Background: Early appropriate diagnosis and treatment of interstitial lung diseases (ILD) is crucial to slow disease progression and improve survival. Yet it is unknown whether initial management in an expert centre is associated with improved outcomes. Therefore, we assessed mortality, hospitalisations and health care costs of ILD patients initially diagnosed and managed in specialised ILD centres versus non-specialised centres and explored differences in pharmaceutical treatment patterns.

Methods: An epidemiological claims data analysis was performed, including patients with different ILD subtypes in Germany between 2013 and 2018. Classification of specialised centres was based on the number of ILD patients managed and procedures performed, as defined by the European Network on Rare Lung Diseases. Inverse probability of treatment weighting was used to adjust for covariates. Mortality and hospitalisations were examined via weighted Cox models, cost differences by weighted gamma regression models and differences in treatment patterns with weighted logistic regressions.

Results: We compared 2022 patients managed in seven specialised ILD centres with 28,771 patients managed in 1156 non-specialised centres. Specialised ILD centre management was associated with lower mortality (HR: 0.87, 95% CI 0.78; 0.96), lower all-cause hospitalisation (HR: 0.93, 95% CI 0.87; 0.98) and higher respiratory-related costs (€669, 95% CI €219; €1156). Although risk of respiratory-related hospitalisations (HR: 1.00, 95% CI 0.92; 1.10) and overall costs (€- 872, 95% CI €- 75; €1817) did not differ significantly, differences in treatment patterns were observed.

Conclusion: Initial management in specialised ILD centres is associated with improved mortality and lower all-cause hospitalisations, potentially due to more differentiated diagnostic approaches linked with more appropriate ILD subtype-adjusted therapy.

Abstract: Childhood interstitial lung disease comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. Patients aged 6-17 years with fibrosing ILD on HRCT and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary endpoints were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. Twenty-six patients received nintedanib and 13 placebo. The geometric mean (gCV%) AUCτ,ss for nintedanib was 175 μg×h·L-1 (85.1) in patients aged 6-11 years and 160 μg×h·L-1 (82.7) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean (se) changes in FVC % predicted at week 24 were 0.3 (1.3) in the nintedanib group and -0.9 (1.8) in the placebo group. In conclusion, in children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

Background: COVID-19 pneumonia is complicated with residual lung fibrosis, as evidenced by imaging and postmortem pathological findings. In addition to steroids, we compared the efficacy of nintedanib and pirfenidone in the management of COVID-19 lung fibrosis measured by CT severity score (CTSS).

Methods: All cases of COVID-19 pneumonia diagnosed as COVID-19 positive by RT-PCR having SpO2 96% and CTSS 10 even after 15 days were included in the study. The patients were divided into three groups. All three groups received steroids at a dose of 1 mg/kg body weight of prednisolone or equivalent. The first group received steroids alone, the second group received pirfenidone with steroids and the third group received nintedanib with steroids. All patients were followed up at 6 and 12 weeks. The primary endpoint of our study was to find out any improvement in CTSS.

Results: Out of 90 patients, 56 patients completed the study. Among three groups, 19 (33.9%) patients received steroids (control) only, 16 (28.6%) patients received steroids with pirfenidone and 21 (37.5%) patients received steroids with nintedanib. The study population had a mean (±SD) age of 52.5 ± 10.1 years, mean (±SD) C-reactive protein of 97.1 ± 102.2 mg/L (normal <6 mg/L), mean (±SD) serum ferritin 459.4 ± 305.5 ng/mL (normal <250 ng/mL), mean (±SD) serum d-dimer level 2.1 ± 2.6 μg/mL (normal <0.5 μg/mL) and mean (±SD) CTSS of 16.9 ± 4.3. There was significant improvement in CTSS in group receiving nintedanib compared to pirfenidone at 12 weeks (3.67 ± 1.21 vs 9.07 ± 1.12) with a p-value <0.01.

Conclusion: Along with steroids in the treatment of COVID-19 lung fibrosis, there was a significant improvement in lung CTSS with nintedanib compared to pirfenidone.

Objective: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype.

Methods: The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs.

Results: Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively.

Conclusion: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients.

Background: Nintedanib is a tyrosine kinase inhibitor used in the treatment of progressive fibrosing interstitial lung diseases (ILDs). We assessed the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs and with other ILDs in subgroups by sex.

Methods: In this post-hoc analysis, we pooled data from the two INPULSIS trials in patients with idiopathic pulmonary fibrosis (IPF), the SENSCIS trial in patients with fibrosing ILDs associated with systemic sclerosis, and the INBUILD trial in patients with progressive fibrosing ILDs other than IPF. In each trial, patients were randomly assigned to receive oral nintedanib 150 mg twice daily or matched placebo. We assessed adverse events reported over 52 weeks in patients with autoimmune disease-related ILDs and other ILDs in subgroups by sex.

Findings: In these analyses, we included 746 patients with autoimmune disease-related ILDs (523 [70%] were female, 223 [30%] were male; 615 [82%] had systemic sclerosis), of whom 370 (50%) received nintedanib (268 [72%] female and 102 [28%] male patients) and 376 (50%) received placebo (255 [68%] female and 121 [32%] male patients); and 1554 patients with other ILDs (437 [28%] female, 1117 [72%] male; 1061 [68%] with IPF), of whom 888 (57%) received nintedanib (237 [27%] female and 651 [73%] male patients) and 666 (43%) received placebo (200 [30%] female and 466 [70%] male patients). Of 102 male and 268 female patients with autoimmune disease-related ILDs treated with nintedanib, nausea was reported in 21 (21%) male and 92 (34%) female patients, vomiting in 12 (12%) male and 73 (27%) female patients, alanine aminotransferase increase in four (4%) male and 31 (12%) female patients, aspartate aminotransferase increase in three (3%) male and 23 (9%) female patients, and adverse events leading to dose reduction in 18 (18%) male and 101 (38%) female patients; 28 (27%) male and 107 (40%) female patients had at least one treatment interruption. Of 651 male and 237 female nintedanib-treated patients with other ILDs, nausea was reported in 135 (21%) male and 95 (40%) female patients, vomiting in 51 (8%) male and 70 (30%) female patients, alanine aminotransferase increase in 19 (3%) male and 31 (13%) female patients, aspartate aminotransferase increase in 17 (3%) male and 26 (11%) female patients, and adverse events leading to dose reduction in 106 (16%) male and 84 (35%) female patients; 155 (24%) male and 82 (35%) female patients had at least one treatment interruption. The proportions of patients with adverse events leading to discontinuation of nintedanib were similar between female and male patients with autoimmune disease-related ILDs (44 [16%] of 268 vs 17 [17%] of 102), but were greater among female than male patients with other ILDs (62 [26%] of 237 vs 112 [17%] of 651). Across subgroups by diagnosis and sex, diarrhoea was the most frequent adverse event associated with nintedanib (autoimmune-related ILDs: 198 [74%] of 268 female and 73 [72%] of 102 male patients; other ILDs: 155 [65%] of 237 female and 408 [63%] of 651 male patients), and was the event that most frequently led to treatment discontinuation (autoimmune-related ILDs: 20 [7%] female and five [5%] male patients; other ILDs: 16 [7%] female and 27 [4%] male patients).

Interpretation: The adverse event profile of nintedanib was generally similar between male and female patients with autoimmune disease-related ILDs, and between male and female patients with other ILDs, but nausea, vomiting, liver enzyme elevations, dose reductions, and treatment interruptions were more frequent in female patients than in male patients. Sex should be considered in the monitoring and management of adverse events that might be associated with nintedanib.

Background: Nintedanib slows the progression of fbrosing ILDs, with a safety profile characterised predominantly by gastrointestinal events.

Objective(s): Assess the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs by sex and age.

Method(s): The SENSCIS trial was conducted in patients with ILD associated with systemic sclerosis. The INBUILD trial was conducted in patients with progressive fbrosing ILDs other than idiopathic pulmonary fbrosis. Patients were randomised to receive nintedanib 150 mg bid or placebo. Dose reductions to 100 mg bid and treatment interruptions were permitted to manage adverse events (AEs). Data from all patients in SENSCIS and patients with autoimmune disease-related ILDs in INBUILD were pooled. In subgroups based on sex and age (<65 and >=65 years) at baseline, we analysed AEs, irrespective of causality, over 52 weeks.

Result(s): Among 746 patients; 70.1% were female; 29.1% were aged >=65 years. Mean (SD) exposure to nintedanib or placebo was 10.8 (3.2) and 11.1 (2.9) months in females and males, and 11.0 (3.0) and 10.6 (3.5) months in patients aged <65 and >=65 years, respectively. The AE profile of nintedanib was similar between males and females, but nausea, vomiting, hepatic adverse events and dose reductions were more frequent in females. The AE profile of nintedanib was similar between patients aged <65 and >=65 years, but nausea, decreased appetite, and weight loss were more frequent in patients aged >=65 years. AEs leading to treatment discontinuation were more frequent in patients aged >=65 years in both treatment groups. Serious AEs were more frequent in males and in patients aged >=65 years in both treatment groups.

Conclusion(s): In patients with autoimmune-disease related ILDs, the AE profile of nintedanib in subgroups by sex and age was generally consistent with the known safety profile, but certain types of AE and dose reductions were more frequent in female patients, while serious AEs were more common in male patients.

Objective: Using data from the SENSCIS trial, these analyses were undertaken to assess the effects of nintedanib versus placebo in subgroups of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), based on characteristics previously identified as being associated with the progression of SSc-ILD.

Methods: Patients with SSc-ILD were randomized to receive either nintedanib or placebo, stratified by anti-topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (expressed in ml/year) over 52 weeks in subgroups based on baseline ATA status, modified Rodnan skin thickness score (MRSS) (<18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]).

Results: At baseline, 60.8% of 576 patients who received treatment with either nintedanib or placebo were positive for ATA, 51.9% had dcSSc, and 77.5% of 574 patients with MRSS data available had an MRSS of <18. The effect of nintedanib versus placebo on reducing the rate of decline in FVC (ml/year) was numerically more pronounced in ATA-negative patients compared to ATA-positive patients (adjusted difference in the rate of FVC decline, 57.2 ml/year [95% confidence interval (95% CI) -3.5, 118.0] versus 29.9 ml/year [95% CI -19.1, 78.8]), in patients with a baseline MRSS ≥18 compared to those with a baseline MRSS of <18 (adjusted difference in the rate of FVC decline, 88.7 ml/year [95% CI 7.7, 169.8] versus 26.4 ml/year [95% CI -16.8, 69.6]), and in patients with dcSSc compared to those with lcSSc (adjusted difference in the rate of FVC decline, 56.6 ml/year [95% CI 3.2, 110.0] versus 25.3 ml/year [95% CI -28.9, 79.6]). However, all exploratory interaction P values were nonsignificant (all P > 0.05), indicating that there was no heterogeneity in the effect of nintedanib versus placebo between these subgroups of patients.

Conclusion: In patients with SSc-ILD, reduction in the annual rate of decline in FVC among patients receiving nintedanib compared to those receiving placebo was not found to be heterogenous across subgroups based on ATA status, MRSS, or SSc subtype.

Background: In the SENSCIS trial conducted in a population of subjects with SSc-ILD with a mean time since frst non-Raynaud symptom of 3.5 years and 52% with diffuse cutaneous SSc (dcSSc), nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 44% versus placebo. Risk factors for a rapid decline in FVC in patients with SSc include early SSc, elevated infammatory markers, signifcant skin involvement, and dcSSc. Patients with SSc with these risk factors for rapid progression of ILD are typically given immunosuppressants but not nintedanib.

Objective(s): To analyse the rate of decline in FVC and the effect of nintedanib on FVC decline in subjects with risk factors for a rapid decline in FVC in the SENSCIS trial.

Method(s): In post-hoc analyses of data from the SENSCIS trial, we analysed the rate of decline in FVC (mL/year) over 52 weeks in all subjects and in those with early SSc (<18 months since frst non-Raynaud symptom), elevated infamma-tory markers (C-reactive protein >=6 mg/L and/or platelets >=330 x 109/L), or sig-nifcant skin fbrosis using two approaches (modifed Rodnan skin score [mRSS] 15-40 or mRSS >18) at baseline. We also analysed the rate of decline in FVC over 52 weeks in subjects with one of these risk factors and dcSSc.

Result(s): Of 575 subjects analysed, 79 (13.7%) had <18 months since frst non-Raynaud symptom, 210 (36.5%) had elevated infammatory markers, 172 (29.9%) had mRSS 15-40 and 118 (20.5%) had mRSS >18. Of 299 subjects with dcSSc, 29 (9.7%) had <18 months since onset of frst non-Raynaud symptom, 129 (43.1%) had elevated infammatory markers, 162 (54.2%) had mRSS 15-40 and 118 (39.5%) had mRSS >18. In the placebo group, the rate of decline in FVC over 52 weeks was numerically greater in subjects with these risk factors for rapid decline in FVC compared with all subjects (Figure 1). Across the subgroups, the rate of decline in FVC was numerically lower in subjects treated with nintedanib than placebo (Figure 1).

Conclusion(s): The SENSCIS trial included a broad range of subjects with a fbrotic ILD complicating SSc, including those with risk factors for a rapid decline in FVC. In the placebo group, subjects with these risk factors had a more rapid decline in FVC over 52 weeks compared with the overall trial population. By targeting fbro-sis with nintedanib, the rate of decline in FVC in patients with risk factors for FVC decline was reduced in patients treated with nintedanib compared with placebo.

Background: Few data are available on the progression and management of ILD, or the management of adverse events associated with drug treatment, in patients with lcSSc. SENSCIS-ON is an open-label extension trial that is collecting data on decline in forced vital capacity (FVC) and adverse events in patients treated with nintedanib over the long term.

Objective(s): To assess decline in FVC and adverse events in patients with lcSSc and ILD treated with nintedanib in SENSCIS-ON.

Method(s): Patients with SSc-ILD were eligible to enter SENSCIS-ON if they completed the randomized placebo-controlled SENSCIS trial (in which patients received trial drug until the last patient reached week 52 but for <=100 weeks) or a drug-drug interaction (DDI) study of nintedanib and oral contraceptive (in which female patients received nintedanib for <=28 days). Among patients with lcSSc, we analysed changes from baseline in FVC and adverse events over 52 weeks of SENSCIS-ON in patients who received nintedanib in SENSCIS and continued it in SENSCIS-ON ('continued nintedanib' group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for a short time in the DDI study ('initiated nintedanib' group). Analyses were descriptive.

Result(s): There were 98 patients with lcSSc in the continued nintedanib group and 127 patients with lcSSc (114 from SENSCIS, 13 from the DDI study) in the initiated nintedanib group. In these groups, respectively, mean (SD) FVC values at inclusion in SENSCIS-ON were 2449 (662) mL and 72.7(16.7) % predicted and 2508 (771) mL and 74.1 (17.4) % predicted. Mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were-45.1 (19.1) mL in the continued nintedanib group,-41.5 (24.0) mL in the initiated nintedanib group, and-43.3 (15.3) mL in all patients with lcSSc, similar to the change in FVC in patients with lcSSc at week 52 of the SENSCIS trial (-39.1 [22.2] mL). The adverse event profile of nintedanib in SENSCIS-ON was consistent with that reported over 52 weeks of the SENSCIS trial (Table 1). Over 52 weeks, adverse events led to discontinuation of nintedanib in 3.1% of patients with lcSSc who continued nintedanib in SENSCIS-ON and 16.5% who initiated nintedanib in SENSCIS-ON.

Conclusion(s): The change in FVC in patients with lcSSc and ILD who received nintedanib over 52 weeks, and the safety profile of nintedanib, in SENSCIS-ON were similar to that observed in patients with lcSSc and ILD who received nintedanib in SENSCIS. These analyses support a continued effect of nintedanib on slowing decline in FVC and the ability to manage adverse events of nintedanib in patients with lcSSc and ILD over the longer term.

Background: Interstitial lung disease (ILD) is common in systemic sclerosis (SSc) patients and despite recent advances in the treatment represents still the major cause of death. It may be established within the frst 4 years of SSc and frequently is subclinical [1]. To evaluate the presence of ILD, there are different available tools in addition to the clinical evaluation including respiratory functional tests (RFT) and imaging methods, especially HRCT which remain the mainstay for the diagnosis of SSc-ILD. It has been recently proposed that pulmonary ultrasound (US) may have a potential role for the assessment of ILD in patients with SSc [2, 3]. Despite the growing body of evidence, there are no established data regarding its potential role in both detecting ILD in subclinical stages and on the follow-up of SSc patients.

Objective(s): To investigate the validity of US in detecting subclinical ILD in SSc and to determine its potential in the follow-up of these patients.

Method(s): 133 patients without respiratory symptoms and 133 healthy controls were included. Borg scale dyspnea index, Rodnan skin score (RSS) and pulmonary auscultation were performed. X-ray and respiratory function tests (RFT) were performed the same day. An expert rheumatologist blinded to clinical assessment performed the US. To determine the concurrent validity high-resolution CT (HRCT) scans was performed. HRCT fndings were scored according to Warrick score whereas US fndings were classifed according the previously proposed scale. An inter-observer reliability was performed. A follow-up including US, RFT and Borg scale was done every 3 months for 12 months.

Result(s): A total of 54 of 133 SSc patients (40.6%) showed US signs of ILD in contrast to healthy controls (4.8%) (p=0.0001). The clinical and laboratory variables associated with ILD were anti-centromere antibodies (p=0.005) and RSS (p=0.004). A positive correlation was demonstrated between the US and HRCT fndings (p=0.001). Sensitivity and specifcity of US in detecting ILD was 91.2% and 88.6% respectively. A good inter-observer reliability was also observed (k = 0.72). In the follow-up, a total of 30 patients (22.6%) that demonstrated US signs of ILD at baseline showed US worsening. Nine patients (30%) developed symptoms of ILD.

Conclusion(s): US is valid to detect subclinical ILD-SSc. Our results showed a high prevalence of this complication. Despite encouraging data, it seems still controversial its role in monitoring the ILD progression in SSc.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality and morbidity. Approval of antifibrotic therapy has ameliorated disease progression, but therapy response is heterogeneous and to date, adequate biomarkers predicting therapy response are lacking. In recent years metabolomic technology has improved and is broadly applied in cancer research thus enabling its use in other fields. Recently both aberrant metabolic and lipidomic pathways have been described to influence profibrotic responses. We thus aimed to characterize the metabolomic and lipidomic changes between IPF and healthy volunteers (HV) and analyze metabolomic changes following treatment with nintedanib and pirfenidone. We collected serial serum samples from two IPF cohorts from Germany (n = 122) and Spain (n = 21) and additionally age-matched healthy volunteers (n = 16). Metabolomic analysis of 630 metabolites covering 14 small molecule and 12 different lipid classes was carried out using flow injection analysis tandem mass spectrometry for lipids and liquid chromatography tandem mass spectrometry for small molecules. Levels were correlated with survival and disease severity. We identified 109 deregulated analytes in IPF compared to HV in cohort 1 and 112 deregulated analytes in cohort 2. Metabolites which were up-regulated in both cohorts were mainly triglycerides while the main class of down-regulated metabolites were phosphatidylcholines. Only a minority of de-regulated analytes were small molecules. Triglyceride subclasses were inversely correlated with baseline disease severity (GAP-score) and a clinical compound endpoint of lung function decline or death. No changes in the metabolic profiles were observed following treatment with pirfenidone. Nintedanib treatment induced up-regulation of triglycerides and phosphatidylcholines. Patients in whom an increase in these metabolites was observed showed a trend towards better survival using the 2-years composite endpoint (HR 2.46, p = 0.06). In conclusion, we report major changes in metabolites in two independent cohorts testing a large number of patients. Specific lipidic metabolite signatures may serve as biomarkers for disease progression or favorable treatment response to nintedanib.