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Treatment strategies for idiopathic interstitial pneumonias

Wells, Athol U.; Kokosi, Maria; Karagiannis, Konstantinos

Current Opinion in Pulmonary Medicine: September 2014 - Volume 20 - Issue 5 - p 442–448
doi: 10.1097/MCP.0000000000000085
INTERSTITIAL LUNG DISEASE: Edited by Francesco Bonella and Steven D. Nathan
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Purpose of review With recent changes in diagnostic algorithms in idiopathic pulmonary fibrosis (IPF) guidelines and treatment advances in IPF, it is now necessary to reappraise the way in which clinicians should formulate treatment strategies in the idiopathic interstitial pneumonias.

Recent findings The idiopathic interstitial pneumonias can usefully be subdivided into the following categories: first, definite IPF, second, probable IPF with major differential diagnoses of fibrotic nonspecific interstitial pneumonia and chronic hypersensitivity pneumonitis and third, apparently idiopathic interstitial pneumonias other than IPF. In definite IPF, the therapeutic landscape has irrevocably changed with the identification of robust treatment effects with pirfenidone and nintedanib, consisting of the prevention of approximately 50% of disease progression (as judged by serial forced vital capacity trends). In probable IPF, generally equating with high resolution computed tomography findings of ‘possible usual interstitial pneumonia’ and the nonperformance of a diagnostic surgical biopsy, management is based on multidisciplinary evaluation, integrating all available information, with a final ‘working diagnosis’ made for treatment purposes. In other idiopathic interstitial pneumonias and their major differentials, removal of potential triggers and immunomodulation remain the cornerstones of therapy, with treatment goals usefully designated using a disease behaviour classification. In mild disease, an initial policy of observation is often appropriate.

Summary The striking recent treatment effects reported in IPF will have major management implications in the idiopathic interstitial pneumonia in general, whenever IPF is in the differential diagnosis.

Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom

Correspondence to Athol U. Wells, Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney St, Fulham, London SW3 6NP, UK. Tel: +44 207 351 8327; e-mail: athol.wells@rbht.nhs.uk

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INTRODUCTION

Amongst the idiopathic interstitial pneumonias (IIPs), progressive fibrosing disorders cause the most difficulties to clinicians, especially when there is major pulmonary function impairment and a ‘track record’ of significant decline. In mild disease, it is sometimes possible to adopt a policy of careful observation with a view to intervention in the event of progression. However, in such cases, disease progression results in exactly the same treatment dilemmas as in more advanced fibrotic disorders. In this review, treatment strategies are summarized, based on the separation of predominantly IIPs into three broad categories: first, definite idiopathic pulmonary fibrosis (IPF), second, probable IPF [usually with a differential diagnosis of chronic hypersensitivity pneumonitis (CHP) or fibrotic nonspecific interstitial pneumonia (fNSIP)] and third, fibrotic disorders other than IPF [including IIPs, apparently idiopathic disease with an underlying diagnosis of occult CHP or connective tissue disease-related interstitial lung disease (CTD-ILD) and a subgroup of patients with unclassifiable disease]. Radical interventions aimed at achieving disease regression or slowing/preventing progression of irreversible disease will be covered. Because of space constraints, important nonradical interventions such as oxygen therapy and rehabilitation are not discussed.

It will be apparent from these subdivisions that the key to a logical treatment strategy is the distinction between IPF and other diseases. The importance of this dichotomy is two-fold. IPF is the most prevalent idiopathic fibrotic disease with a treated outcome that is worse than that seen in most malignant disorders and at present, despite recent advances, long-term stabilization is usually unattainable, although, based on recent studies, major reduction in the rate of progression may be within our grasp. By contrast, the complete prevention of disease progression is the primary goal in fibrotic disorders other than IPF. Equally important is the fact that in IPF, the ‘inflammatory/fibrotic’ pathogenetic model, in which inflammation precedes and leads to progression, has been discredited [1▪▪]: intensive anti-inflammatory and immunosuppressive therapy is actively damaging in IPF, essentially an ‘epithelial/fibrotic’ disorder. However, in the other progressive fibrosing disorders, an ‘inflammatory/fibrotic’ model is broadly appropriate for practical treatment purposes. In these disorders, immune dysregulation is a unifying feature and this includes IIPs, apparently idiopathic disease in which the underlying diagnosis is CTD-ILD or CHP, and those cases of unclassifiable disease in which IPF is not the underlying diagnosis. It should be understood that the ‘inflammatory/fibrotic’ model is oversimplistic. Given the overlapping disease mechanisms between IPF and a histological pattern of usual interstitial pneumonia in other settings, it is likely that IPF therapies will have beneficial treatment effects on selected non-IPF patients with a progressive fibrosis phenotype that is resistant to immunomodulation. However, until this is established by controlled studies, the accurate deployment of currently available treatments in the IIPs is dependent on the confirmation or exclusion of a diagnosis of IPF.

Box 1

Box 1

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DEFINITE IDIOPATHIC PULMONARY FIBROSIS

IPF is the most prevalent of the IIPs with an average survival of approximately 3 years from diagnosis. Worthwhile treatment effects have not emerged in a number of trials performed since the millennium. However, significant benefits, as judged by placebo-controlled reductions in the rate of decline of forced vital capacity (FVC), had been reported with N-acetyl cysteine (NAC) (given in combination with prednisolone and azathioprine) [2], nintedanib [3] and in two of three trials of pirfenidone [4,5]. Until recently, the clinical significance of these treatment effects, emerging in single trials or as conflicting data, had been viewed by some as uncertain. However, in a dramatic denouement at the 2014 American Thoracic Society meeting, new placebo-controlled treatment data were presented for all three agents, published simultaneously in the New England Journal of Medicine[6▪▪–8▪▪], with strikingly positive outcomes for both pirfenidone and nintedanib therapy [6▪▪,7▪▪]. It seems likely that the specialty of interstitial lung disease will never again be the same.

In the phase III ASCEND trial of pirfenidone [6▪▪], the primary analysis, a nonparametric comparison of FVC trends was unequivocally positive in favour of active treatment (P < 0.00001). The amplitude of the benefit across all time points amounted to a relative reduction in disease progression of approximately 50%, whether evaluated as ‘progression-free survival’, the prevalence of a ‘significant’ decline in FVC (an absolute reduction of 10% of predicted normal) or the rate of FVC decline (evaluated both as change from the first to the last reading and as a linear slope analysis integrating all serial FVC data). Significant benefits with active treatment were seen with progression-free survival (P < 0.001) and the 6-min walk distance (P = 0.04). Individual studies were not powered to detect a significant mortality benefit. However, with prespecified pooling of data from the two CAPACITY studies and the ASCEND study at 52 weeks, a significant benefit with active treatment was observed for all cause mortality (P = 0.01). Treatment effects on serial changes in dyspnoea were not statistically significant.

In the two phase III INPULSIS trials of nintedanib [7▪▪], the treatment effects on FVC were remarkably similar to that in the ASCEND study with, in pooled data, an active treatment benefit of approximately 50% on the rate of decline in FVC, quantified using linear slope analysis, without imputation for missing data (the primary end-point) (P < 0.0001). The statistical significance and amplitude of this finding were robust with the use of three different data imputation models. There was a significant reduction in investigator-reported acute exacerbations (P = 0.005) in one of the two studies, and a significant reduction in adjudicated acute exacerbations (P = 0.001), with prespecified pooling of data. Quality of life improvements in the active-treatment arm were seen in one study.

Both agents were reasonably well tolerated. In the ASCEND study, a handful of patients chose to withdraw because of gastrointestinal side-effects or rashes, supporting recent anecdotal clinical experience that with anticipation of side-effects longer-term continuation of pirfenidone is tolerated by a large majority of patients. Discontinuation of treatment was more frequent in the nintedanib studies, mainly because of diarrhoea, but differed by only approximately 5% on average between the active-treatment and placebo arms.

Taken together, it would appear that clinicians will shortly have access to two therapies which are generally well tolerated and have now been shown to halve the rate of progression in IPF during the first year of treatment. It can now be seriously questioned whether it is ethical, any longer, to perform placebo-controlled trials in IPF. On the basis of precedents in the field of oncology, it can also be argued that the amplitude of the observed treatment benefits justifies the view that we now have a ‘best current treatment’ ethos in IPF. Regarding treatment strategies, the recent trials, taken together with earlier data, amply justify the immediate introduction of pirfenidone or nintedanib in those patients with a multidisciplinary diagnosis of IPF, with disease severity lying within the range of that included in these seminal trials. Important ongoing questions include the efficacy of both agents in severe disease and in non-IPF patients with pulmonary fibrosis that is progressive despite standard current therapies. It is not yet known whether efficacy is maintained after the first year of therapy. In the more distant future, there may be difficult decisions to make on whether to use these agents sequentially, in combination or in discrete patient subgroups using a personalized medicine algorithm, based, it might be hoped, on biomarker signal [9].

By contrast, outcomes in a placebo-controlled trial of NAC monotherapy were disappointing. Following encouraging initial findings reported in the IFIGENIA trial, the United States of America's IPF clinical research network has now reported negative placebo-controlled studies for triple therapy (prednisolone, azathioprine and NAC) [10] and NAC monotherapy [8▪▪]. Although both studies can be criticized on a number of grounds (not reviewed here because of space constraints), the negative outcomes stand in stark contrast to the efficacy of pirfenidone and nintedanib.

Given the excitement generated by recent studies, it is easy to overlook the potential importance of treating gastroesophageal reflux (GER) in IPF. There are currently no controlled data establishing the efficacy of anti-GER treatment in slowing disease progression. However, in a recent meta-analysis of the placebo arms of three United States of America's IPF-net studies, it was observed that patients receiving antiacid therapy were characterized by a significantly slower decline in FVC [11▪]. Given the high prevalence of GER in IPF, including reflux to the proximal esophagus which is often asymptomatic [12], there is an urgent need for controlled data to establish whether antireflux treatment slows disease progression. In the meantime, it is reasonable to adopt a strategy of rigorous medical treatment of IPF patients with symptoms of GER.

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PROBABLE IDIOPATHIC PULMONARY FIBROSIS

Patients with probable IPF and a differential diagnosis of fNSIP or CHP pose the greatest current management dilemma for ILD specialists. In this patient subgroup, there is no history of connective tissue disease, significant environmental exposures relevant to CHP or other factors associated with the development of pulmonary fibrosis. High resolution computed tomography (HRCT) abnormalities are not typical of IPF but are those designated as ‘possible’ usual interstitial pneumonia (UIP): predominantly subpleural and basal reticulation with no honeycomb change, little or no ground-glass attenuation and no other HRCT features incompatible with IPF [13]. For one reason or another, a diagnostic surgical biopsy is not possible in these cases. In the 2011 international guideline for the diagnosis and management of IPF, this frequent problem was not defined or addressed and these patients, who do not meet diagnostic criteria for IPF, must therefore be viewed as having unclassifiable disease with differential diagnoses that include IPF, fNSIP and CHP (without an overt antigen).

The high prevalence of an HRCT pattern of ‘possible’ UIP in biopsy-proven IPF was recently highlighted in a pharmaceutical cohort [14▪]. In a single retrospective study of over 130 patients with this HRCT appearance, performed at a single centre, it was reported that in patients over the age of 65 years with at least moderately extensive reticular abnormalities (i.e., involving three or more lobes), the likelihood of an underlying UIP pattern at biopsy exceeded 95% [15]. It should, however, be stressed that CHP may have been under-represented in this study. Indeed, based on recent data, CHP may be significantly underdiagnosed, even when HRCT appearances are typical of UIP [16▪].

In this difficult scenario, clinicians face a choice between making a ‘working’ multidisciplinary diagnosis of IPF for treatment purposes (with a view to instituting IPF-specific therapy) and treating empirically with immunomodulatory therapy as for fNSIP or CHP, on the grounds that a bad longer-term outcome is likely if either disorder is present and left untreated. No published data currently exist to guide clinicians in making this difficult choice. However, it is clearly important that all available clinical data that might influence the likelihood of a diagnosis other than IPF be considered at a multidisciplinary meeting, including bronchoalveolar lavage findings, features that are suggestive but not diagnostic of an underlying connective tissue disease and observed disease behaviour to that point, with or without therapy. In the absence of a validated management algorithm, the authors share the widely held empirical view that in patients aged over 65 years, with an HRCT picture of possible UIP and no clinical features suggestive of an alternative diagnosis (i.e., absence of a bronchoalveolar lavage lymphocytosis, features suggestive of connective tissue disease or a pattern of disease behaviour that is atypical for IPF), it is reasonable to make a working diagnosis of IPF and manage accordingly. In other cases, in which IPF is considered to be less probable (although often the most likely diagnosis), the introduction of immunomodulatory therapy is appropriate with the intention that if progression occurs despite this approach, the diagnosis of IPF might then be made on review at a multidisciplinary meeting, with a corresponding change in therapy. Further studies are urgently required in order to confirm that underlying UIP is almost always present in apparently idiopathic disease with an HRCT appearance of ‘possible’ UIP and to validate the management strategies detailed above.

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OTHER IDIOPATHIC INTERSTITIAL PNEUMONIAS AND DIFFERENTIAL DIAGNOSES

In general, these disorders can be conceptualized using the historical ‘inflammation/ fibrosis’ pathogenetic model, in which inflammation precedes and leads to fibrosis. The most prevalent apparently idiopathic disorders included in this broad category are idiopathic fNSIP, CHP without an identifiable antigen, ILD in association with possible connective tissue disease and patients with unclassifiable disease, in whom the underlying diagnosis is not IPF. It should be stressed that there is a paucity of controlled treatment data to guide management of these disorders, with the only current placebo-controlled trials conducted in lung disease associated with systemic sclerosis [17,18]. In view of the absence of a definitive evidence base, management strategies can usefully be built around a recently proposed ‘disease behaviour classification[19▪], developed in the first place to provide a logical framework for the management of unclassifiable disease (see Table 1). In essence, treatment decisions are informed by the designation of disease into one of five categories, based on severity, cause (if present), the predominance of reversible or irreversible disease (as judged by HRCT or biopsy appearances) and the integration of information on observed disease behaviour.

Table 1

Table 1

Broad management strategies across non-IPF ILDs can be subdivided into the following:

  1. Removal of all possible triggers of disease progression. It is not uncommon to identify potential triggers of questionable significance in apparently idiopathic disease, including drug exposures, symptoms of reflux, equivocal environmental exposures that have potential relevance to CHP and smoking (which may potentiate disease progression in pulmonary fibrotic disorders). Taking measures to remove all possible triggers from the clinical equation (e.g., exposure avoidance, drug cessation, smoking cessation and medical treatment of GER) may hold the key to ensuring that disease is self-limited.
  2. Careful observation without immediate intervention. The staging of ILD is in its infancy. Categorizing ILD in systemic sclerosis as ‘mild’ or ‘severe’ was found to have major prognostic implications [20], confirmed in a recent Australian study [21], but if this system is to be used to justify nonintervention in mild disease, meticulous monitoring is necessary with a view to early intervention in the event of disease progression. No comparable dichotomous staging model has been developed in idiopathic disease. However, it has recently been shown that the three-stage GAP system (gender, age and two lung physiology variables), initially developed in IPF [22], provides very similar prognostic separations in CHP, ILD in connective tissue disease and unclassifiable disease [23▪]. This system may be useful in justifying an initial policy of observation in ILD in general, and in IIPs in particular, but this hypothesis plainly needs to be explored further in clinical studies.
  3. Traditional immunomodulatory therapies. As discussed earlier, fibrosing ILDs other than IPF have largely been managed using a model of immune dysregulation, with corticosteroid monotherapy often used in mild disease and combination therapy with low-dose corticosteroids and immunosuppressive agents (such as cyclophosphamide, azathioprine, methotrexate and mycophenolate mofetil) deployed in more severe or progressive disease. Following initial multidisciplinary evaluation, the degree of likely reversibility is often uncertain. To provide clarity on whether all possible treatment effects have been achieved, initial high-dose corticosteroid therapy (0.75–1 mg/kg/day) is generally preferable in the presence of suspected major inflammation. Fulminant disease may require high-dose intravenous methylprednisolone (750–1000 mg/day for 3 days). Steroid responsiveness should be evaluated at 4–6 weeks with tapering over the next months to the lower possible dose (preferably prednisolone 10 mg daily or less) in order to maintain the initial response. In a large recent retrospective series of patients with CTD-ILD, mycophenolate mofetil therapy was associated with stabilization of disease for at least 2 years in most cases [24], a finding that it is reasonable to extrapolate to patients with progressive IIP and suspected underlying connective tissue disease. It should again be stressed that these recommendations are drawn from accumulated clinical experience and, with the exception of cyclophosphamide in scleroderma-associated ILD, have not been validated by controlled treatment data.
  4. Novel forms of immunomodulation. The single most promising novel immunomodulatory agent is rituximab, but it is currently uncertain whether this agent will provide additional treatment benefits in the IIPs. Following the publication of promising open pilot data in patients with interstitial lung disease associated with polymyositis or dermatomyositis [25] or systemic sclerosis [26], rituximab was reported to be an effective rescue therapy in a handful of patients with life-threatening CTD-ILD which had continued to progress despite intense corticosteroid and immunosuppressive therapy [27]. In a retrospective report of 50 individuals with non-IPF ILD (including a majority with CTD-ILD, but also patients with desquamative interstitial pneumonia, idiopathic fNSIP or IIP with possible associated connective tissue disease), characterized by severe functional impairment and ongoing progression despite aggressive conventional therapy, rituximab therapy was associated with a median improvement in FVC of 6.7% and stabilization of carbon monoxide diffusing capacity over the next 6–12 months [28].
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CONCLUSION

Treatment data just released in IPF, including placebo-controlled trials of pirfenidone and nintedanib, have transformed the therapeutic landscape in apparently idiopathic lung disease. Never before has the accuracy of the diagnosis of IPF been more important. Key future research includes the efficacy of these agents in more severe IPF than currently studied and in progressive fibrosing disorders other than IPF, and the duration of treatment benefits beyond 1 year. These data have increased the dilemmas faced by clinicians in achieving best management when the diagnosis of IPF is probable but not definite. In other IIPs and in apparently idiopathic CHP and occult CTD-ILD, the removal of triggers and use of immunomodulation remain the cornerstones of management. Rituximab has produced promising results in CTD-ILD and is the novel immunomodulatory agent that may be most relevant to progressive IIPs other than IPF, given their current conceptualization as forms of immune dysregulation.

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Acknowledgements

This project was supported by the National Institute of Health Research Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, United Kingdom.

Disclosures: A.U.W. has received consultancy fees related to study design and advisory board activity from Actleion, Almirali, Boehringer Ingelheim, Centocor, Genentech, Gilead, Intermune, Medimmune, Novartis and Takeda. M.K. and K.K. have no disclosures.

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Conflicts of interest

None declared.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1▪▪. Selman M, King TE Jr, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134:136–151.

Outstanding review article, outlining a major shift in the perception of pathogenetic mechanisms in IPF, which is increasingly viewed as an ‘epithelial fibrotic’ disease, rather than an inflammatory disorder. Elegant outline of future therapeutic implications.

2. Demedts M, Behr J, Buhl R, et al. IFIGENIA Study GroupHigh-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353:2229–2242.
3. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365:1079–1087.
4. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone Clinical Study Group in JapanPirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35:821–829.
5. Noble PW, Albera C, Bradford WZ, et al. CAPACITY Study GroupPirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377:1760–1769.
6▪▪. King TE Jr, Bradford WZ, Castro-Bernadini S, et al. ASCEND Study GroupA phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:2083–2092.

Seminal trial in which active treatment was associated with a 50% reduction in disease progression. The study finally establishes that treatment benefits with pirfenidone are clinically important and, along with the nintedanib study below, may spell the end of placebo-controlled trials in IPF.

7▪▪. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:2071–2082.

Report of two seminal phase III placebo-controlled trials of nintedanib, a triple kinase inhibitor. Active treatment was associated with a 50% reduction in disease progression: the amplitude of the treatment benefit was virtually identical to that seen in the pirfenidone study above.

8▪▪. Martinez FJ, de Andrade JA, Anstrom KJ, et al. The Idiopathic Pulmonary Fibrosis Clinical Research NetworkRandomised trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:2093–2101.

Placebo-controlled trial of antioxidant monotherapy in IPF. The study was negative overall, although there is ongoing discussion about recruitment issues following early abandonment of a ‘triple therapy’ arm. However, even if this problem resulted in an understatement of beneficial trends with active treatment, the results of this study stand in stark contrast to the nintedanib and pirfenidone studies above.

9. Loomis-King H, Flaherty KR, Moore BB. Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis. Curr Opin Pharmacol 2013; 13:377–385.
10. Raghu G, Anstrom KJ, King TE Jr, et al. The Idiopathic Pulmonary Fibrosis Clinical Research NetworkPrednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366:1968–1977.
11▪. Lee JS, Collard HR, Anstrom K, et al. IPFnet InvestigatorsAnti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data in three randomised controlled trials. Lancet Respir Med 2013; 1:369–376.

Meta-analysis of the placebo arms of three trials, in which disease progression was evaluated against treatment with antiacid therapy. Progression, as judged by decline in FVC, was significantly less in patients receiving antiacid treatment, a finding which, it can be hoped, will lead to future controlled trials.

12. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27:136–142.
13. Raghu G, Collard HR, Egan JJ, et al. ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary FibrosisAn official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183:788–824.
14▪. Raghu G, Lynch D, Godwin JD, et al. Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial. Lancet Respir Med 2014; 2:277–284.

In this IPF pharmaceutical cohort, associations between HRCT appearances of ‘possible UIP’ and an underlying histological pattern of UIP are described. However, these findings cannot be extrapolated to routine practice. In this cohort, patients were excluded if local pathologists diagnosed disorders other than IPF on biopsy. The study provides no major insights into the predictive value of ‘possible UIP’ on HRCT for underlying UIP at biopsy in a general ILD population.

15. Fell CD, Martinez FJ, Liu LX, et al. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2010; 181:832–837.
16▪. Morell F, Villar A, Montero MA, et al. Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir Med 2013; 1:685–694.

In a cohort of patients with definite IPF, as judged by current guideline criteria, a high prevalence of previously undiagnosed CHP was identified. Although the diagnostic criteria for CHP in this study can be questioned, the findings underline the importance of a definitive exposure history in patients with an apparently obvious diagnosis of IPF.

17. Tashkin DP, Elashoff R, Clements PJ, et al. Scleroderma Lung Study Research GroupCyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354:2655–2666.
18. Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006; 54:3962–3970.
19▪. Travis WD, Costabel U, Hansell DM, et al. ATS/ERS Committee on idiopathic interstitial pneumoniasAn official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188:733–748.

Included in the updated classification of the IIPs is a clinical disease behaviour classification, developed in order to provide pragmatic management guidance for clinicians, when the diagnosis is uncertain or disease is unclassifiable and there is not a definitive evidence base on which to base treatment decisions.

20. Goh NS, Desai SR, Veerarhagavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med 2008; 177:1248–1254.
21. Moore OA, Goh N, Corte T, et al. Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology (Oxford) 2013; 52:155–160.
22. Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 2012; 156:684–691.
23▪. Ryerson CJ, Vittinghoff E, Ley B, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest 2013; 145:723–728.

The applicability of the GAP staging model to ILDs other than IPF is evaluated in this study. The model provided remarkably similar prognostic distinctions in IPF, CTD-ILD. Idiopathic nonspecific interstitial pneumonia, CHP and unclassifiable disease. The findings provide support for the concept of a staging system that is applicable across fibrotic LDL.

24. Fischer A, Brown KK, du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol 2013; 40:640–646.
25. Sem M, Molberg O, Lund MB, Gran JT. Rituximab treatment of the anti-synthetase syndrome: a retrospective case series. Rheumatology (Oxford) 2009; 48:968–971.
26. Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford) 2010; 49:271–280.
27. Keir GJ, Maher TM, Hansell DM, et al. Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy. Eur Respir J 2012; 40:641–648.
28. Keir GJ, Maher TM, Ming D, et al. Rituximab in severe refractory interstitial lung disease. Respirology 2014; 19:353–359.
Keywords:

disease behaviour classification; idiopathic pulmonary fibrosis; nintedanib; pirfenidone

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