Fifteen studies were potentially eligible, but were excluded because of inadequate methodologies.12 The authors concluded that that currently there is no evidence to support the routine use of corticosteroids as monotherapy in the management of IPF. It is important also to remember the considerable toxicity related to corticosteroid therapy. In a prospective study of 41 patients with previously untreated biopsy proven IPF, all patients experienced at least 1 steroid-induced effect.92 Despite this, in patients in whom a diagnosis of IPF is not certain, it is still reasonable to try an empirical trial of oral corticosteroid (+/ azathioprine) and it is sobering to note that similar views were expressed in the British Journal of Diseases of the Chest over 40 years ago!91 No other treatment apart from oxygen, digitalis, diuretics and antibiotics for superadded infections can, however, be offered and steroids must always be given a trial.

Role of immunomodulatory agents A recent Cochrane review has assessed the effect of immunomodulatory agents in the treatment of IPF.13 Fifty-nine studies were identified, published up until April 2003, but quality was generally poor, and only three randomised controlled trials were suitable for meta-analysis,70,93,94 with two lesser quality randomised controlled trials included in discussion only.95,96 The authors concluded there was little good-quality information regarding the efficacy of non-corticosteroid agents in IPF, and little justification for their routine use in the management of IPF.13

Possible future therapies Our increasing understanding of the pathogenesis of IPF has led to the development of a vast array of potential new therapies. These have been comprehensively reviewed elsewhere, space precluding a more detailed discussion here.14,45 In future, it may be that a combination of therapies, similar to the management of other chronic diseases, may be employed, such as an anti-oxidant e.g. N-acetyl cysteine, in conjunction with an anti-fibrotic agent e.g. pirfenidone. An overview of published, randomised, placebo-controlled trials in IPF is presented

n

27

27

330

107

Azathioprine Winterbauer96

Raghu et al.93

Interferon g-1b Raghu et al.97

Pirfenidone Azuma et al.98 IPF diagnosed on clinical, HRCT and histological criteria. Demonstrated desaturation o90% on exertion. Approx 20% had surgical lung biopsies

IPF diagnosed on clinical, HRCT and histological criteria. Surgical lung biopsy in approximately 60% patients

Symptomatic patients, progressive disease, previously untreated. All patients underwent lung biopsy (23 had surgical lung biopsy)

IPF, diagnostic methods not provided

Inclusion criteria

Pirfenidone (maximal dose 600mg tid) or placebo

Interferon g-1b 100 mg 3 times/week for 2 weeks, followed by 200 mg 3 times/ week) or placebo and followed for at least 48 weeks

Prednisone in high dose (1.5 mg/kg for 2 weeks, with bi-weekly taper until maintenance dose of 20 mg/day) plus azathioprine (3 mg/kg/day) or placebo Prednisone in high dose (1.5 mg/kg/day initially, tapering to 20 mg/day) plus azathioprine (3 mg/kg)or placebo

Treatments

Published randomised, double blind, placebo-controlled trials of therapy in IPF.

Clinical trials

Table 2

11 EP negative. Trend in favour of pirfenidone at 9 months. In prespecificed subset, lowest O2 saturation at 6 and 9 months better in pirfenidone group. Of other EPs, number of patients with m or stable VC and TLC was greater in pirfenidone group. Trial halted early because 5 patients (all in placebo group) experienced exacerbations

Interferon g-1b did not alter progression free survival. No other significant effects on 21 EP. Subset analysis suggested m benefit in patients with baseline FVC 462% predicted (the median value). 4% interferon group died compared with 12% of placebo treated patients, P ¼ 0:04

At 1 year, no significant difference. 6/14 (43%) in azathioprine group vs. 10/33 (77%) in placebo group died during 9-year follow up. Significant survival for combined therapy when adjusted for age

Marginal improvement with azathioprine, number of patients showing k in alveolar-arterial oxygen difference greater in azathioprine group (7/14) vs. placebo group (2/13)

Results

1878

21 EP—exacerbations, PFTs, HRCT, serum makers, QOL

11 EP—D lowest O2 saturation during 6-min steady state exercise test

Progression free survival, pulmonary function, QOL and breathlessness index

Survival, PFTs, side effects

PFTs, survival

Endpoints

ARTICLE IN PRESS O.J. Dempsey

158

Bosentan King et al. (abstract only)101 Note excluded patients with FVC o50% predicted, and clinically significant pulmonary hypertension. Approx two thirds had surgical lung biopsies

IPF diagnosed on clinical, HRCT and histological criteria. Excluded patients with severe disease (FVC o45% predicted, gas transfer o25% predicted, oxygen saturation o88% at rest)

IPF diagnosed on clinical, HRCT and histological criteria. 48% underwent surgical lung biopsies

Bosentan 62.5 mg bd or placebo

Etanercept 25 mg subcutaneous twice weekly or placebo

N-acetyl cysteine (NAC) 600 mg tid or placebo. In addition, patients all received prednisolone and azathioprine, as per ATS/ ERS guidelines7

Exercise capacity (6-min walk test), time to death or treatment failure, QOL, safety, tolerability

21 EP–Other PFTs, 6-min walk distance

11 EP—% predicted FVC and gas transfer, alveolararterial difference at 48 weeks

21 EP—PFTs, HRCT scores, breathlessness/QOL scores

11 EP—absolute D FVC and gas transfer at 12 months

11 EP negative. Trend towards delayed time to progression in bosentan group. Fewer patients with bosentan worsened. No significant difference in adverse events or mortality. Phase III study proposed (BUILD 3)

11 EPs negative, post hoc analysis suggested trend towards reduced disease progression in etanercept group

NAC supplementation slowed the deterioration in FVC and gas transfer at 12 months. Significant absolute difference in FVC change 0.18L (relative difference 9%) and gas transfer 0.75 mmol/min/kPa (relative difference 24%). No effect on mortality. Significantly lower myelotoxicity in group on NAC

CXR, chest radiograph; db, double blind; HRCT, high-resolution computerised tomography; IPF, idiopathic pulmonary fibrosis; pc, placebo controlled; NAC, N-acetyl cysteine; PFT, pulmonary function tests; r, randomized; UIP, usual interstitial pneumonia; D, change in; 11/21 EP, primary/secondary endpoint(s).

87

Etanercept Raghu et al. (abstract only)100

N-acetyl cysteine (NAC) Demedts et al.99 182

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Idiopathic pulmonary fibrosis 1879

Anti-fibrotic. Recent db,pc, mc trial, 107 Japanese patients with IPF.98 No sig change in the 11 EP (6-min walk O2 saturation at 6 months), trend favouring pirfenidone if milder disease. Some 21 EPs positive, incl. D in VC at 9 months and episodes of acute exacerbations (only occurred in placebo group, trial stopped early as a result)

Semi-synthetic derivative of tetracycline. Animal and lab data suggesting anti-angiogenesis effects.

Pirfenidone (5-methyl1-phenyl-2 (1H)pyridone)

Minocycline

Cytokine, anti-fibrotic effects. No effect on disease progression free survival in large (n ¼ 330) landmark study. Subgroup analysis suggested potential mortality benefit with interferon g-1b in patients with milder disease97

Background

r, db, pc, parallel group, safety/efficacy pilot study 48 weeks

2 trials (CAPACITY 1 and 2), r, db, pc, mc , dose ranging. Rx for 60 weeks, with further 4 week follow up

r, db, pc, mc, minimum of 2 years active drug or placebo (INSPIRE trial)

Design

18

580

600

n

Completed

Recruiting, started April 2006

Closed recruiting May 2006, expected to complete during third quarter of 2007

Status

IPF, aged 20–79. Currently on ‘‘standard therapy’’ i.e. low dose prednisone and either azathioprine/ cyclophosphamide, FVC 440% and o90%, gas transfer 420% predicted

IPF, aged 40–80, FVC X50% predicted, gas transfer X35% predicted, 6 min walk distance X150 m, with an O2 saturation X83%

IPF, aged 40–79, FVC X55% and p 90% predicted, gas transfer X35% and p90% predicted

Main inclusion criteria

Minocycline 100 mg bd

CAPACITY 1 trial 267 mg pirfenidone tid CAPACITY 2 trial 801 mg tid

Interferon g-1b 200 mg subcutaneously three times a week

Active treatments

Current and recently completed randomised, double-blind, placebo-controlled trials of therapy in IPF.

Phase III clinical trials Interferon g-1b

Drug

Table 3

11 EP—Safety, efficacy

11 EP—D in % predicted FVC at 60 weeks 21 EP—PFTs, symptoms, functional status, QOL

11 EP—Survival time from randomization 21 EP—D from baseline in PFTs, hospitalisation, QOL

Primary EP

www.clinicaltrials.gov Sponsored by University of California

Sponsored by InterMune

www.capacitytrials.com

Sponsored by InterMune

www.inspiretrial.com

Further information

ARTICLE IN PRESS

1880 O.J. Dempsey

Macrolide immunosuppressant, potent anti-proliferative effects 105–107 Orally active analogue of rapamycin, 40O-(2hydroxyethyl)— rapamycin SDX RAD, now available

PDE5 inhibitor, small study suggested preferential pulmonary vasodilatation and m gas exchange in patients with lung fibrosis and pulmonary hypertension 108

5-lipoxygenase (5-LO) inhibitor. Leukotrienes are profibrotic, patients with IPF have m levels of LTB4/ LTC4 levels, suggesting constitutive activation of 5-LO pathway109

Rapamycin (also known as sirolimus)

Sildenafil

Zileuton r, open label, active control, parallel group, safety/efficacy study 6 months

r, pc, db, crossover Single dose study, 3 weeks

r, db, pc, mc, pilot study, 48 weeks

r, db, pc, mc Treatment up to 2 years

r, db, pc, mc 12 weeks db, followed by 24 weeks open label

140

20

32

120

51

Recruiting

Recruiting

Recruiting

Completed

Completed

IPF, aged 35–80

IPF, aged X19, pulmonary hypertension (mean PAP X25 mmHg by right heart catheterization)

IPF

IPF, aged 20–79. FVC 455%, gas transfer 435%

IPF and mild-moderate pulmonary hypertension. Aged 40–80, 6 min walk distance 100–380 m, NYHA functional class II–IV

Zileuton or standard therapy

50 mg sildenafil

Prednisolone 10 mg plus rapamycin or standard therapy

Imatinib 600 mg od

Iloprost 5 mg via breath actuated device 6–9 x day

11 EP—LTB4 levels in BAL 21 EP—Progression free survival, change in dyspnoea, QOL, physiology

11 EP—6 min walk distance 21 EP—breathlessness and oxygenation

11 EP—Safety and efficacy (absence of disease progression)

11 EP—Progression of IPF (defined by 410% fall in FVC) or death 21 EP—Other PFTs, oxygenation, HRCT, QOL, mortality, symptom scores

11 EP—Safety 21 EP—6-min walk test, NYHA class change, haemodynamic parameters

Sponsored by University of Michigan

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Sponsored by National Heart, Lung and Blood Institute

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Sponsored by Novartis

www.clinicaltrials.gov

www.clinicaltrials.gov www.cotherix.com Sponsored by Cotherix

CXR, chest X-ray; HRCT, high-resolution computerised tomography; IPF, idiopathic pulmonary fibrosis; LTB4, leukotriene B4; NYHA, New York Heart Association grading; PFT, pulmonary function tests; QOL, quality of life; UIP, usual interstitial pneumonia; r, randomised; db, double blind; PAP, pulmonary artery pressure; pc, placebo controlled.

Inhibits platelet-derived growth factor (PDGF) receptor tyrosine kinase. PDGF is key growth factors in pathogenesis of pulmonary fibrosis. Imatinib in clinical use already (chronic myeloid leukaemia, GI tumours)103,104

Synthetic analogue of prostaglandin PGI2. Dilates systemic and pulmonary arterial beds. Used in treatment of pulmonary arterial hypertension102

Imatinib mesylate (phenylaminopyrimidine derivative and signal transduction inhibitor)

Phase II clinical trials Iloprost

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Idiopathic pulmonary fibrosis 1881

ARTICLE IN PRESS 1882 in Table 2, with current phase II/III trials presented in Table 3.

Conclusions These are exciting times in IPF. While much remains to be discovered, we are now beginning to unravel the pathogenesis of this deadly disease. As a result, new therapies are beginning to be developed which are being assessed in suitably powered multicentre trials. It is to be hoped that when the next Centennial Review is published in Respiratory Medicine, in 2107, its author will regard IPF as historical curiosity, and a disease that is either preventable, or at the very least, eminently treatable.

Acknowledgement Special thanks to Dr. Andrea Chapman (Consultant Pathologist) for the picture of a fibroblastic focus.

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