Racial and ethnic disparities in antifibrotic therapy in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Racial disparities have been documented in care of many respiratory diseases but little is known about the impact of race on the treatment of interstitial lung diseases. The purpose of this study was to determine how race and ethnicity influence treatment of idiopathic pulmonary fibrosis. METHODS: Adults with idiopathic pulmonary fibrosis (>18 years) were identified using TriNetX database and paired-wised comparisons were performed for antifibrotic treatment among White, Black, Hispanic and Asian patients. Mortality of treated and untreated IPF patients was compared after propensity score matching for age, sex, nicotine dependence, oxygen dependence and predicted FVC. Additional comparisons were performed in subgroups of IPF patients older than 65 years of age and with lower lung function. RESULTS: Of 47,184 IPF patients identified, the majority were White (35,082), followed by Hispanic (6079), Black (5245) and Asian (1221). When subgroups were submitted to matched cohort pair-wise comparisons, anti-fibrotic usage was lower among Black patients compared to White (6.2% vs. 11.4%, p-value <0.0001), Hispanic (10.8% vs. 20.2%, p-value <0.0001) and Asian patients (9.6% vs. 14.7%, p-value = 0.0006). Similar treatment differences were noted in Black individuals older than 65 years and those with lower lung function. Mortality among White patients, but not Hispanic, Black, or Asian patients, was lower in patients on antifibrotic therapy versus not on therapy. CONCLUSION: This study demonstrated that Black IPF patients had lower antifibrotic use compared to White, Hispanic and Asian patients. Our findings suggest that urgent action is needed to understand the reason why racial disparities exist in the treatment of IPF.

Mortality Trends of Idiopathic Pulmonary Fibrosis in the United States From 2004 Through 2017.

BACKGROUND: The burden of idiopathic pulmonary fibrosis (IPF)-related mortality in the United States in recent years is not well characterized. RESEARCH QUESTION: What are the trends in IPF-related mortality rates in the United States from 2004 through 2017? STUDY DESIGN AND METHODS: We used the Multiple Cause of Death Database available through the Centers for Disease Control and Prevention website, which contains data from all deceased US residents. IPF-related deaths were identified using International Classification of Diseases, 10th revision, codes. We examined annual trends in age-adjusted mortality rates stratified by age, sex, race, and state of residence. We also evaluated trends in place of death and underlying cause of death. RESULTS: From 2004 through 2017, the age-adjusted mortality decreased by 4.1% in men (from 75.5 deaths/1,000,000 in 2004 to 72.4 deaths/1,000,000 in 2017) and by 13.4% in women (from 46.3 deaths/1,000,000 in 2004 to 40.1 deaths/1,000,000 in 2017). This overall decrease was driven mainly by a decline in IPF-related mortality in patients younger than 85 years. The decreasing trend also was noted in all races except White men, in whom the rate remained stable. The most common cause of death was pulmonary fibrosis. The percentage of deaths occurring in the inpatient setting and nursing homes decreased, whereas the percentage of deaths occurring at home and hospice increased. INTERPRETATION: From 2004 through 2017, the IPF age-adjusted mortality rates decreased. This may be explained partly by a decline in smoking in the United States, but further research is needed to evaluate other environmental and genetic contributors.

Autoantibody status is not associated with change in lung function or survival in patients with idiopathic pulmonary fibrosis.

INTRODUCTION: A proportion of patients with idiopathic pulmonary fibrosis (IPF) have autoantibodies directed against intracellular targets. This study aimed to determine the relationship between serologic status, lung function decline and survival. METHODS: IPF patients assessed for antinuclear antibody (ANA) and related antigen-specific serology detected by addressable laser bead immunoassay (ALBIA) were included. Demographics, serial pulmonary function tests and survival were compared between patients with and without autoantibodies. Linear mixed models were used to estimate changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time. Cox-proportional hazards models were used to compare survival, adjusted for a composite score including age, sex and baseline lung function. RESULTS: Of 61 included patients, the mean baseline age was 70 years (SD = 9), 77% were male, and 87% were Caucasian. Either ANA or antigen-specific serology by ALBIA was positive in 25 (41%) during follow-up. ANA was detected in 23 (38%), and specific autoantibodies by ALBIA in 6 (10%). There was no difference in age, sex, race, smoking status, anti-fibrotic use or baseline FVC or DLCO in patients with and without autoantibodies. There was no association between autoantibody status and survival (HR = 1.18, 95% CI 0.61, 2.29), rate of decline in FVC or DLCO (difference in FVC = 4.2 mL/year, p = 0.82; difference in DLCO = 4.6*10-4 mL/min/mmHg/year, p = 0.20). CONCLUSION: These data suggest that autoantibodies are common in IPF and that patients with a subset of autoantibodies, but without features of autoimmunity, demonstrate similar disease behaviour to those without autoantibodies.

Ethnic differences in idiopathic pulmonary fibrosis: The Japanese perspective.

Epidemiologic data suggest that there are ethnic differences between Japanese and other populations with regard to the important clinical aspects of interstitial lung disease (ILD), such as the cause of death and prognostic factors in patients with idiopathic pulmonary fibrosis (IPF). Acute exacerbation (AE) of IPF may be more common in Japan than in the rest of the world, although this suggestion remains controversial. Moreover, AE of ILD induced by gefitinib may also be more common in Japan, indicating that Japanese patients have a genetic vulnerability or susceptibility to AE. Recent large-scale studies are starting to reveal ethnic differences in the genetics of ILD, including the prevalence of the genetic polymorphisms associated with the clinical course of ILD. We anticipate that ongoing and upcoming research regarding ethnic differences will continue to provide valuable insights into the pathogenesis and management of ILD.

Patient eligibility for anti-fibrotic therapy in idiopathic pulmonary fibrosis can be altered by use of different sets of reference values for calculation of FVC percent predicted.

Antifibrotic drugs for idiopathic pulmonary fibrosis patients in England and Scotland are only available to those with FVC percent predicted (FVC%pred) less than or equal to 80%. The prescribing guidance does not state which set of reference values should be used and we show that a patient's FVC%pred can change by 4-6% depending on the choice of reference. We calculated FVC%pred for a group of 528 IPF patients using three different sets of reference values. 90% of patients with FVC%pred 80-85% calculated using European Community Coal and Steel (ECSC) reference values fall into the eligible range when NHANES reference values are used.

Subgroup analysis of Asian patients in the INPULSIS® trials of nintedanib in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: In the two-replicate randomized Phase III INPULSIS® trials in patients with idiopathic pulmonary fibrosis (IPF), nintedanib 150 mg bd significantly reduced the annual rate of decline in forced vital capacity (FVC) compared with placebo. The key secondary endpoints were time to first investigator-reported acute exacerbation and change from baseline in St George's Respiratory Questionnaire total score, both over 52 weeks. Here, we assessed the effect of nintedanib in Asian patients. METHODS: Pre-specified subgroup analyses of the effect of nintedanib on the primary and key secondary endpoints in Asian versus White patients were undertaken based on pooled data from the two INPULSIS® trials. Safety data were analyzed descriptively. RESULTS: Of the treated patients, 322 were Asian (nintedanib n = 194; placebo n = 128) and 608 were White (nintedanib n = 360; placebo n = 248). In Asian patients, the nintedanib versus placebo difference in the adjusted annual rate of decline in FVC was 94.1 mL/year (95% CI: 33.7, 154.6). The treatment effect of nintedanib on the annual rate of decline in FVC in Asian and White patients was similar (treatment-by-subgroup interaction P = 0.72) and consistent with the overall population. No significant treatment-by-subgroup interaction was observed for the key secondary endpoints between Asian and White patients. In Asian patients, the most common adverse event in the nintedanib group was diarrhoea (56.2% of patients vs 15.6% for placebo). CONCLUSION: In pre-specified subgroup analyses of Asian versus White patients with IPF in the INPULSIS® trials, race did not influence the effect of nintedanib on disease progression.

The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries.

BACKGROUND: Polymorphisms in the MUC5B promoter, TOLLIP, and nine additional genetic loci have been associated with idiopathic pulmonary fibrosis (IPF) within non-Hispanic white populations. It is unknown whether these variants account for risk of IPF in other racial/ethnic populations. We conducted a candidate single nucleotide polymorphism (SNP) association study in cohorts of Mexican and Korean patients with IPF. METHODS: We chose 12 SNPs from 11 loci that are associated with IPF among non-Hispanic whites and genotyped these SNPs in cohorts of Mexican (83 patients, 111 control subjects) and Korean (239 patients, 87 control subjects) people. Each SNP was tested for association with IPF, after adjusting for age and sex. RESULTS: The MUC5B promoter SNP rs35705950 was associated with IPF in the Mexican (OR = 7.36, P = .0001), but not the Korean (P = .99) cohort. The SNP in IVD (chromosome15, rs2034650) was significantly associated with pulmonary fibrosis in both the Mexican (OR = 0.40, P = .01) and Korean (OR = 0.13, P = .0008) cohorts. In the Korean cohort, there were no other variants associated with disease. In the Mexican cohort, SNPs on chromosomes 3, 4, and 11 were also associated with disease. CONCLUSIONS: The strongest identified genetic risk factor for IPF among the non-Hispanic white population, the MUC5B promoter polymorphism, is also a strong risk factor in a Mexican population, but is very rare in a Korean population. The majority of genetic variants that account for risk of IPF in groups other than non-Hispanic whites are unknown. Hispanic and Asian populations should be studied separately to identify genetic risk loci for IPF.

Validation of the GAP score in Korean patients with idiopathic pulmonary fibrosis.

BACKGROUND: No study has determined whether the risk of mortality predicted by the GAP (gender, age, and physiologic variables) model matches the observed mortality from idiopathic pulmonary fibrosis (IPF) in non-Western populations. We evaluated the clinical course of IPF and validated the GAP model in Korean patients with IPF. METHODS: We included 268 patients who received a diagnosis of IPF at Seoul National University Hospital between 2005 and 2009. For each patient, demographics and clinical data, such as lung physiologic parameters at IPF diagnosis, were evaluated. We validated the GAP model using discrimination and calibration to predict the risk of death in Korean patients with IPF. RESULTS: The study population comprised 181 men and 87 women (mean age, 65.9 years). The mean baseline % predicted FVC was 77, and % predicted diffusing capacity of lung for carbon monoxide was 65.9. A total of 157 deaths (58.6%) occurred during follow-up, and the median time to death was 4.64 years. The observed cumulative mortality at 1, 2, and 3 years was 10.4%, 20.9%, and 31.0%, respectively. The GAP model produced estimates of 1-year mortality risk consistent with the observed data (C statistic: GAP calculator, 0.74; GAP index and staging system, 0.72; P < .29). However, calibration of the GAP model at 3 years was not satisfactory. CONCLUSIONS: The GAP model showed similar discrimination power compared with the original cohort but did not predict the 3-year risk of death accurately. Further multinational validation studies are needed.

Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) has an unknown etiology and poor prognosis. Several large-scale epidemiologic studies have been conducted predominantly in Western countries. There are few studies reported from Asian countries. It remains unclear whether ethnic difference exists in IPF. It is important to determine the current IPF status in Asian populations and compare it with that of Western populations. OBJECTIVES: To provide the epidemiologic status of IPF in Japan and to investigate ethnic differences. METHODS: We selected Hokkaido prefecture (population, 5.6 million) as the epidemiologic cohort of IPF among Japanese. On the basis of the clinical records of 553 patients with IPF who were accepted based on the application of the Certificate of Medical Benefit between 2003 and 2007, we conducted a retrospective epidemiologic and prognostic analysis. MEASUREMENTS AND MAIN RESULTS: The prevalence and cumulative incidence of IPF was 10.0 and 2.23 per 100,000 population, respectively, with 72.7% predominance of males and an increase in frequency with age. The median survival time was 35 months, and the most common (40%) cause of death was acute exacerbation. The most important factor influencing IPF prognosis was the percent vital capacity. CONCLUSIONS: The status of IPF in the Japanese population was clarified for the first time through our study. Our results showed that in men, the incidence of death caused by acute exacerbation was higher and that caused by cardiovascular disease was lower in Japan than in Western countries. These results may suggest ethnic differences in IPF.

Association of the SNP rs1800925(C/T) in the interleukin-13 gene promoter with pulmonary function in Chinese Han patients with idiopathic pulmonary fibrosis.

The present report studied potential association of the rs1800925(C/T) single nucleotide polymorphism (SNP) of the Interleukin (IL)-13 gene promoter with idiopathic pulmonary fibrosis (IPF) in patients of Chinese Han ethnicity. Seventy patients with IPF were enrolled and divided into three subgroups: group A (61-79 % pred. DLCO; n = 22), group B (51-60% pred. DLCO; n = 20), and group C (≤50% pred. DLCO; n = 28). Control group consisted of 80 healthy individuals of Chinese Han ethnicity. The SNP rs1800925(C/T) was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The IL-13 CC genotype was present in 28/70 (40.0%), homozygous TT in 6/70 (8.6%) and heterozygous CT in 36/70 (51.4%) patients with IPF. In control group, these genotypes were present in 30/80 (37.5%), 11/80 (13.75%), 39/80 (48.75%), respectively, indicating that the distribution of the above three genotypes was not significantly different between patients with IPF and healthy controls. When the patients were stratified according to their DLCO and DLCO/VA, the frequencies of genotypes CT and TT in the groups A, B, and C were, respectively, 40.9% (9/22), 50% (10/20), and 82.1% (23/28). Thus, significant differences in the distribution of alleles at -1112 region of IL-13 gene were observed among the study groups A, B, and C, with the highest frequency in group C (p < 0.05). In conclusion, the rs1800925 T allele of the IL-13 gene is associated with worse pulmonary function in patients with IPF of Chinese Han ethnicity.

TGF-ß1 T869C polymorphism may affect susceptibility to idiopathic pulmonary fibrosis and disease severity.

BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) is a key cytokine that plays a critical role in idiopathic pulmonary fibrosis (IPF). The genotypes of T869C polymorphism may be associated with the susceptibility to fibrotic lung disease. METHODS: We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 (T â†’ C) of the TGF-ß1 gene. Eighty-five healthy controls and 85 subjects with surgically confirmed IPF were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques. RESULTS: The IPF patients consisted of 55 men and 30 women. The mean age was 61 ± 8 years. Fifty-one (60 %) of the 85 IPF patients were smokers and 34 were nonsmokers. The distribution of genotypes between IPF patients and controls was significantly different (IPF: TT 43.5 % and TC or CC 56.5 %; controls: TT 27.1 % and TC or CC 72.9 %, p = 0.037). TT genotype was significantly associated with decreased PaO2 and increased D(A-a)O2 upon initial diagnosis (p = 0.006 and 0.009, respectively). There was a positive association between TT genotype and IPF development (odds ratio [OR] = 2.1, 95 % confidence interval [CI] = 1.1-4.0, p = 0.028). CONCLUSIONS: This study suggests that the TGF-ß1 gene T869C polymorphism may affect susceptibility to IPF in Koreans. Larger studies are required to confirm the genetic association of TGF-ß1 gene polymorphism and IPF.

Ethnic and racial differences in the presence of idiopathic pulmonary fibrosis at death.

BACKGROUND: In studies of idiopathic pulmonary fibrosis (IPF), whites makeup the vast majority of subjects. Whether ethnic/racial differences in idiopathic pulmonary fibrosis occur in the general population is unknown. METHODS: To compare the presence of IPF between ethnic/racial groups of U.S. decedents from 1989 to 2007 by using the National Center for Health Statistics database. RESULTS: There were 251,058 U.S. decedents with IPF; 87.2% were non-Hispanic whites (White), 5.1% were non-Hispanic African American (black), 5.4% were Hispanic, and 2.2% were from other ethnic/racial groups (other). Whites coded with IPF died older than those in the other groups (77.9 years vs. 72.1 years for blacks, 75.3 years for Hispanics, and 75.6 years for others; p < 0.0001 for all pairwise comparisons). When controlling for age and for sex, compared with whites, both Hispanics and Others were more likely to be coded with IPF (OR = 1.47, 95% CI 1.44-1.49, p < 0.0001 and OR = 1.29, 95% CI 1.26-1.36, p < 0.0001 respectively), while blacks were significantly less likely to be coded with IPF (OR = 0.48, 95% CI 0.47-0.49, p < 0.0001). Among decedents with IPF, Hispanics were more likely, and blacks were less likely, than whites to die from IPF (OR = 1.24, 95% CI 1.20-1.29, p < 0.0001 and OR = 0.91, 95% CI 0.87-0.94, p < 0.0001). CONCLUSION: From 1989 to 2007, black decedents were less-and Hispanics were more-likely than whites to die of/with IPF. Research is needed to determine if genetic differences between ethnic/racial groups explain these findings.

Clinical and functional outcomes in Middle Eastern patients with idiopathic pulmonary fibrosis.

BACKGROUND: Baseline clinical and physiological variables have been described as relevant predictors of survival among patients with idiopathic pulmonary fibrosis (IPF). However, substantial heterogeneity in both survival time and mortality has been observed with many of these predictive factors. The incidence and mortality rates of IPF vary from country to country, with race potentially contributing to such variations. OBJECTIVE: We sought to describe baseline clinical features to determine their predictive value among Middle Eastern patients diagnosed with IPF. METHODS: We retrospectively examined 61 patients diagnosed with IPF at a university hospital in Riyadh, Saudi Arabia. RESULTS: At presentation, most patients exhibited either dyspnea or cough. The median survival time for all patients was 92 months. Diminished survival was significantly associated with finger clubbing (P = 0.01). Factors not influencing survival were age, gender, percent predicted forced vital capacity, percent predicted forced expiratory volume in 1 s, percent predicted total lung capacity, percent predicted diffusion capacity of the lung for carbon monoxide and resting oxygen saturation. CONCLUSIONS: Finger clubbing is a significant predictive variable and was associated with a 5-fold increase in mortality. Other baseline demographic characteristics as well as pulmonary function tests were not predictive of prognosis in Middle Eastern patients with IPF. It appears that IPF patients of Middle Eastern descent have a longer median survival curve compared to other races.