Improved Survival of IPF patients Treated With Antifibrotic Drugs Compared With Untreated Patients.

PURPOSE: Pirfenidone and nintedanib unequivocally inhibit FVC decline, but have been inconsistently linked to reduced mortality in phase III studies. On the contrary, real-world data show a survival benefit of antifibrotic drugs. However, it is unknown what this benefit is across different Gender, Age, and Physiology (GAP) stages. RESEARCH QUESTIONS: Is there a difference in transplant-free (TPF) survival of IPF patients receiving antifibrotic drugs (IPFAF) compared with an untreated cohort (IPFnon-AF)? Is this different for patients with GAP stage I, II, or III. METHODS: This is a single-center observational cohort study using prospectively included patients diagnosed with IPF between 2008-2018. Primary outcomes were TPF survival difference and 1-, 2-, and 3-year cumulative mortality for IPFAF and IPFnon-AF. This was repeated after stratification for GAP stage. RESULTS: In total, 457 patients were included. The median transplant-free survival was 3.4 years in IPFAF (n = 313) and 2.2 years in IPFnon-AF (n = 144, p = 0.005). For GAP stage II, a median survival of 3.1 and 1.7 years was noted for IPFAF (n = 143) and IPFnon-AF (n = 59, p < 0.001), respectively. A significantly lower 1-, 2-, and 3- year cumulative mortality was found for IPFAF with GAP stage II (1 yr: 7.0% vs 35.6%, 2 yr: 26.6% vs 55.9%, and 3 yr: 46.9% vs 69.5%). The 1-year cumulative mortality of IPFAF with GAP III was also significantly lower (19.0% vs 65.0%). CONCLUSION: This large real-world study showed a survival benefit in IPFAF compared with IPFnon-AF. This especially holds true for patients with GAP stage II and III.

Decreased Survival and Lung Function in Progressive Pulmonary Fibrosis.

Background and Objectives: Progressive pulmonary fibrosis (PPF) is a recently described term reserved for patients with fibrotic ILD other than idiopathic pulmonary fibrosis (IPF) with fast clinical deterioration. Here, survival and prognostic biomarkers at the time of diagnosis for PPF are investigated in a fibrotic ILD other than IPF cohort (non-IPF). Materials and Methods: Patients diagnosed during the period of 2012-2018 at the ILD Center of Excellence (St. Antonius Hospital, Nieuwegein, The Netherlands) with a fibrotic ILD were included in this study. The presence of PPF was investigated using the criteria from the updated IPF/PPF guideline during the first year after diagnosis. Logistic regression analysis was used to determine risk factors for PPF. A Kaplan-Meier survival analysis with log-rank test was conducted to analyze survival in patients with and without PPF. Results: This study included 304 non-IPF patients and, for comparison, 379 IPF patients. In non-IPF patients, 146 (46%) fulfilled ≥2 criteria for PPF. These patients had a median transplant-free survival rate of 2.9 ± 0.4 years, which was worse than non-IPF patients without PPF (10.1 ± 1.8 years, p < 0.001). The risk for PPF was increased in patients with FVC < 50% (odds ratio (OR) of 2.50, 95% CI = 1.01-6.17, p = 0.047) or DLCOc ≤ 35% (OR = 2.57, 95% CI = 1.24-5.35, p = 0.011). In the first 3 years after diagnosis, survival in PPF and IPF is the same, while in the following years IPF has a significantly worse survival. Conclusions: The non-IPF cohort with PPF had a significantly worse transplant-free survival compared with the non-IPF cohort without PPF. Independent risk factors for PPF in non-IPF were FVC < 50% and DLCOc ≤ 35%.

ABCA3 mutations in adult pulmonary fibrosis patients: a case series and review of literature.

PURPOSE OF REVIEW: The current review aims to recognize the variability in clinical presentation of adult patients with bi-allelic ABCA3 mutations, create more depth in ABCA3 mutations reported and highlight the influence of environmental factors on disease course. RECENT FINDINGS: Mutations in ABCA3 are predominantly linked to neonatal and pediatric interstitial lung disease (ILD) with a minority surviving beyond puberty. Here, we present three patients with ABCA3 mutations who present with disease at the age of 19, 61 and 77. Moreover, we identified c.4451G>C (p.R1484P), c.1675G>A (p.G559R) and c.4745C>G (p.T1582S) as three novel ABCA3 mutations. In addition, we identified six additional patients with ABCA3 mutations in literature who reached an age above 18. Furthermore, we discuss the influence of infections, drugs and smoking on disease course. SUMMARY: Although extremely rare, patients with bi-allelic mutations in ABCA3 may present at adulthood. Late onset of disease may be influenced by type of mutation or environmental factors.

Progressive Disease With Low Survival in Adult Patients With Pulmonary Fibrosis Carrying Surfactant-Related Gene Mutations: An Observational Study.

BACKGROUND: In some patients with progressive fibrosing interstitial lung disease (ILD), disease is caused by carriage of a mutation in a surfactant-related gene (SRG) such as SFTPC, SFTPA2, or ABCA3. However, no aggregated data on disease evolution and treatment outcome have been presented for these patients. RESEARCH QUESTION: In adult patients with ILD with an SRG mutation, what is the course of lung function after diagnosis and during treatment and the survival in comparison with patients with sporadic idiopathic pulmonary fibrosis (sIPF) and familial pulmonary fibrosis (FPF)? STUDY DESIGN AND METHODS: We retrospectively examined the clinical course of a cohort of adults with an SRG mutation by screening 48 patients from 20 families with an SRG mutation for availability of clinical follow-up data. For comparison, 248 patients with FPF and 575 patients with sIPF were included. RESULTS: Twenty-three patients with ILD (median age: 45 years; 11 men) with an SRG mutation fulfilled criteria. At diagnosis, patients with an SRG mutation were younger and less often male, but had lower FVC (72% predicted) and diffusing capacity of the lungs for carbon monoxide (46% predicted) compared with patients with FPF or sIPF. In the SRG mutation group, median FVC decline 6 months after diagnosis was -40 mL and median transplant-free survival was 44 months and not different from patients with FPF or sIPF. FVC course was not different among the three cohorts; however, a significantly larger decrease in FVC was found while patients received immunomodulatory or antifibrotic treatment compared with those receiving no treatment. Subsequent analysis in the SRG group showed that patients with a surfactant mutation (n = 7) treated for 6 months with antifibrotic drugs showed stable lung function with a median change in FVC of +40 mL (interquartile range, -40 to 90 mL), whereas patients with an SRG mutation treated with immunomodulatory drugs showed a variable response dependent on the gene involved. INTERPRETATION: This study showed that patients with ILD carrying an SRG mutation experience progressive loss of lung function with severely reduced survival despite possible beneficial effects of treatment.

Prevalence and clinical associations of myositis antibodies in a large cohort of interstitial lung diseases.

BACKGROUND: Serologic testing for autoantibodies is recommended in interstitial lung diseases (ILDs), as connective tissue diseases (CTDs) are an important secondary cause. Myositis antibodies are associated with CTD-ILD, but clinical associations with other ILDs are unclear. In this study, associations of myositis antibodies in various ILDs were evaluated. METHODS: 1463 ILD patients and 116 healthy subjects were screened for myositis antibodies with a line-blot assay on serum available at time of diagnosis. Additionally, bronchoalveolar lavage fluid (BALf) was analysed. RESULTS: A total of 394 patients demonstrated reactivity to at least one antibody, including anti-Ro52 (36.0%), anti-Mi-2ß (17.3%) and anti-Jo-1 (10.9%). Anti-Jo-1 (OR 6.4; p<0.100) and anti-Ro52 (OR 6.0; p<0.001) were associated with CTD-ILD. Interestingly, anti-Mi-2ß was associated with idiopathic pulmonary fibrosis (IPF; OR 5.3; p = 0.001) and hypersensitivity pneumonitis (HP; OR 5.9; p<0.001). Furthermore, anti-Mi-2ß was strongly associated with a histological usual interstitial pneumonia (UIP) pattern (OR 6.5; p < 0.001). Moreover, anti-Mi-2ß reactivity was identified in BALf and correlated with serum anti-Mi-2ß (r = 0.64; p = 0.002). No differences were found in survival rates between ILD patients with and without serum Mi-2ß reactivity (hazard ratio 0.835; 95% CI 0.442-1.575; p = 0.577). CONCLUSION: In conclusion, novel associations of antibody Mi-2ß with fibrotic ILD were found. Furthermore, serum anti-Mi-2ß was associated with a histological UIP pattern and presence of anti-Mi-2ß in BALf. Possibly, anti-Mi-2ß could be implemented as a future diagnostic biomarker for fibrotic ILD.

Prevalence of Novel Myositis Autoantibodies in a Large Cohort of Patients with Interstitial Lung Disease.

Connective tissue diseases (CTDs) are an important secondary cause of interstitial lung disease (ILD). If a CTD is suspected, clinicians are recommended to perform autoantibody testing, including for myositis autoantibodies. In this study, the prevalence and clinical associations of novel myositis autoantibodies in ILD are presented. A total of 1194 patients with ILD and 116 healthy subjects were tested for antibodies specific for Ks, Ha, Zoα, and cN1A with a line-blot assay on serum available at the time of diagnosis. Autoantibodies were demonstrated in 63 (5.3%) patients and one (0.9%) healthy control (p = 0.035). Autoantibodies were found more frequently in females (p = 0.042) and patients without a histological and/or radiological usual interstitial pneumonia (UIP; p = 0.010) and a trend towards CTD-ILDs (8.4%) was seen compared with other ILDs (4.9%; p = 0.090). The prevalence of antibodies specific for Ks, Ha, Zoα, and cN1A was, respectively, 1.3%, 2.0%, 1.4%, and 0.9% in ILD. Anti-Ha and Anti-Ks were observed in males with unclassifiable idiopathic interstitial pneumonia (unclassifiable IIP), hypersensitivity pneumonitis (HP), and various CTD-ILDs, whereas anti-cN1A was seen in females with antisynthetase syndrome (ASS), HP, and idiopathic pulmonary fibrosis (IPF). Anti-Zoα was associated with CTD-ILD (OR 2.5; 95%CI 1.11-5.61; p = 0.027). In conclusion, a relatively high prevalence of previously unknown myositis autoantibodies was found in a large cohort of various ILDs. Our results contribute to the awareness that circulating autoantibodies can be found in ILDs with or without established CTD. Whether these antibodies have to be added to the standard set of autoantibodies analysed in conventional myositis blot assays for diagnostic purposes in clinical ILD care requires further study.