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Abstract Background In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical “gold standard” of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs. Purpose The objective of this statement is to update the 2002 ATS/ERS classification of IIPs. Methods An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011. Results Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis–interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous. Acute exacerbation of IIPs is now well defined. A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury. A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course. A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced. The rapidly evolving field of molecular markers is reviewed with the intent of promoting additional investigations that may help in determining diagnosis, and potentially prognosis and treatment. Conclusions This update is a supplement to the previous 2002 IIP classification document. It outlines advances in the past decade and potential areas for future investigation.

Patients with interstitial lung disease associated with systemic sclerosis were treated with usual care plus placebo or nintedanib. The annual rate of change in forced vital capacity assessed over a 52-week period was −52.4 ml per year with nintedanib and −93.3 ml per year with placebo. There were no differences in other measures of systemic sclerosis.

ObjectiveTo assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II.MethodsSLS I randomised 158 patients with SSc-ILD to 1  year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling.ResultsAfter a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data.ConclusionIn addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

BackgroundUncertainty exists regarding the clinical relevance of exercise training across the range of interstitial lung diseases (ILDs).ObjectiveTo establish the impact of exercise training in patients with ILDs of differing aetiology and severity.Methods142 participants with ILD (61 idiopathic pulmonary fibrosis (IPF), 22 asbestosis, 23 connective tissue disease-related ILD (CTD-ILD) and 36 with other aetiologies) were randomised to either 8 weeks of supervised exercise training or usual care. Six-minute walk distance (6MWD), Chronic Respiratory Disease Questionnaire (CRDQ), St George Respiratory Questionnaire IPF-specific version (SGRQ-I) and modified Medical Research Council dyspnoea score were measured at baseline, 9 weeks and 6 months.Measurements and main resultsExercise training significantly increased 6MWD (25 m, 95% CI 2 to 47 m) and health-related quality of life (CRDQ and SGRQ-I) in people with ILD. Larger improvements in 6MWD, CRDQ, SGRQ-I and dyspnoea occurred in asbestosis and IPF compared with CTD-ILD, but with few significant differences between subgroups. Benefits declined at 6 months except in CTD-ILD. Lower baseline 6MWD and worse baseline symptoms were associated with greater benefit in 6MWD and symptoms following training. Greater gains were seen in those whose exercise prescription was successfully progressed according to the protocol. At 6 months, sustained improvements in 6MWD and symptoms were associated with better baseline lung function and less pulmonary hypertension.ConclusionsExercise training is effective in patients across the range of ILDs, with clinically meaningful benefits in asbestosis and IPF. Successful exercise progression maximises improvements and sustained treatment effects favour those with milder disease.Trial registration numberResults, ACTRN12611000416998.

Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. In this study, we aimed to describe the baseline severity and evolution of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) in patients with SSc-ILD and to assess the baseline clinical, biological and high-resolution CT scan (HRCT) predictors of this evolution. Baseline and serial FVC and DLCO were collected in 75 SSc-ILD patients followed during 6.4±4.2 years (n = 557 individual data). FVC and DLCO evolution was modelled using a linear mixed model with random effect. During follow-up, FVC was stable while DLCO significantly decreased (-1.5±0.3%/year (p<0.0001). Baseline NYHA functional class III/IV, extensive SSc-ILD on HRCT and DLCO<80% were associated with a lower baseline FVC. Absence of digital ulcers extensive SSc-ILD, and FVC<80% and were associated with a lower baseline DLCO. Presence or history of digital ulcers and presence of pulmonary hypertension at baseline or during follow-up were associated with a faster decline of DLCO overtime. Neither age, gender, subtype of SSc nor specificity of autoantibodies were associated with baseline severity or outcome of lung function tests. In this SSc-ILD population, FVC was therefore stable while DLCO significantly declined over time. ILD extension was associated with baseline FVC and DLCO but not with their evolution. Presence or history of digital ulcers and pulmonary hypertension were predictors of a faster decline of DLCO over time.

To investigate the clinical features, risk factors and outcomes of patients with interstitial pneumonia with autoimmune features (IPAF). A total of 1429 patients with idiopathic interstitial pneumonia (IIP) and undifferentiated connective tissue disease-associated interstitial lung disease (UCTD-ILD) were screened to identify patients who met IPAF criteria. Clinical, serological, and morphological features of patients with IPAF were characterized. Outcomes between patients with IPAF, UCTD-ILD, and IIP who were divided into idiopathic pulmonary fibrosis (IPF) and non-IPF groups were compared using survival as an endpoint. Patients with IPAF were much common in young female and had lower percentage of ever smoking and a significantly shorter survival than those with non-IPAF (P < 0.001). Subgroup analysis revealed that IPAF cohort survival was worse than that in non-IPF (P < 0.001), but better than that in IPF (P < 0.001). In IPAF cohort, the most common systemic symptom and serological abnormality were Raynaud’s phenomenon (12.9%) and ANA ≥ 1:320 (49.2%); the most frequent high-resolution computed tomography (HRCT) pattern was nonspecific interstitial pneumonia (NSIP) (61.6%). Multivariate analysis indicated that several factors including age, smoking history, organizing pneumonia (OP) pattern in HRCT, and anti-RNP positivity were independently associated with significantly worse survival. IPAF had the distinct clinical features and outcomes compared with other groups of ILD. Additional studies should be needed to explore the underlying autoimmune mechanism and to determine risk stratification in future clinical research.

Background Few data are available on the long-term effect of pulmonary rehabilitation (PR) and on long PR programs in interstitial lung diseases (ILD). We aimed to evaluate the effects of PR on exercise capacity (6-Minute Walking Distance, 6MWD; Peak Work Rate, W max ), quality of life (St George’s Respiratory Questionnaire, SGRQ), quadriceps force (QF) and objectively measured physical activity in ILD after the 6-month PR-program and after 1 year. Methods 60 patients (64 ± 11 years; 62% males; 23% with IPF) were randomly assigned to receive a 6 month-PR program or usual medical care. Results Exercise capacity, quality of life and muscle force increased significantly after the program as compared to control (mean,95%CI[ll to ul]; 6MWD + 72,[36 to 108] m; W max 19, [8 to 29]%pred; SGRQ − 12,[− 19 to − 6] points; QF 10, [1 to 18] %pred). The gain was sustained after 1 year (6MWD 73,[28 to 118] m; Wmax 23, [10 to 35]%pred; SGRQ − 11,[− 18 to − 4] points; QF 9.5, [1 to 18] %pred). Physical activity did not change. Conclusions PR improves exercise tolerance, health status and muscle force in ILD. The benefits are maintained at 1-year follow-up. The intervention did not change physical activity. Trial registration Clinicaltrials.gov NCT00882817 .

Background The forced vital capacity (FVC) is the most commonly used endpoint in registrational trials for systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, the FVC has known methodological pitfalls, is affected by extra-pulmonary SSc manifestations and may not be clinically meaningful to patients. Combining individual outcomes into a composite endpoint is an attractive alternative for measuring treatment response and augmenting statistical efficiency in SSc-ILD trials. Methods We previously developed a composite endpoint for SSc-ILD using data from the Scleroderma Lung Study (SLS) I (comparing cyclophosphamide versus placebo for SSc-ILD), which included physiological (FVC), radiological (quantitative extent of fibrosis in the zone of maximum involvement) and patient-reported outcomes (transitional dyspnea index and health assessment disability questionnaire), which demonstrated a more robust treatment effect of cyclophosphamide than the FVC alone. The purpose of this post-hoc analysis was to validate this composite endpoint in an external clinical trial cohort (SLS II [cyclophosphamide versus mycophenolate for SSc-ILD). A secondary goal was to determine whether the composite endpoint predicted long-term mortality in SLS I and II. Results Seventy-two of the 142 randomized participants in SLS II had all composite endpoint components at 24 months and were included in this analysis. In both SLS I and II, the standardized effect size (Cohen’s d) was greater when the composite endpoint model was applied than when the FVC alone model was applied. In SLS I and II, the composite endpoint was a better predictor of long-term survival (HR 0.76 vs. 0.98 and 0.59 vs. 0.98, for the composite index vs. FVC Cox proportional hazards models in SLS I and II, respectively). Patients with high composite outcomes scores in both SLS I and II had significantly worse long-term survival than patients with low scores ( p  = 0.039 for log-rank test). Conclusion The results of this post-hoc analysis provide further evidence that a composite endpoint comprised of physiological, radiological and patient-reported outcomes is a promising endpoint for SSc-ILD trials. Future validation studies are needed. Trial registration SLS II: NCT00883129 (Date of registration April 17, 2009); SLS I: NCT00004563 (Date of registration: February 10, 2000).

The efficacy and safety of mycophenolate mofetil (MMF) has been studied in patients with systemic sclerosis (SSc)-related interstitial lung disease (ILD) with moderate–severe impairment. There is no study on its use in patients with mildly impaired lung function. The objective of this study is to determine the efficacy and safety of MMF for treating mild SSc-ILD (forced vital capacity (FVC) ≥ 70% predicted). This was a double-blind, randomized, placebo-controlled pilot trial. The subjects with SSc-ILD with FVC ≥ 70% were randomized to receive either MMF (2 g/day) or placebo for 6 months. FVC, diffusing capacity of lungs for carbon monoxide (DLCO), modified Rodnan skin score (mRSS), Short Form-36 (SF36v2), Mahler’s Dyspnoea Index (MDI), and 6-min walk distance (6MWD) were recorded at baseline and at 6 months. Forty-one subjects were included in the study (MMF: 20, placebo: 21). FVC decreased by a median of 2.7% (range − 21 to 9) in MMF arm and increased by 1% (range − 6 to 10) in placebo arm (p = 0.131). SF36v2 scores improved in both the groups. Median change in MDI (3 vs 3), DLCO (1% vs 1.5%), and 6MWD (0 m vs 0 m) was similar between the study groups. MMF was effective in improving mRSS (− 5 vs − 1, p = 0.045) compared to placebo. Adverse events occurred with similar frequency in both the study groups. In this pilot study, MMF did not result in significant improvement in lung function in SSc-ILD with minimally impaired lung function, but was effective in reducing the skin tightness. Larger studies are needed to confirm these findings. This study was registered at ClinicalTrials.gov (NCT02896205).

Background Interstitial lung disease (ILD) frequently complicates systemic autoimmune disorders resulting in considerable morbidity and mortality. The connective tissue diseases (CTDs) most frequently resulting in ILD include: systemic sclerosis, idiopathic inflammatory myositis (including dermatomyositis, polymyositis and anti-synthetase syndrome) and mixed connective tissue disease. Despite the development, over the last two decades, of a range of biological therapies which have resulted in significant improvements in the treatment of the systemic manifestations of CTD, the management of CTD-associated ILD has changed little. At present there are no approved therapies for CTD-ILD. Following trials in scleroderma-ILD, cyclophosphamide is the accepted standard of care for individuals with severe or progressive CTD-related ILD. Observational studies have suggested that the anti-CD20 monoclonal antibody, rituximab, is an effective rescue therapy in the treatment of refractory CTD-ILD. However, before now, there have been no randomised controlled trials assessing the efficacy of rituximab in this treatment population. Methods/design RECITAL is a UK, multicentre, prospective, randomised, double-blind, double-dummy, controlled trial funded by the Efficacy and Mechanism Evaluation Programme of the Medical Research Council and National Institute for Health Research. The trial will compare rituximab 1 g given intravenously, twice at an interval of 2 weeks, with intravenously administered cyclophosphamide given monthly at a dose of 600 mg/m 2 body surface area in individuals with ILD due to systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) or mixed connective tissue disease. A total of 116 individuals will be randomised 1:1 to each of the two treatment arms, with stratification based on underlying CTD, and will be followed for a total of 48 weeks from first dose. The primary endpoint for the study will be change in forced vital capacity (FVC) at 24 weeks. Key secondary endpoints include: safety, change in FVC at 48 weeks as well as survival, change in oxygen requirements, total 48-week corticosteroid exposure and utilisation of health care resources. Discussion This is the first randomised control trial to study the efficacy of rituximab as first-line treatment in CTD-associated ILD. The results generated should provide important information on the treatment of a life-threatening complication affecting a rare group of CTDs. Trial registration ClinicalTrials.gov, NCT01862926. Registered on 22 May 2013.