FinnishIPF - A national real-world study on disease characteristics, pharmacotherapy, and prognosis in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rare disease characterized by the progressive scarring of lung tissue. Common symptoms are dyspnea and a prolonged cough. The majority of IPF patients die in respiratory failure. The cause of the disease is still unclear; consequently, there is no cure for IPF. Two antifibrotic medications are currently available: pirfenidone and nintedanib, both of which may slow down disease progression. As better treatment options have become available, an accurate diagnosis of IPF has become more important than ever. The FinnishIPF project was initiated to gain real-world data on the prevalence, diagnosis, treatment, and prognosis of IPF patients in Finland. In this thesis, we aimed to identify reliable methodologies used in studies related to the epidemiology of IPF. The FinnishIPF project began by describing the clinical characteristics and the diagnostic accuracy of IPF in the university hospital cohort. The prognosis and clinical predictors of survival were then analyzed and the use of antifibrotic medications and comedications was evaluated. Only a limited number of epidemiological studies on IPF have been published. Various epidemiological methodologies have been used but none are without limitations. The exact prevalence of IPF is not known. The ICD-10 coding system is an inaccurate tool for IPF. The use of hospital registries in epidemiological studies may give an unreliable prevalence of this rare disease if the diagnoses are not validated. According to the FinnishIPF study, lung function is usually quite well preserved at diagnosis. After the multidisciplinary re-evaluation of prior diagnoses, nearly 10% of the cases did not fulfill the current criteria of IPF. Antifibrotic treatment is initiated for every second IPF patient. Younger age at diagnosis predicts initiation of the treatment. Lower lung function at diagnosis predicts earlier (≤ 1 year) initiation. Polypharmacy is common, as nearly 60% of IPF patients have ≥ 5 simultaneous medications at diagnosis. The median overall survival of IPF is 4.5 years. High age and low pulmonary function at diagnosis are predictors of mortality.FinnishIPF – Kansallinen tosielämän tutkimus idiopaattisen keuhkofibroosin taudinkuvasta, lääkehoidosta ja ennusteesta Idiopaattinen keuhkofibroosi (idiopathic pulmonary fibrosis, IPF) on harvinainen ja etenevä keuhkokudosta arpeuttava sairaus. Taudin oireita ovat hengenahdistus ja pitkittynyt yskä. Suuri osa IPF-potilaista kuolee hengitysvajaukseen. Taudin perimmäinen syy on edelleen epäselvä, eikä näin ollen ole pystytty kehittämään parantavaa lääkehoitoa. Hoito on kuitenkin kehittynyt antifibroottisten lääkkeiden tultua markkinoille. Antifibroottiset lääkkeet: pirfenidoni ja nintedanibi voivat hidastaa taudin etenemistä. Parempien hoitomahdollisuuksien myötä, IPF:n täsmällinen diagnostiikka on tullut entistä tärkeämmäksi. FinnishIPF-projektin tarkoituksena on ollut kerätä tietoa IPF:n esiintyvyydestä, diagnostiikasta, hoidosta ja ennusteesta Suomessa. Väitöskirjatutkimuksen ensimmäisenä tavoitteena oli etsiä luotettava epidemiologinen menetelmä taudin esiintyvyyden arvioimiseksi analysoimalla kirjallisuutta. FinnishIPF-tutkimus aloitettiin kuvaamalla yliopistosairaaloissa hoidettujen IPF-potilaiden kliinisiä piirteitä. Diagnostiikan osuvuutta arvioitiin moniammatillisesti. IPF-potilaiden ennustetta ja ennusteeseen vaikuttavia tekijöitä analysoitiin. Lisäksi selvitettiin antifibroottisten hoitojen toteutumista. IPF:stä on julkaistu niukasti epidemiologisia tutkimuksia. Tutkimuksissa on käytetty vaihtelevia menetelmiä, joissa kaikissa on puutteita. IPF:n tarkkaa esiintyvyyttä ei tiedetä. ICD-10-tautiluokitus ei ole riittävän täsmällinen epidemiologinen työkalu IPF:n osalta. Sairaalarekisterit tuottavat epäluotettavia epidemiologisia lukuja, jos IPF-diagnooseja ei varmisteta. FinnishIPF-tutkimuksen mukaan IPF-potilaiden keuhkotilavuudet ovat hyvätasoisia diagnoosivaiheessa. Yliopistosairaalakohortissa 10 % vanhoista IPFdiagnooseista ei täyttänyt taudin nykykriteerejä moniammatillisen arvioinnin perusteella. Antifibroottinen lääke on aloitettu noin joka toiselle IPF-potilaalle. Nuorempi ikä ennustaa lääkkeen aloitusta. Diagnoosivaiheen alentunut keuhkofunktio ennustaa aikaisempaa (≤ 1 v. diagnoosista) lääkkeen aloitusta. Polyfarmasia on yleistä. Lähes 60 %:lla IPF-potilaista on ≥ 5 lääkettä käytössä diagnoosivaiheessa. IPF:n elinajanennusteen mediaani on 4.5 vuotta. Diagnoosivaiheen korkea ikä ja matala keuhkojen toimintakokeiden taso ennustavat kuolleisuutta

Idiopaattinen keuhkofibroosi - muuttuva diagnostiikka ja hoito

English summaryPeer reviewe

Demographics and survival of patients with idiopathic pulmonary fibrosis in the FinnishIPF registry

Peer reviewe

Forced Vital Capacity (FVC) decline, mortality and healthcare resource utilization in idiopathic pulmonary fibrosis

Aim of the study: Potential care implications of antifibrotic reimbursement restrictions werestudied by forced vital capacity (FVC) decline, mortality and specialty care related healthcareresource utilization in patients with idiopathic pulmonary fibrosis (IPF).Material and methods: IPF patients were identified from the electronic medical records of theHospital District of Southwest Finland between 2005 and 2017. Text-mining was used for patientidentification to exclude other interstitial lung diseases (ILD) from the cohort. FVC reimbursementrestriction (FVC 50-90%) was used for stratification.Results: Out of all patients with ILD, 27% (N = 266) were identified to have IPF. At baseline, 24%presented with FVC>90% and 63% with FVC 50-90% predicted. FVC at diagnosis did not improveduring the study period. Median survival decreased by severity from 6.7 years in FVC>90% atbaseline to 0.7 years in patient with FVC90% group, 14% died beforea change in FVC category could be noted. Overall, 4.7 million euro worth of specialty careresources were spent on IPF patients. The highest cost driver was inpatient days.Conclusions: IPF is associated with a high burden of disease, and reimbursement restrictions arein conflict with early care. As there are antifibrotic treatment options for IPF patients, early diagnosis is important.</div

Demographics and survival of patients with idiopathic pulmonary fibrosis in the FinnishIPF registry

Idiopathic pulmonary fibrosis (IPF) is characterised by unpredictable disease course and poor survival. After the introduction of novel antifibrotic drugs, the prognosis of patients with IPF is probably changing.FinnishIPF, a nationwide registry of carefully characterised patients, was initiated in Finland in 2011. For the data analysis, we included 453 incident IPF patients diagnosed during 2011–2015. In this study, we describe the demographics and prognosis of these real-life patients.The median overall survival time of registered IPF patients was 4.5 years. The transplant-free survival at 1, 2, 3, 4 and 5 years was 95%, 83%, 70%, 58% and 45%, respectively. Smoking did not have any effect on survival. 117 (26%) patients received pirfenidone or nintedanib. Patients who received ≥6 months of treatment had better survival compared with those who did not receive treatment but this difference disappeared after age adjustment. The transplantation rate was 3%.Although IPF is diagnosed in Finland at a older age, the prognosis is better than expected due to a relatively well preserved lung function at diagnosis. Age and pulmonary function were identified as independent predictors of survival in the entire IPF patient population as well as in patients who had received antifibrotic treatment.</p

Re-evaluation of diagnostic parameters is crucial for obtaining accurate data on idiopathic pulmonary fibrosis

Background: The FinnishIPF registry is a prospective, longitudinal national registry study on the epidemiology of idiopathic pulmonary fibrosis (IPF). It was designed to describe the characteristics, management and prognosis of prevalent and incident IPF patients. The study was initiated in 2012. Methods: We present here results limited to five university hospitals. Patients with IPF were screened from hospital registries using ICD-10 diagnosis codes J84.1 and J84.9. All patients who gave informed consent were included and evaluated using novel diagnostic criteria. Point prevalence on the 31st of December in 2012 was calculated using the reported population in each university hospital city as the denominator. Results: Patients with ICD-10 codes J84.1 and J84.9 yielded a heterogeneous group - on the basis of patient records assessed by pulmonologists only 20-30 % of the cases were IPF. After clinical, radiological and histological re-evaluation 111 of 123 (90 %) of patients fulfilled the clinical criteria of IPF. The estimated prevalence of IPF was 8.6 cases/100 000. 60.4 % were men. Forty four percent of the patients were never-smokers. At diagnosis, the patients' mean age was 73.5 years and mean FVC was 80.4 % and DLCO 57.3 % of predicted. Conclusions: Our results suggest that hospital registries are inaccurate for epidemiological studies unless patients are carefully re-evaluated. IPF is diagnosed in Finland at a stage when lung function is still quite well preserved. Smoking in patients with IPF was less common than in previous reports.Peer reviewe

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.Peer reviewe

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.</p

Common Inflammation-Related Candidate Gene Variants and Acute Kidney Injury in 2647 Critically Ill Finnish Patients

Acute kidney injury (AKI) is a syndrome with high incidence among the critically ill. Because the clinical variables and currently used biomarkers have failed to predict the individual susceptibility to AKI, candidate gene variants for the trait have been studied. Studies about genetic predisposition to AKI have been mainly underpowered and of moderate quality. We report the association study of 27 genetic variants in a cohort of Finnish critically ill patients, focusing on the replication of associations detected with variants in genes related to inflammation, cell survival, or circulation. In this prospective, observational Finnish Acute Kidney Injury (FINNAKI) study, 2647 patients without chronic kidney disease were genotyped. We defined AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We compared severe AKI (Stages 2 and 3, n = 625) to controls (Stage 0, n = 1582). For genotyping we used iPLEX(TM) Assay (Agena Bioscience). We performed the association analyses with PLINK software, using an additive genetic model in logistic regression. Despite the numerous, although contradictory, studies about association between polymorphisms rs1800629 in TNFA and rs1800896 in IL10 and AKI, we found no association (odds ratios 1.06 (95% CI 0.89-1.28, p = 0.51) and 0.92 (95% CI 0.80-1.05, p = 0.20), respectively). Adjusting for confounders did not change the results. To conclude, we could not confirm the associations reported in previous studies in a cohort of critically ill patients.Peer reviewe