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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.

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.

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.

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).

Background Systemic sclerosis (SSc) is a rare connective tissue disease associated with rapidly evolving interstitial lung disease (ILD), driving its mortality. Specific imaging-based biomarkers associated with the evolution of lung disease are needed to help predict and quantify ILD. Methods We evaluated the potential of an automated ILD quantification system (icolung ® ) from chest CT scans, to help in quantification and prediction of ILD progression in SSc-ILD. We used a retrospective cohort of 75 SSc-ILD patients to evaluate the potential of the AI-based quantification tool and to correlate image-based quantification with pulmonary function tests and their evolution over time. Results We evaluated a group of 75 patients suffering from SSc-ILD, either limited or diffuse, of whom 30 presented progressive pulmonary fibrosis (PPF). The patients presenting PPF exhibited more extensive lesions (in % of total lung volume (TLV)) based on image analysis than those without PPF: 3.93 (0.36–8.12)* vs. 0.59 (0.09–3.53) respectively, whereas pulmonary functional test showed a reduction in Force Vital Capacity (FVC)(pred%) in patients with PPF compared to the others : 77 ± 20% vs. 87 ± 19% ( p  < 0.05). Modifications of FVC and diffusing capacity of the lungs for carbon monoxide (DLCO) over time were correlated with longitudinal radiological ILD modifications ( r =-0.40, p  < 0.01; r =-0.40, p  < 0.01 respectively). Conclusion AI-based automatic quantification of lesions from chest-CT images in SSc-ILD is correlated with physiological parameters and can help in disease evaluation. Further clinical multicentric validation is necessary in order to confirm its potential in the prediction of patient’s outcome and in treatment management.

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.

BackgroundChildhood interstitial lung disease (chILD) encompasses a group of rare heterogeneous respiratory conditions associated with significant morbidity and mortality. Reports suggest that many patients diagnosed with chILD continue to have potentially progressive or fibrosing disease into adulthood. Over the last decade, the spectrum of conditions within chILD has widened substantially, with the discovery of novel entities through advanced genetic testing. However, most evidence is often limited to small case series, with reports disseminated across an array of subspecialty, clinical and molecular journals. In particular, the frequency, management and outcome of paediatric pulmonary fibrosis is not well characterised, unlike in adults, where clear diagnosis and treatment guidelines are available.Methods and resultsThis review assesses the current understanding of pulmonary fibrosis in chILD. Based on registry data, we have provisionally estimated the occurrence of fibrosis in various manifestations of chILD, with 47 different potentially fibrotic chILD entities identified. Published evidence for fibrosis in the spectrum of chILD entities is assessed, and current and future issues in management of pulmonary fibrosis in childhood, continuing into adulthood, are considered.ConclusionsThere is a need for improved knowledge of chILD among pulmonologists to optimise the transition of care from paediatric to adult facilities. Updated evidence-based guidelines are needed that incorporate recommendations for the diagnosis and management of immune-mediated disorders, as well as chILD in older children approaching adulthood.

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).

BackgroundThe majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year.MethodOver a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly.ResultsAt the end of the observation period, median age was 6.3 years (IQR: 2.8–11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss −1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function.ConclusionThe natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.