Progressive Disease With Low Survival in Adult Patients With Pulmonary Fibrosis Carrying Surfactant-Related Gene Mutations

BackgroundIn 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 QuestionIn 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 MethodsWe 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.ResultsTwenty-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.InterpretationThis 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. 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. 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)? 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. 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. 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. FOR EDITORIAL COMMENT, SEE PAGE 744Take-home PointsStudy Question: In adults with pulmonary fibrosis carrying a surfactant-related gene (SRG) mutation, what is the course of lung function after diagnosis and during treatment and what is the survival in comparison with that of patients with sporadic idiopathic pulmonary fibrosis (sIPF) and familial pulmonary fibrosis (FPF)?Results: Adults with an SRG mutation have lung function with a highly variable course after diagnosis and during treatment and low median survival of 44 months, comparable with those of patients with FPF and sIPF.Interpretation: Adults with interstitial lung disease carrying an SRG mutation experience progressive loss of lung function with severely reduced survival despite treatment. FOR EDITORIAL COMMENT, SEE PAGE 744 Study Question: In adults with pulmonary fibrosis carrying a surfactant-related gene (SRG) mutation, what is the course of lung function after diagnosis and during treatment and what is the survival in comparison with that of patients with sporadic idiopathic pulmonary fibrosis (sIPF) and familial pulmonary fibrosis (FPF)? Results: Adults with an SRG mutation have lung function with a highly variable course after diagnosis and during treatment and low median survival of 44 months, comparable with those of patients with FPF and sIPF. Interpretation: Adults with interstitial lung disease carrying an SRG mutation experience progressive loss of lung function with severely reduced survival despite treatment. Interstitial lung diseases (ILDs) are a group of diseases characterized by inflammation, by fibrosis of the alveoli, distal airways, and interstitium of the lungs, or by both. In some adults with ILD, mutations in surfactant-related genes (SRGs), such as SFTPC, SFTPA1, SFTPA2, and ABCA3, have been identified. These genes encode for products involved in the production of the surfactant fluid by alveolar epithelial type 2 cells. Pathogenic mutations in these genes cause autosomal dominant (SFTPC, SFTPA1, or SFTPA2) or recessive (ABCA3) inheritance of progressive pulmonary fibrosis1Lawson P.R. Reid K.B. The roles of surfactant proteins A and D in innate immunity.Immunol Rev. 2000; 173: 66-78Crossref PubMed Scopus (132) Google Scholar, 2Weaver T.E. Conkright J.J. Function of surfactant proteins B and C.Annu Rev Physiol. 2001; 63: 555-578Crossref PubMed Scopus (311) Google Scholar, 3Mulugeta S. Gray J.M. 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Management of suspected monogenic lung fibrosis in a specialised centre.Eur Respir Rev. 2017; 26: 160122Crossref PubMed Scopus (51) Google Scholar, 6Garcia C.K. Idiopathic pulmonary fibrosis: update on genetic discoveries.Proc Am Thorac Soc. 2011; 8: 158-162Crossref PubMed Scopus (97) Google Scholar whereas in < 1% of the patients with sporadic pulmonary fibrosis, a mutation in SFTPC was found.6Garcia C.K. Idiopathic pulmonary fibrosis: update on genetic discoveries.Proc Am Thorac Soc. 2011; 8: 158-162Crossref PubMed Scopus (97) Google Scholar Penetrance is very high: asymptomatic dominant and recessive SRG mutation carriers are extremely rare. Although age at diagnosis is usually younger than 50 years, it is highly unpredictable. Although many case reports exist, no aggregated data on disease evolution and therapeutic response have been reported for patients with an SRG mutation. Adults carrying SRG mutations are part of the spectrum of patients with FPF or monogenic disease, although they usually seem to be younger, with both sexes being affected equally.4van Moorsel C.H.M. van der Vis J.J. Grutters J.C. Genetic disorders of the surfactant system: focus on adult disease.Eur Respir Rev. 2021; 30: 200085Crossref PubMed Scopus (17) Google Scholar Moreover, patients with an SRG mutation were shown to demonstrate radiologic and pathologic features suggestive of a role for inflammation in disease pathogenesis. Adults with disease caused by carriage of a mutation in SFTPC, SFTPA1, or SFTPA2 have been reported to demonstrate a pattern on high-resolution CT (HRCT) imaging that often is indeterminate for usual interstitial pneumonia (UIP) because of the presence of ground-glass opacities (GGOs) and lack of an apicobasal gradient, whereas histologic findings often meet the criteria for a UIP pattern with sometimes concomitant features of desquamative interstitial pneumonia or nonspecific interstitial pneumonia.7van Moorsel C.H.M. van Oosterhout M.F.M. Barlo N.P. et al.Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort.Am J Respir Crit Care Med. 2010; 182: 1419-1425Crossref PubMed Scopus (217) Google Scholar, 8van Moorsel C.H.M. ten Klooster L. van Oosterhout M.F.M. et al.SFTPA2 mutations in familial and sporadic idiopathic interstitial pneumonia.Am J Respir Crit Care Med. 2015; 192: 1249-1252Crossref PubMed Scopus (58) Google Scholar, 9Wang Y. Kuan P.J. Xing C. et al.Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer.Am J Hum Genet. 2009; 84: 52-59Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 10Doubková M. Staňo Kozubík K. Radová L. et al.A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.Hum Genome Var. 2019; 612Crossref PubMed Scopus (13) Google Scholar, 11Ono S. Tanaka T. 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Baga M. et al.Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis.Mod Pathol. 2004; 17: 973-980Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar The HRCT scans in adults with ABCA3 mutations often show GGOs with no or minimal honeycombing and with emphysema, whereas histologic analysis rarely shows a UIP pattern, but often a mix of findings such as mild alveolar epithelial type 2 cell hyperplasia, increased alveolar macrophages, and infiltrates, and also desquamative interstitial pneumonia-like and pulmonary alveolar proteinosis-like features may be present.16Klay D. Platenburg M.G.J.P. van Rijswijk R.H.N.A.J. Grutters J.C. van Moorsel C.H.M. ABCA3 mutations in adult pulmonary fibrosis patients: a case series and review of literature.Curr Opin Pulm Med. 2020; 26: 293-301Crossref PubMed Scopus (25) Google Scholar, 17Campo I. Zorzetto M. 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Nathan N. et al.Bi-allelic missense ABCA3 mutations in a patient with childhood ILD who reached adulthood.ERJ Open Res. 2019; 5Crossref PubMed Scopus (14) Google Scholar Because of these marked differences with patients with IPF, who characteristically show radiologic and histologic UIP, differences also may exist in survival and best treatment approach. IPF therapy currently consists of treatment with antifibrotic drugs, whereas treatment with immunomodulatory drugs was shown to be harmful.22Raghu G. Anstrom K. King T. Lasky J. Martinez F. Network I.P.F.C.R. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.N Engl J Med. 2012; 366: 1968-1977Crossref PubMed Scopus (1207) Google Scholar,23Wiertz I.A. Wuyts W.A. van Moorsel C.H.M. et al.Unfavourable outcome of glucocorticoid treatment in suspected idiopathic pulmonary fibrosis.Respirology. 2018; 23: 311-317Crossref PubMed Scopus (11) Google Scholar However, in children with ILD caused by SRG mutations, immunomodulatory drugs were shown sometimes to be successful.24Kröner C. Reu S. Teusch V. et al.Genotype alone does not predict the clinical course of SFTPC deficiency in paediatric patients.Eur Respir J. 2015; 46: 197-206Crossref PubMed Scopus (56) Google Scholar,25Thouvenin G. Taam R.A. Flamein F. et al.Characteristics of disorders associated with genetic mutations of surfactant protein C.Arch Dis Child. 2010; 95: 449-454Crossref PubMed Scopus (88) Google Scholar This suggests that a similar approach in theory could be beneficial in adults with SRG mutation-related disease. At present, no studies have evaluated survival and treatment outcomes in patients with an SRG mutation. The aim of this retrospective study was to present the clinical course of a real-world cohort of adults with pulmonary fibrosis and an SRG mutation and to investigate the evolution of lung function after diagnosis and under treatment with immunomodulatory or antifibrotic drugs. Furthermore, demographics, course of lung function, and survival of the study population were compared with data from a cohort of patients with sporadic idiopathic pulmonary fibrosis (sIPF) and FPF. Forty-eight adults from 20 families with SRG mutations were screened for eligibility for inclusion in this study. In total, 23 of the 48 adults with signed informed consent, carrying an SRG mutation, and having a diagnosis of ILD were included for evaluation of clinical course and treatment effect (Fig 1). The included patients with ILD carried an SRG mutation in SFTPC (n = 12; heterozygotes), SFTPA2 (n = 8; heterozygotes), or ABCA3 (n = 3; compound heterozygotes). Patients received a diagnosis between 1997 and 2017 and belonged to 16 families, of which four with an SFTPC mutation were described previously,7van Moorsel C.H.M. van Oosterhout M.F.M. Barlo N.P. et al.Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort.Am J Respir Crit Care Med. 2010; 182: 1419-1425Crossref PubMed Scopus (217) Google Scholar five with an SFTPA2 mutation8van Moorsel C.H.M. ten Klooster L. van Oosterhout M.F.M. et al.SFTPA2 mutations in familial and sporadic idiopathic interstitial pneumonia.Am J Respir Crit Care Med. 2015; 192: 1249-1252Crossref PubMed Scopus (58) Google Scholar and three with ABCA3 mutations16Klay D. Platenburg M.G.J.P. van Rijswijk R.H.N.A.J. Grutters J.C. van Moorsel C.H.M. ABCA3 mutations in adult pulmonary fibrosis patients: a case series and review of literature.Curr Opin Pulm Med. 2020; 26: 293-301Crossref PubMed Scopus (25) Google Scholar described previously. For comparison, we additionally retrieved two cohorts of unrelated patients from our ILD biobank. For survival analysis, 248 patients with pulmonary fibrosis with at least one family member with pulmonary fibrosis, referred to as FPF, and 575 patients with sIPF with a definite IPF diagnosis based on the American Thoracic Society and European Respiratory Society guidelines or a working IPF diagnosis after multidisciplinary discussion were included.26Raghu G. Collard H.R. Egan J.J. et al.An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.Am J Respir Crit Care Med. 2011; 183: 788-824Crossref PubMed Scopus (5483) Google Scholar, 27Walsh S.L.F. Lederer D.J. Ryerson C.J. et al.Diagnostic likelihood thresholds that define a working diagnosis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2019; 200: 1146-1153Crossref PubMed Scopus (46) Google Scholar, 28Sgalla G. Greco E. L.o. Calvello M. et al.Disease progression across the spectrum of idiopathic pulmonary fibrosis: a multicentre study.Respirology. 2020; 25: 1144-1151Crossref PubMed Scopus (6) Google Scholar All patients with FPF and patients with IPF of a relatively young age (≤ 55 years) at diagnosis were screened and found to show negative results for mutations in SFTPC and SFTPA2 exon 6 and for ABCA3 E292V. All participants signed written consent for the study approved by the Medical Research Ethics Committees United of the St. Antonius Hospital (Identifier, R05-08A). Clinical parameters including sex, age at diagnosis, survival data, smoking status, FVC % predicted, absolute FVC at diagnosis, and diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted at diagnosis were obtained from medical records. For 21 patients with an SRG mutation, the results of at least two pulmonary function tests (PFTs) carried out after diagnosis and treatment information were available in medical records. In total, 17 of these patients used lung medication. Treatment information and the results of at least two PFTs carried out after diagnosis also were available for 120 patients with FPF and 280 patients with sIPF. Only treatment with duration of at least 3 months was included. We defined two treatment groups: immunomodulatory treatment including prednisone, azathioprine, or hydroxychloroquine and antifibrotic treatment including pirfenidone or nintedanib. Time frames that included treatment with drugs from two different treatment groups at the same time were excluded from the progression analysis. Statistical analyses were performed using SPSS version 26 software (SPSS, Inc.) and R version 4.2.1 software (R Foundation for Statistical Computing). To analyze differences among patients with an SRG mutation, patients with FPF, and patients with sIPF, the χ 2Weaver T.E. Conkright J.J. Function of surfactant proteins B and C.Annu Rev Physiol. 2001; 63: 555-578Crossref PubMed Scopus (311) Google Scholar test and Kruskal-Wallis test were used for discrete and continuous variables, respectively. Because of the small sample size and nonnormal distribution of the data, the Wilcoxon signed-rank test was used to analyze the differences in FVC between baseline and the different time points in the SRG cohort and the Kruskal-Wallis test was used to analyze differences in FVC change between baseline and the different time points among the three patient groups (surfactant mutation treated with antifibrotic drugs, surfactant mutation treated immunomodulatory drugs, and ABCA3 mutations treated immunomodulatory drugs). In addition, we used a linear mixed model for repeated measures over time to analyze the differences of the three groups regarding FVC at baseline and follow-up with fixed effects of time, group, and the interaction between time and group, which tries to find a difference in changes over time among the three groups. This analysis prevented list-wise deletion because of missing data. To adjust for differences in baseline FVC, baseline FVC was added as covariate to the model. In the linear mixed model, patients with a surfactant mutation treated with immunomodulatory drugs and FVC 12 months after initiation of treatment were used as references. A linear mixed model for repeat measures over time also was used to analyze differences in longitudinal change in FVC adjusted for treatment exposure among the three cohorts (patients with SRG mutations, patients with FPF, and patients with sIPF). Treatment (none, immunomodulatory therapy, or antifibrotic therapy) was indicated for each FVC point. Time was defined as the difference in months between date of diagnosis and date of FVC and was modeled flexibly using restricted cubic splines. Effect of cohort (patients with SRG mutations, patients with FPF, and patients with sIPF), treatment (none, immunomodulatory therapy, and antifibrotic therapy), time, and their interaction terms were included in the model. The patients with SRG mutations and no treatment served as references. Differences in transplant-free survival were analyzed with the Kaplan-Meier method with log-rank test. Lung transplantation and death both were marked as an event. Evaluation of 48 eligible relatives in families with SRG mutations (mean age: 43.7 years; 20 men) provided 23 patients with ILD fulfilling inclusion criteria (Fig 1). Additionally, 575 patients with sIPF and 248 patients with FPF were included in this study. Demographic and clinical characteristics are shown in Tables 1 and 2. The SRG mutation cohort had a median age at diagnosis of 45.0 years (range, 19-77 years), which was significantly lower than that of the FPF and sIPF cohorts. Twenty patients with an SRG mutation had familial disease and belonged to 13 families with ILD, whereas three patients with an SRG mutation showed a negative family history for ILD. Patients 4 and 6 were asymptomatic when screened in the context of familial risk for FPF. Patient 19 already had shown symptoms for 2 years before a definite diagnosis was drawn. Mean FVC % predicted at diagnosis was 72.4% (SD, 18.8%) in the SRG mutation cohort and was significantly lower than that in the FPF cohort, whereas Dlco % predicted was 45.6% (SD, 16.9%) in the SRG mutation cohort and was comparable with that in the sIPF and FPF cohorts. For 21 of 23 patients with ILD, the results of at least two PFTs and treatment information were available.Table 1Clinical Characteristics of Patient CohortsVariablePatients With SRG MutationPatients With FPFPatients With sIPFP ValueNo. of patients23248575. . .Age at diagnosis, y45.0 (31.0-61.0)67.0 (59.0-74.0)72.0 (65.0-77.0)< .001Male sex11 (48)163 (66)472 (82)< .001FVC, LaEighteen patients with an SRG mutation, 225 patients with FPF, and 529 patients with sIPF.2.9 ± 1.13.1 ± 1.02.9 ± 0.9.016FVC, % predictedaEighteen patients with an SRG mutation, 225 patients with FPF, and 529 patients with sIPF.72.4 ± 18.886.9 ± 22.980.2 ± 19.6< .001Dlco, % predictedbEighteen patients with an SRG mutation, 206 patients with FPF, and 480 patients with sIPF.45.6 ± 16.950.1 ± 17.243.7 ± 13.8< .001cPost hoc analysis showed a difference only between patients with FPF and patients with sIPF.Ever smokerdTwenty patients with an SRG mutation, 208 patients with FPF, and 525 patients with sIPF.12 (60)153 (74)437 (83).001Transplant event7 (30)20 (8)21 (4)< .001Deaths9 (39)115 (46)335 (58).002Survival time, median (SE), mo44 (11.7)38 (3.5)36 (2.0).701Data are presented as No. (%), mean ± SD, or median (interquartile range), unless otherwise indicated. Dlco = diffusing capacity of the lungs for carbon monoxide; FPF = familial pulmonary fibrosis; sIPF = sporadic idiopathic pulmonary fibrosis; SRG = surfactant-related gene.a Eighteen patients with an SRG mutation, 225 patients with FPF, and 529 patients with sIPF.b Eighteen patients with an SRG mutation, 206 patients with FPF, and 480 patients with sIPF.c Post hoc analysis showed a difference only between patients with FPF and patients with sIPF.d Twenty patients with an SRG mutation, 208 patients with FPF, and 525 patients with sIPF. Open table in a new tab Table 2Demographics, HRCT Scan Pattern, and Treatment Type in Surfactant-Related Gene Mutation CarriersPatient No.Age at Diagnosis, ySexMutation ProteinHRCT Scan FindingsApicobasal GradientGround-Glass OpacitiesHistologic FindingsTreatment161FABCA3 E292V and R1484PInconsistent with UIPNoYesNAPDN230FSFTPC I73TInconsistent with UIPNoYesUIPNone331FSFTPC I73TInconsistent with UIPNoYesUIPPDN and AZA446MSFTPC I73TInconsistent with UIPNoNoNANone533MSFTPC IVS4+2End-stage fibrosisNoNoUIPUnknown621FSFTPA2 N171YInconsistent with UIPNoNoUIPNone719FABCA3 E292V and R280CInconsistent with UIPNoYesNot UIPPDN973MSFTPC I73TDefinite UIPYesNoNANTD1070MSFTPA2 V178MInconsistent with UIPNoNoNAPFD and NTD1128FSFTPC Y113CInconsistent with UIPNoNoNAPFD1245FSFTPA2 G231RInconsistent with UIPYesYesNANTD1330MSFTPC M71VInconsistent with UIPNoYesUIPPFD1440MSFTPA2 N210TDefinite UIPYesMinimalUIPPDN and AZA1543MSFTPA2 G231RInconsistent with UIPYesYesUIPPDN1644FSFTPA2 G231RInconsistent with UIPNoYesNAPFD1758MSFTPC I73TEnd stage fibrosisNoNoUIPUnknown1958FSFTPC Y113CInconsistent with UIPNoYesNAPDN and HCQ2065MSFTPA2 N210TDefinite UIPYesNoNANone2154FSFTPC L137PDefinite UIPYesYesaAcute exacerbation.UIPPDN2234FSFTPA2 N171YInconsistent with UIPNoNoUIPPDN2345MSFTPC M60VInconsistent with UIPYesYesNANTD2477MABCA3 G559R and T1582SPossible UIPYesMinimalNAAZA2573FSFTPC I73TPossible UIPYesMinimalNAPDNAZA = azathioprine; F = female; HCQ = hydroxychloroquine; M = male; NA = not applicable; NTD = nintedanib; PFD = pirfenidone; PDN = prednisone; UIP = usual interstitial pneumonia.a Acute exacerbation. Open table in a new tab Data are presented as No. (%), mean ± SD, or median (interquartile range), unless otherwise indicated. Dlco = diffusing capacity of the lungs for carbon monoxide; FPF = familial pulmonary fibrosis; sIPF = sporadic idiopathic pulmonary fibrosis; SRG = surfactant-related gene. AZA = azathioprine; F = female; HCQ = hydroxychloroquine; M = male; NA = not applicable; NTD = nintedanib; PFD = pirfenidone; PDN = prednisone; UIP = usual interstitial pneumonia. Treatment per patient is presented in Table 2. Change in FVC after diagnosis was highly variable, with a median decline in the SRG mutation cohort of 40 mL (interquartile range [IQR], -241 to 125 mL; n = 16) after 6 months and 117 mL (IQR, -528 to 115 mL; n = 14) after 12 months. HRCT imaging and histologic characteristics of the SRG mutation cohort are shown in Table 2. In total, 15 of 23 patients with an SRG mutation showed a pattern inconsistent with UIP on HRCT imaging, whereas on histologic examination, 10 of 11 patients showed a UIP pattern. Comparison of change in FVC 6 months after diagnosis between patients with an SRG mutation with and without GGOs on HRCT imaging showed no significant difference between the groups (P = .442; median change without GGO, –90 mL [n = 8]; median change with GGO, +50 mL [n = 8]). In addition, comparison of change in FVC 12 months after diagnosis between the groups also showed no significant difference (P = .573; median change without GGO, –227 mL [n = 8]; median change with GGO, –10 mL [n = 6]). Effect of treatment on FVC could be analyzed for 17 patients with an SRG mutation. For each patient, the FVC course is presented in e-Figure 1, with time point zero representing the start of treatment. For 12 of the 17 patients, Dlco % predicted was available before and after treatment and is shown in e-Figure 2A. During treatment, one patient died and one patient underwent lung transplantation. Three patients (patients 9, 12, and 15) used both immunomodulatory and antifibrotic drugs during follow-up. Their treatment and lung function course is shown in e-Figure 2B-2D, and case descriptions are provided in e-Appendix 1. To investigate whether differences exist in longitudinal change in FVC adjusted for treatment exposure among the three cohorts (patients with SRG mutations, patients with FPF, and patients with sIPF), a linear mixed-model analysis was performed (Fig 2). Significant main effects of time (P < .001) and treatment (P < .001) were found, indicating that FVC decreased over time and that FVC was different between treatments (none, immunomodulatory therapy, and antifibrotic therapy). In addition, a significant interaction between cohort and treatment was found (P < .001), indicating a difference in FVC between different cohort and treatment combinations. A significant difference in FVC was found while patients with FPF received immunomodulatory (P < .001) or antifibrotic (P < .001) treatment, and patients with an SRG mutation received immunomodulatory treatment (P < .001) compared with while they received no treatment. Interaction between cohort and time (P = .032) and interaction between treatment and time (P < .001) also were significant, indicating that a significant differe