Proportion and predictors of FVC decline in patients with interstitial lung disease.

RATIONALE: The proportion of patients who develop progressive pulmonary fibrosis (PPF), along with risk factors for progression remain poorly understood. OBJECTIVES: To examine factors associated with an increased risk of developing PPF among patients at a referral center. METHODS: We identified patients with a diagnosis of interstitial lung disease (ILD) seen within the Cleveland Clinic Health System. Utilizing a retrospective observational approach we estimated the risk of developing progression by diagnosis group and identified key clinical predictors using the FVC component of both the original progressive fibrotic interstitial lung disease (PFILD) and the proposed PPF (ATS) criteria. RESULTS: We identified 5934 patients with a diagnosis of ILD. The cumulative incidence of progression over the 24 months was similar when assessed with the PFILD and PPF criteria (33.1 % and 37.9 % respectively). Of those who met the ATS criteria, 9.5 % did not meet the PFILD criteria. Conversely, 4.3 % of patients who met PFILD thresholds did not achieve the 5 % absolute FVC decline criteria. Significant differences in the rate of progression were seen based on underlying diagnosis. Steroid therapy (HR 1.46, CI 1.31-1.62) was associated with an increased risk of progressive fibrosis by both PFILD and PPF criteria. CONCLUSION: Regardless of the definition used, the cumulative incidence of progressive disease is high in patients with ILD in the 24 months following diagnosis. Some differences are seen in the risk of progression when assessed by PFILD and PPF criteria. Further work is needed to identify modifiable risk factors for the development of progressive fibrosis.

Impact of Baseline Neuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study.

INTRODUCTION: Hereditary transthyretin (ATTRv, v for variant) amyloidosis is a rare, progressive, fatal disease with multisystem manifestations, caused by pathogenic variants in the transthyretin (TTR) gene. Vutrisiran, an RNA interference therapeutic that results in rapid TTR knockdown, improved neuropathy and quality of life (QOL) versus external placebo in patients with ATTRv amyloidosis with polyneuropathy in the phase 3 HELIOS-A study (NCT03759379). This post hoc analysis evaluates the impact of baseline neuropathy severity on response to vutrisiran treatment. METHODS: Patients were randomized (3:1) to vutrisiran (n = 122; 25 mg subcutaneous injection once every 3 months) or patisiran (n = 42; 0.3 mg/kg intravenous infusion once every 3 weeks), which served as a reference group. In this post hoc analysis, patients were grouped into quartiles of increasing baseline Neuropathy Impairment Score (NIS): Quartile (Q)1 ≥ 5.0 to ≤ 20.5; Q2 > 20.5 to ≤ 44.1; Q3 > 44.1 to ≤ 73.1; Q4 > 73.1 to ≤ 127.0. Mean change from baseline to Month 18 was summarized by quartile for a range of efficacy endpoints. RESULTS: Across all baseline NIS quartiles, vutrisiran demonstrated benefit versus external placebo in measures of neuropathy severity (modified NIS + 7), QOL (Norfolk Quality of Life-Diabetic Neuropathy), disability (Rasch-built Overall Disability Scale), gait speed (10-m walk test), and nutritional status (modified body mass index). Overall, patients in lower versus higher NIS quartiles (less severe neuropathy) at baseline maintained better scores at Month 18. The external placebo group progressively worsened in all measures at Month 18. CONCLUSIONS: Vutrisiran demonstrated benefit in neurologic function and other key efficacy measures versus external placebo across all four baseline neuropathy severity quartiles. Patients initiating vutrisiran earlier in their disease course retained the highest neurologic function level after 18 months, highlighting the importance of early diagnosis and treatment. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03759379.

Lung function trajectories in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterised by decline in lung function. We evaluated trajectories of forced vital capacity (FVC) and diffusing capacity (DLco) in a cohort of patients with IPF. METHODS: Patients with IPF that was diagnosed or confirmed at the enrolling centre in the previous 6 months were enrolled into the IPF-PRO Registry between June 2014 and October 2018. Patients were followed prospectively, with lung function data collected as part of routine clinical care. Mean trajectories of FVC and DLco % predicted in all patients and in subgroups by characteristics assessed at enrolment were estimated using a joint model that accounted for factors such as disease severity and visit patterns. RESULTS: Of 1002 patients in the registry, 941 had ≥ 1 FVC and/or DLco measurement after enrolment. The median (Q1, Q3) follow-up period was 35.1 (18.9, 47.2) months. Overall, mean estimated declines in FVC and DLco % predicted were 2.8% and 2.9% per year, respectively. There was no evidence that the mean trajectories of FVC or DLco had a non-linear relationship with time at the population level. Patients who were male, white, had a family history of ILD, were using oxygen, or had prior/current use of antifibrotic therapy at enrolment had greater rates of decline in FVC % predicted. Patients who were male or white had greater rates of decline in DLco % predicted. CONCLUSIONS: Data from the IPF-PRO Registry suggest a constant rate of decline in lung function over a prolonged period, supporting the inexorably progressive nature of IPF. A graphical abstract summarising the data in this manuscript is available at: https://www.usscicomms.com/respiratory/IPF-PRORegistry_LungFunctionTrajectories . TRIAL REGISTRATION: NCT01915511.

Anti-fibrotic therapy and lung transplant outcomes in patients with idiopathic pulmonary fibrosis.

BACKGROUND: It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis. OBJECTIVES: To investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications. METHODS: We assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone. RESULTS: Among patients taking nintedanib (n = 107) or pirfenidone (n = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], p = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], p = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant. CONCLUSION: Anastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued. REGISTRATION: clinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT04316780.

Effect of Antifibrotic Therapy on Survival in Patients With Idiopathic Pulmonary Fibrosis.

PURPOSE: Real-world studies have reported reduced mortality in patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotic therapy; however, the initiation or discontinuation of therapy during these studies may have introduced bias. This study investigated the effect of antifibrotic therapy on mortality and other outcomes in patients with IPF using causal inference methodology. METHODS: Data from a multicenter US registry of patients with IPF were used to assess the effect of antifibrotic therapy (nintedanib or pirfenidone) on death, death or lung transplant, respiratory-related hospitalization, and acute worsening of IPF (defined as any health care encounter deemed due to acute worsening of IPF). This study used the Gran method, which accounts for differences in patient characteristics and for treatment initiations and discontinuations during follow-up. The analysis cohort was limited to patients who started antifibrotic therapy on or after the day of enrollment or had never taken it. FINDINGS: Among the 499 patients analyzed, 352 (70.5%) received antifibrotic therapy. Estimated event rates of death at 1 year were 6.6% (95% CI, 6.1-7.1) for treated patients and 10.2% (95% CI, 9.5-10.9) for control patients. There was a numerical reduction in the risk of death (hazard ratio [HR], 0.53; 95% CI, 0.28-1.03; P = 0.060) but numerical increases in risks of respiratory-related hospitalization (HR, 1.88; 95% CI, 0.90-3.92; P = 0.091) and acute worsening of IPF (HR, 1.71; 95% CI, 0.36-8.09; P = 0.496) in treated versus control patients. IMPLICATIONS: Analyses based on causal inference methodology suggest that patients with IPF who receive antifibrotic therapy have improved survival.

Use of Concurrent Anti-diabetes Medications in Patients With Type 2 Diabetes in Clinical Practice in the United States.

PURPOSE: This report describes the use of combination therapy in patients with type 2 diabetes mellitus (T2DM) who had been initially prescribed metformin in the United States. METHODS: Retrospective claims data from a de-identified database were used to identify individuals aged ≥18 years with ≥1 claim for a metformin-containing regimen dated between January 1, 2018, and December 31, 2018. Demographics, insurance type, and prescriber type were compared among subgroups receiving two (dual) or three or more (triple+) anti-diabetes therapies. All analyses were descriptive; no formal comparisons were conducted. FINDINGS: Data from 353,062 patients were included. Demographic and other baseline characteristics were similar between the groups receiving dual or triple+ therapy (n = 213,871 and 139,191, respectively). A small age difference was observed between patients receiving dual versus triple+ therapy (mean [SD], 66.5 [11.8] and 65.8 [10.8] years, respectively). Mean (SD) glycosylated hemoglobin levels were lower among patients receiving dual therapy versus triple+ therapy: 7.6% (1.7) versus 8.0% (1.7). The most frequent combination was metformin plus a sulfonylurea (33.4%). The percentage receiving combination therapy with newer treatments was relatively low, and slightly greater in younger patients. Total health care costs were similar with dual and triple+ therapies. IMPLICATIONS: The current descriptive analysis demonstrated generally similar features, with regard to the evaluated factors, in cohorts receiving dual versus triple+ T2DM therapy. However, differences between unmeasured factors could exist and require further evaluation. These findings, based on data from a cohort of patients from clinical practice who had initially been prescribed metformin, provide a useful snapshot of current prescribing practices and can be used to inform future research and evidence-based policy decisions.

Disparities in Lung Transplant among Patients with Idiopathic Pulmonary Fibrosis: An Analysis of the IPF-PRO Registry.

Rationale: Lung transplant offers the potential to extend life for patients with idiopathic pulmonary fibrosis (IPF); yet, this therapeutic modality is only available to a small proportion of patients. Objectives: To identify clinical characteristics and social determinants of health that differentially associate with lung transplant compared with death in patients with IPF. Methods: We evaluated data from the Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry, a multicenter U.S. registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were enrolled between June 2014 and October 2018. Patients who were listed for lung transplant were not eligible to enroll in the registry, but patients could be listed for transplant after enrollment. We performed a multivariable time-to-event analysis incorporating competing risks methodology to examine differential associations between prespecified covariates and the risk of lung transplant versus death. Covariates included factors related to lung transplant eligibility, clinical characteristics of IPF, and social determinants of health. Covariates were modeled as time independent or time dependent as appropriate. Results: Among 955 patients with IPF, event rates of lung transplant and death were 7.4% and 16.3%, respectively, at 2 years. Covariates with the strongest differential association were age, median zip code income, and enrollment at a center with a lung transplant program. Lung transplant was less likely (hazard ratio [HR], 0.13 [95% confidence interval (CI), 0.06-0.28] per 5-yr increase) and death more likely (HR, 1.41 [95% CI, 1.22-1.64] per 5-yr increase) among those older than 70 years of age. Higher median zip code income was associated with lung transplant (HR, 1.22 [95% CI, 1.13-1.31] per $10,000 increase) but not death (HR, 0.99 [95% CI, 0.94-1.04] per $10,000 increase). Enrollment at a center with a lung transplant program was associated with lung transplant (HR, 4.31 [95% CI, 1.76-10.54]) but not death (HR, 0.99 [95% CI, 0.69-1.43]). Oxygen use with activity was associated with both lung transplant and death, but more strongly with lung transplant. A higher number of comorbidities was associated with an increased likelihood of death but not lung transplant. Conclusions: For patients in the Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry, median zip code income and access to a lung transplant center differentially impact the risk of lung transplant compared with death, regardless of disease severity measures or other transplant eligibility factors. Interventions are needed to mitigate inequalities in lung transplantation based on socioeconomic status. Clinical trial registered with www.clinicaltrials.gov (NCT01915511).

Clinical Outcomes of Patients with Combined Idiopathic Pulmonary Fibrosis and Emphysema in the IPF-PRO Registry.

PURPOSE: To assess the impact of concomitant emphysema on outcomes in patients with idiopathic pulmonary fibrosis (IPF). METHODS: The IPF-PRO Registry is a US registry of patients with IPF. The presence of combined pulmonary fibrosis and emphysema (CPFE) at enrollment was determined by investigators' review of an HRCT scan. Associations between emphysema and clinical outcomes were analyzed using Cox proportional hazards models. RESULTS: Of 934 patients, 119 (12.7%) had CPFE. Compared with patients with IPF alone, patients with CPFE were older (median 72 vs 70 years); higher proportions were current/former smokers (88.2% vs 63.7%), used oxygen with activity (49.6% vs 31.9%) or at rest (30.8% vs 18.4%), had congestive heart failure (13.6% vs 4.8%) and had prior respiratory hospitalization (25.0% vs 16.7%); they had higher FVC (median 71.8 vs 69.4% predicted) and lower DLco (median 35.3 vs 43.6% predicted). In patients with CPFE and IPF alone, respectively, at 1 year, rates of death or lung transplant were 17.5% (95% CI: 11.7, 25.8) and 11.2% (9.2, 13.6) and rates of hospitalization were 21.6% (14.6, 29.6) and 20.6% (17.9, 23.5). There were no significant associations between emphysema and any outcome after adjustment for baseline variables. No baseline variable predicted outcomes better in IPF alone than in CPFE. CONCLUSION: Approximately 13% of patients in the IPF-PRO Registry had CPFE. Physiologic characteristics and comorbidities of patients with CPFE differed from those of patients with IPF alone, but the presence of emphysema did not drive outcomes after adjustment for baseline covariates. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01915511; registered August 5, 2013.

Associations between resources and practices of ILD centers and outcomes in patients with idiopathic pulmonary fibrosis: data from the IPF-PRO Registry.

BACKGROUND: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes. METHODS: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient case mix by adjusting for known predictors of each outcome. We assessed whether site-level heterogeneity existed for each patient-level outcome, and if so, we investigated potential drivers of the heterogeneity. RESULTS: All 27 sites that enrolled ≥ 10 patients returned the questionnaire. Most sites were actively following > 100 patients with IPF (70.4%), had a lung transplant program (66.7%), and had a dedicated ILD nurse leader (77.8%). Substantial heterogeneity was observed in the event rates of clinically relevant outcomes across the sites. After controlling for patient case mix, there were no outcomes for which the site variance component was significantly different from 0, but the p-value for hospitalization was 0.052. Starting/completing an ILD-related quality improvement project in the previous 2 years was associated with a lower risk of hospitalization (HR 0.60 [95% CI 0.44, 0.82]; p = 0.001). CONCLUSIONS: Analyses of data from patients with IPF managed at sites across the US found no site-specific characteristics or practices that were significantly associated with clinically relevant outcomes after adjusting for patient case mix. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511.

Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009).

Implementation of guideline recommendations and outcomes in patients with idiopathic pulmonary fibrosis: Data from the IPF-PRO registry.

BACKGROUND: Few data are available on the extent to which clinical practice is aligned with international guidelines for the management of idiopathic pulmonary fibrosis (IPF). We investigated the extent to which management guidelines for IPF have been implemented in the US IPF-PRO Registry and associations between implementation of guidelines and clinical outcomes. METHODS: We assessed the implementation of eight recommendations in clinical practice guidelines within the 6 months after enrollment: visit to a specialized clinic; pulmonary function testing; use of oxygen in patients with resting hypoxemia and exercise-induced hypoxemia; referral for pulmonary rehabilitation; treatment of gastro-esophageal reflux disease; initiation of anti-fibrotic therapy; referral for lung transplant evaluation. An implementation score was calculated as the number of recommendations achieved divided by the number for which the patient was eligible. Associations between implementation score and outcomes were analyzed using logistic regression and Cox proportional hazards models. RESULTS: Among 727 patients, median (Q1, Q3) implementation score was 0.6 (0.5, 0.8). Patients with an implementation score >0.6 had greater disease severity than those with a lower score. Implementation was lowest for referral for pulmonary rehabilitation (19.5%) and lung transplant evaluation (22.3%). In unadjusted models, patients with higher implementation scores had a greater risk of death, death or lung transplant, and hospitalization, but no significant associations were observed in adjusted models. CONCLUSIONS: Management guidelines were more likely to be implemented in patients with IPF with greater disease severity. When adjusted for disease severity, no association was found between implementation of management guidelines and clinical outcomes.

Hospitalizations in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Hospitalizations are common among patients with idiopathic pulmonary fibrosis (IPF). We investigated the impact of hospitalizations on outcomes in patients with IPF. METHODS: The IPF-PRO Registry is an observational US registry that enrolled patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Associations between patient characteristics and hospitalization, and between hospitalization and mortality, were analyzed using Cox regression models. RESULTS: A total of 1002 patients with IPF were enrolled into the IPF-PRO Registry. Over a median follow-up time of 23.7 months (maximum: 67.0 months), 568 patients (56.7%) had at least one hospitalization. Of these patients, 319 (56.2%) had at least one respiratory-related hospitalization and 120 (21.1%) had at least one hospitalization with ventilatory support. Younger age (HR 0.68 [95% CI 0.55, 0.84] per 5-year increase for patients < 62 years), lower BMI (0.96 [0.93, 0.98] per 1-point increase), lower FVC % predicted (0.90 [0.83, 0.97] per 10% increase), oxygen use at rest (2.85 [2.18, 3.72]) and history of pulmonary hypertension (2.02 [1.37, 2.96]) at enrollment were associated with an increased risk of respiratory-related hospitalization during follow-up. In a multivariable model, there was an eightfold increase in the risk of mortality during hospitalization or within 90 days of discharge compared with outside of this period. The risk of mortality associated with a respiratory hospitalization or a hospitalization with ventilatory support was even greater. CONCLUSIONS: Data from the IPF-PRO Registry demonstrate that hospitalizations are common among patients with IPF. The risk of mortality during hospitalization or within 90 days of discharge was high, particularly among patients who were hospitalized for a respiratory cause or received ventilatory support. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511.

Changes in Body Composition, Muscle Strength, and Fat Distribution Following Kidney Transplantation.

RATIONALE & OBJECTIVE: Low muscle mass relative to fat mass (relative sarcopenia) has been associated with mortality and disability but has not been examined after kidney transplantation. We studied how measures of body composition change after receipt of a kidney allograft. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 60 kidney transplant recipients, aged 20-60 years, at the University of Pennsylvania. EXPOSURE: Kidney transplantation. OUTCOME: Dual-energy x-ray absorptiometry measures of fat mass index (FMI) and appendicular lean mass index (ALMI, representing muscle mass), computed tomography measures of muscle density (low density represents increased intramuscular adipose tissue), dynamometer measures of leg muscle strength, and physical activity. ALMI relative to FMI (ALMFMI) is an established index of relative sarcopenia. ANALYTICAL APPROACH: Measures expressed as age, sex, and race-specific z scores for transplant recipients were compared with 327 healthy controls. Regression models were used to identify correlates of change in outcome z scores and compare transplant recipients with controls. RESULTS: At transplantation, ALMI, ALMIFMI, muscle strength, and muscle density z scores were lower versus controls (all P≤0.001). Transplant recipients received glucocorticoids throughout. The prevalence of obesity increased from 18% to 45%. Although ALMI increased after transplantation (P<0.001) and was comparable with the controls from 6 months onward, gains were outpaced by increases in FMI, resulting in persistent ALMIFMI deficits (mean z score of-0.31 at 24 months; P=0.02 vs controls). Muscle density improved after transplantation despite gains in FMI (P=0.02). Muscle strength relative to ALMI also improved (P=0.04) but remained low compared with controls (P=0.01). Exercise increased in the early months after transplantation (P<0.05) but remained lower than controls (P = 0.02). LIMITATIONS: Lack of muscle biopsies precluded assessment of muscle histology and metabolism. CONCLUSIONS: The 2-year interval after kidney transplantation was characterized by gains in muscle mass and strength that were outpaced by gains in fat mass, resulting in persistent relative sarcopenia.

Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung: Final analysis of the randomised phase 3 LUX-Lung 8 trial.

BACKGROUND: LUX-Lung 8 was a randomised, controlled, phase 3 study comparing afatinib and erlotinib as second-line treatment of patients with advanced squamous cell carcinoma (SCC) of the lung. We report the final overall survival (OS) and safety analyses of LUX-Lung 8 and investigate the characteristics of patients who achieved long-term benefit (≥12 months' treatment). METHODS: LUX-Lung 8 (NCT01523587) enroled patients between March 2012 and January 2014 in 183 cancer centres located in 23 countries worldwide and this final analysis had a data cut-off of March 2018. Eligible patients had stage IIIB or IV lung SCC and had progressed after at least four cycles of platinum-based chemotherapy. Patients were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. Endpoints included OS and safety; a post-hoc analysis of patients with long-term benefit (≥12 months on treatment) was also conducted. FINDINGS: 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). OS was significantly prolonged with afatinib compared with erlotinib (median 7·8 months vs 6·8 months; hazard ratio 0·84; 95% CI 0·73-0·97; p = 0·0193). These findings were consistent with those of the primary analysis and were consistent across subgroups. Adverse events (AEs) were manageable with dose interruption and reduction, with similar AEs being experienced between both groups. Twenty-one (5·3%) patients receiving afatinib and 13 (3·3%) patients receiving erlotinib achieved long-term benefit; median OS was 34·6 months and 20·1 months, respectively. Amongst 132 afatinib-treated patients who underwent tumour genetic analysis, ERBB family mutations were more common in patients with long-term benefit than in the overall population (50% vs 21%). INTERPRETATION: Afatinib is a treatment option for patients with SCC of the lung progressing on chemotherapy who are ineligible for immunotherapy, particularly those with ERBB family genetic aberrations. Afatinib has a predictable and manageable tolerability profile, and long-term treatment may be well tolerated.

Characteristics of hospitalizations and emergency department visits due to generalized pustular psoriasis in the United States.

OBJECTIVES: Generalized pustular psoriasis (GPP) is a rare and severe, inflammatory skin disease. GPP is characterized by recurrent flares that consist of disseminated erythematous skin rash with sterile neutrophil-filled pustules that can result in an emergency department (ED) visit or hospital stay due to systemic complications. This study characterizes hospitalizations, ED visits, and inpatient treatment due to GPP in the United States (US). METHODS: A descriptive, retrospective cross-sectional analysis was conducted in Cerner Health Facts, a US electronic medical record database. Hospitalizations and ED visits were identified between 1 October 2015 and 1 July 2017. Visits were included in the study if they were GPP-related, defined as a GPP diagnosis (ICD-10-CM code: L40.1) in the first or second position at admission or discharge, and if the discharge date was within the study period. Hospitalizations and ED visits were the units of analysis. Demographics, comorbidities, medication use, and outcomes were characterized with descriptive statistics. Outcomes included length of stay, intensive care unit (ICU) admission, and death. RESULTS: A total of 71 GPP-related hospitalizations and 64 GPP-related ED visits were included in the study. Other specified inflammatory skin conditions (OSICS)/skin and subcutaneous tissue infections (54%/34%), fluid and electrolyte disorders (46%), hypertension (30%), septicemia (24%), and acute renal failure (18%) were the most frequently coded conditions accompanying a GPP-related hospitalization. OSICS/skin and subcutaneous tissue infections (47%/42%) were the most commonly coded conditions accompanying a GPP-related ED visit. Medication use during GPP-related hospitalizations included topicals (triamcinolone (42%); clobetasol (17%)), systemic corticosteroids (prednisone (20%); methylprednisolone (11%)), and non-biologic and biologic immunosuppressants (cyclosporine (6%); methotrexate (4%); etanercept (1%)). Analgesics (acetaminophen 67%; morphine 24%), and antibiotics (vancomycin 21%) were also common. The median length of stay for hospitalizations was 5 days. Three hospitalizations included an ICU admission and two hospitalizations resulted in death. CONCLUSIONS: The presence of concurrent immune-mediated conditions, and frequent prescribing of analgesics, including opioids, illustrate the burden of GPP in patients requiring acute and inpatient care.

The first-order Markov conditional linear expectation approach for analysis of longitudinal data.

We consider longitudinal discrete data that may be unequally spaced in time and may exhibit overdispersion, so that the variance of the outcome variable is inflated relative to its assumed distribution. We implement an approach that extends generalized linear models for analysis of longitudinal data and is likelihood based, in contrast to generalized estimating equations (GEE) that are semiparametric. The method assumes independence between subjects; first-order antedependence within subjects; exponential family distributions for the first outcome on each subject and for the subsequent conditional distributions; and linearity of the expectations of the conditional distributions. We demonstrate application of the method in an analysis of seizure counts and in a study to evaluate the performance of transplant centers. Simulations for both studies demonstrate the benefits of the proposed likelihood based approach; however, they also demonstrate better than anticipated performance for GEE.

A retrospective study of in-hospital mortality in patients with idiopathic pulmonary fibrosis between 2015 and 2018.

Hospitalizations are common in patients with idiopathic pulmonary fibrosis (IPF) and are associated with high mortality. We used data from the Premier Healthcare Database to determine in-hospital mortality rates and the factors associated with in-hospital mortality in patients with IPF in the era of approved antifibrotic drugs.The Premier Healthcare Database is a detailed and broadly representative database of hospital admissions and discharges in the US. Patients with IPF who were hospitalized between 1 January 2015 and 28 February 2018 were identified using a diagnostic algorithm comprising International Classification of Diseases -9 and International Classification of Diseases -10 diagnostic codes and billing data. Associations between patient-, hospital- and treatment-related factors and a composite outcome of death during the index visit, lung transplant during the index visit but >1 day after admission, or death during a readmission within 90 days of the index visit were analyzed using logistic regression.The cohort comprised 9667 hospitalized patients with IPF. In total, 1414 patients (14.6%) met the composite outcome: 1036 (10.7%) died during the index visit, 371 (3.8%) died during a readmission within 90 days; 7 (0.1%) underwent lung transplant >1 day after admission. Factors significantly associated with a higher risk of the composite outcome included mechanical ventilation (odds ratio 6.41 [95% CI: 5.24, 7.84]), admission to the intensive care unit (1.73 [1.49, 2.00]), attendance by a critical care physician (2.12 [1.33, 3.38]), older age (1.20 [1.12, 1.28] per 10-year increase), and use of intravenous steroids (1.16 [1.00, 1.34]), intravenous antibiotics (1.49 [1.22, 1.83]) and opioids (3.41 [2.95, 3.93]). Factors significantly associated with a lower risk of the composite outcome included female sex (0.70 [0.61, 0.80]), comorbid chronic obstructive pulmonary disease (0.69 [0.60, 0.78]), attendance by a family medicine physician (0.67 [0.48, 0.94]) or internal medicine physician (0.59 [0.46, 0.75]), and use of oral steroids (0.62 [0.51, 0.77]), statins (0.76 [0.67, 0.87]) and proton pump inhibitors (0.80 [0.70, 0.92]).In conclusion, patients with IPF are at risk of mortality during a hospital stay or readmission within 90 days, particularly those who receive mechanical ventilation.

Incidence and prevalence of systemic sclerosis and systemic sclerosis with interstitial lung disease in the United States.

BACKGROUND: Although systemic sclerosis (SSc) with interstitial lung disease (SSc-ILD) is a serious condition and incurs a substantial clinical burden, the epidemiology has not been well characterized. OBJECTIVE: To estimate the incidence and prevalence of SSc and SSc-ILD among commercially insured adults in the United States. METHODS: Adults with medical claims between 2011 and 2016 for SSc or SSc-ILD with and without high-resolution computed tomography scans were identified from the Optum Clinformatics Data Mart. Incidence and prevalence were calculated as rates per 100,000 person-years and 100,000 people, respectively. The crude and age- and sex-adjusted prevalence and incidence of SSc and SSc-ILD were estimated and stratified by year and geography. Sensitivity analyses were conducted based on different cohort identification algorithms. RESULTS: Overall, the crude incidence rates of SSc and SSc-ILD were 16.4 and 1.2 per 100,000 person-years, respectively, and the crude prevalence was 24.4 and 6.9 per 100,000 people, respectively. Patient characteristics were generally similar between the SSc and SSc-ILD groups. Mean age range was 59.2-59.9 years and 61.8-62.9 years in the SSc and SSc-ILD groups, respectively. SSc had an age- and sex-adjusted incidence rate of 15.1 per 100,000 person-years and an adjusted prevalence of 25.9 per 100,000 people. The adjusted incidence rate of SSc-ILD was 1.1 per 100,000 person-years and the adjusted prevalence was 7.3 per 100,000 people. CONCLUSIONS: This study provides current estimates of the national incidence and prevalence of SSc and SSc-ILD, which have not been previously well characterized. Further research in the future may help to support health management strategies and resource allocation for adults with SSc and SSc-ILD in the United States. DISCLOSURES: This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI), which reviewed the manuscript for medical and scientific accuracy, as well as intellectual property considerations. All authors are employed by BIPI and did not receive direct compensation related to the development of the manuscript.

Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Global Pharmacovigilance Data.

INTRODUCTION: The safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) have been characterized using data from clinical trials. METHODS: We further characterized the safety and tolerability of nintedanib in patients with IPF in clinical practice using the global pharmacovigilance database. The database included spontaneously reported adverse events and data collected via solicited reporting in patients treated with nintedanib from 15 October 2014 to 15 October 2018. Adverse events were coded using the Medical Dictionary for Regulatory Activities. Cumulative exposure to nintedanib was estimated on the basis of sales data. RESULTS: Cumulative exposure to nintedanib was estimated as 60,107 patient-years. Diarrhea was the most frequent event (301.6 events per 1000 patient-years). Most (97.0%) diarrhea events were non-serious. The median (25th, 75th percentile) time to onset of the first diarrhea event was 60 (11, 182) days. Elevated liver enzyme or bilirubin levels were reported at a rate of 31.5 events per 1000 patient-years. Bleeding was reported at a rate of 36.8 events per 1000 patient-years; 81.0% of events were non-serious. Major cardiovascular adverse events were reported at a rate of 13.4 events per 1000 patient-years and myocardial infarction at a rate of 4.3 events per 1000 patient-years. Gastrointestinal perforation was reported at a rate of 1.0 event per 1000 patient-years. CONCLUSIONS: On the basis of pharmacovigilance data collected over 4 years, the safety profile of nintedanib in patients with IPF was consistent with that observed in clinical trials and described in the product label, with no new safety concerns observed.

Time to diagnosis of idiopathic pulmonary fibrosis in the IPF-PRO Registry.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. Patient characteristics associated with diagnostic delays are not well described. METHODS: Subjects who had not been diagnosed with IPF prior to referral and received a new diagnosis of IPF at an enrolling centre for the IPF-PRO (Idiopathic Pulmonary Fibrosis Prospective Outcomes) Registry were characterised as having a longer (>1 year) or shorter (≤1 year) time from symptom onset to diagnosis and from first imaging evidence of fibrosis to diagnosis. Patient characteristics, evaluations and time to death or lung transplant were compared between these cohorts. RESULTS: Among 347 patients with a symptom onset date, 49% were diagnosed with IPF >1 year after symptom onset. These patients were slightly younger and had more cardiac comorbidities than patients diagnosed ≤1 year after symptom onset. Among 454 patients with a date for imaging evidence of fibrosis, 78% were diagnosed with IPF ≤1 year later. A greater proportion of patients with >1 year versus ≤1 year from imaging evidence of fibrosis to diagnosis had cardiac comorbidities and gastro-oesophageal reflux. There was no significant difference in time to death or lung transplant between groups by time to diagnosis. CONCLUSIONS: The time from symptom onset to diagnosis remains over 1 year in approximately half of the patients with IPF, but once imaging evidence is obtained, most of the patients are diagnosed within a year. Cardiac conditions and gastro-oesophageal disorders were more commonly reported in patients with a longer time to diagnosis.