Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

Asthmatic patients with high serum amyloid A have proinflammatory HDL: Implications for augmented systemic and airway inflammation.

RATIONALE: Serum amyloid A (SAA) is bound to high-density lipoproteins (HDL) in blood. Although SAA is increased in the blood of patients with asthma, it is not known whether this modifies asthma severity. OBJECTIVE: We sought to define the clinical characteristics of patients with asthma who have high SAA levels and assess whether HDL from SAA-high patients with asthma is proinflammatory. METHODS: SAA levels in serum from subjects with and without asthma were quantified by ELISA. HDLs isolated from subjects with asthma and high SAA levels were used to stimulate human monocytes and were intravenously administered to BALB/c mice. RESULTS: An SAA level greater than or equal to 108.8 µg/mL was defined as the threshold to identify 11% of an asthmatic cohort (n = 146) as being SAA-high. SAA-high patients with asthma were characterized by increased serum C-reactive protein, IL-6, and TNF-α; older age; and an increased prevalence of obesity and severe asthma. HDL isolated from SAA-high patients with asthma (SAA-high HDL) had an increased content of SAA as compared with HDL from SAA-low patients with asthma and induced the secretion of IL-6, IL-1ß, and TNF-α from human monocytes via a formyl peptide receptor 2/ATP/P2X purinoceptor 7 axis. Intravenous administration to mice of SAA-high HDL, but not normal HDL, induced systemic inflammation and amplified allergen-induced neutrophilic airway inflammation and goblet cell metaplasia. CONCLUSIONS: SAA-high patients with asthma are characterized by systemic inflammation, older age, and an increased prevalence of obesity and severe asthma. HDL from SAA-high patients with asthma is proinflammatory and, when intravenously administered to mice, induces systemic inflammation, and amplifies allergen-induced neutrophilic airway inflammation. This suggests that systemic inflammation induced by SAA-high HDL may augment disease severity in asthma.

Serum levels of small HDL particles are negatively correlated with death or lung transplantation in an observational study of idiopathic pulmonary fibrosis.

BACKGROUND: Serum lipoproteins, such as high-density lipoproteins (HDL), may influence disease severity in idiopathic pulmonary fibrosis (IPF). Here, we investigated associations between serum lipids and lipoproteins and clinical end-points in IPF. METHODS: Clinical data and serum lipids were analysed from a discovery cohort (59 IPF subjects, 56 healthy volunteers) and validated using an independent, multicentre cohort (207 IPF subjects) from the Pulmonary Fibrosis Foundation registry. Associations between lipids and clinical end-points (forced vital capacity, 6-min walk distance, gender age physiology (GAP) index, death or lung transplantation) were examined using Pearson's correlation and multivariable analyses. RESULTS: Serum concentrations of small HDL particles measured using nuclear magnetic resonance spectroscopy (S-HDLPNMR) correlated negatively with the GAP index in the discovery cohort of IPF subjects. The negative correlation of S-HDLPNMR with GAP index was confirmed in the validation cohort of IPF subjects. Higher levels of S-HDLPNMR were associated with lower odds of death or its competing outcome, lung transplantation (OR 0.9 for each 1-µmol·L-1 increase in S-HDLPNMR, p<0.05), at 1, 2 and 3 years from study entry in a combined cohort of all IPF subjects. CONCLUSIONS: Higher serum levels of S-HDLPNMR are negatively correlated with the GAP index, as well as with lower observed mortality or lung transplantation in IPF subjects. These findings support the hypothesis that S-HDLPNMR may modify mortality risk in patients with IPF.

Long-term tolerability of phosphodiesterase-5 inhibitors in pulmonary hypertension of sickle cell disease.

OBJECTIVES: Sickle cell disease-related pulmonary hypertension (SCD-PH) is a complex disorder with multifactorial contributory mechanisms. Previous trials have evaluated the efficacy of pulmonary arterial hypertension (PAH) therapies in SCD-PH with mixed results. We hypothesized that a subset of patients with right heart catheterization (RHC) confirmed disease may benefit from PAH therapy. METHODS: We performed a retrospective chart review of patients with SCD-PH diagnosed by RHC who were treated with phosphodiesterase 5 inhibitor (PDE5-I) therapy for ≥4 months between 2008 and 2019 at two institutions. RESULTS: Thirty-six patients were included in the analysis. The median age (IQR) upon PDE5-I initiation was 47.5 years (35-51.5 years); 58% were female and twenty-nine (81%) had HbSS disease. Of these, 53% of patients had a history of acute chest syndrome, 42% had a history of venous thromboembolism, and 38% had imaging consistent with chronic thromboembolic PH. Patients were treated for a median duration of 25 months (IQR 13-60 months). Use of PDE5-I was associated with a significant improvement in symptoms as assessed by NYHA Class (P = .002). CONCLUSIONS: In SCD patients with PH defined by RHC, PDE5-I therapy was tolerated long-term and may improve physical activity.

High density lipoproteins and type 2 inflammatory biomarkers are negatively correlated in atopic asthmatics.

Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL and apoA-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics and 163 nonasthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and NMR spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys® periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL cholesterol and total HDL particles measured by NMR spectroscopy (HDLNMR). Serum periostin levels negatively correlated with total HDLNMR In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma.

Pulmonary artery size as a predictor of outcomes in idiopathic pulmonary fibrosis.

UNLABELLED: IPF patients have heightened propensity for pulmonary hypertension, which portends a worse outcome. Presence of pulmonary hypertension may be reflected in an enlarged pulmonary artery. We investigated pulmonary artery size measured on high-resolution computed tomography (HRCT) as an outcome predictor in IPF.We retrospectively reviewed all IPF patients evaluated at a tertiary-care centre between 2008 and 2013. Pulmonary artery and ascending aorta diameters were measured from chest HRCT with pulmonary artery:ascending aorta diameter (PA:A) ratio calculations. Outcome analysis defined by either death or lung transplant based on pulmonary artery size and PA:A ratio over 60 months was performed. Independent effects of different variables on overall outcomes were evaluated using the Cox proportional hazards model.98 IPF patients with available HRCT scans had a mean pulmonary artery diameter and PA:A ratio of 32.8 mm and 0.94, respectively. Patients with a PA:A ratio >1 had higher risk of death or transplant compared with a PA:A ratio ≤1 (p<0.001). A PA:A ratio >1 was also an independent predictor of outcomes in unadjusted and adjusted outcomes analyses (hazard ratio 3.99, p<0.001 and hazard ratio 3.35, p=0.002, respectively).A PA:A ratio >1 is associated with worse outcomes in patients with IPF. HRCT PA: A ratio measurement may assist in risk stratification and prognostication of IPF patients.

Serum apolipoprotein A-I and large high-density lipoprotein particles are positively correlated with FEV1 in atopic asthma.

RATIONALE: Although lipids, apolipoproteins, and lipoprotein particles are important modulators of inflammation, varying relationships exist between these parameters and asthma. OBJECTIVES: To determine whether serum lipids and apolipoproteins correlate with the severity of airflow obstruction in subjects with atopy and asthma. METHODS: Serum samples were obtained from 154 atopic and nonatopic subjects without asthma, and 159 subjects with atopy and asthma. Serum lipid and lipoprotein levels were quantified using standard diagnostic assays and nuclear magnetic resonance (NMR) spectroscopy. Airflow obstruction was assessed by FEV1% predicted. MEASUREMENTS AND MAIN RESULTS: Serum lipid levels correlated with FEV1 only in the subjects with atopy and asthma. Serum levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) were positively correlated with FEV1 in subjects with atopy and asthma, whereas a negative correlation existed between FEV1 and serum levels of triglycerides, low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), and the apoB/apoA-I ratio. NMR spectroscopy identified a positive correlation between FEV1 and HDLNMR particle size, as well as the concentrations of large HDLNMR particles and total IDLNMR (intermediate-density lipoprotein) particles in subjects with atopy and asthma. In contrast, LDLNMR particle size and concentrations of LDLNMR and VLDLNMR (very-low-density lipoprotein) particles were negatively correlated with FEV1 in subjects with atopy and asthma. CONCLUSIONS: In subjects with atopy and asthma, serum levels of apoA-I and large HDLNMR particles are positively correlated with FEV1, whereas serum triglycerides, LDL cholesterol, and apoB are associated with more severe airflow obstruction. These results may facilitate future studies to assess whether apoA-I and large HDLNMR particles can reduce airflow obstruction and disease severity in asthma.

Gender and the association of smoking with sleep quantity and quality in American adults.

Smoking and gender are known risk factors for sleep disorders. Studies of samples from Norway and Japan have suggested stronger associations between smoking and disrupted sleep in women; therefore, we examined, gender differences in the association in the U.S. population. We analyzed data from the 2005-2006 National Health and Nutrition Examination Survey. We examined the associations between smoking and self-reported measures of sleep disorders (i.e., snoring, short sleep, long sleep, poor sleep, and health care provider diagnosis of sleep disordered breathing) using multivariate logistic regression with odds ratios (OR) and 95% confidence intervals (CI) as measures of association. We also assessed whether the associations varied by gender using a gender x smoking interaction term. Compared to never smokers, current smokers had significantly higher odds of self-reported snoring (OR = 2.0; 95% CI = 1.56-2.56), short sleep (OR 1.68; 95% CI = 1.35-2.10) and poor sleep (OR = 1.38; 95% CI = 1.09-1.74). A dose-response relationship was observed between the amount smoked and sleep symptoms. In multivariate analyses, no significant gender x smoking interaction was observed for snoring, short sleep or poor sleep. Current smoking was independently associated with increased odds of snoring, short sleep, and poor sleep in women and men among U.S. adults.

Transition of PH patients from sildenafil to tadalafil: feasibility and practical considerations.

BACKGROUND: Sildenafil was the only phosphodiesterase-5 inhibitor available for the treatment of pulmonary arterial hypertension (PAH) until the approval and availability of once-daily tadalafil. Since no direct comparative study is likely to be performed between these agents, we sought to evaluate the feasibility of transitioning stable PAH patients from sildenafil to tadalafil. METHODS: The primary end point was continuation on tadalafil without clinical deterioration. A functional outcome through an evaluation of serial change in the 6-min walk test distance (6MWD) was also performed. RESULTS: Thirty-five patients on sildenafil qualified for the analysis, of which 85.7 % (30/35) were successfully transitioned. The remaining 14.3 % (5/30) (failure group) were switched back to sildenafil due to worsening symptoms. The mean pretransition 6MWD was 363 m, with an average change in the success group of +16.4 m (range = -64 to +140 m) compared to -45 m (range = -123 to +32 m) in the failure group at 1-3 months post switch (p = 0.02). All 30 patients in the success group remained on tadalafil, with an average improvement in the 6MWD of +37.04 m (range = -36.5 to +236.5 m) at 12 months post switch. The failure group had a higher daily sildenafil dose (180 vs. 115.5 mg; p = 0.06), with 42.8 % of patients at the highest sildenafil dose failing the transition. CONCLUSION: The transition from sildenafil to tadalafil is safe and generally well tolerated. Patients with more severe disease and those on higher doses of sildenafil are more likely to fail the transition and should be monitored closely post switch.

The value of computed tomography scanning for the detection of coronary artery disease in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Patients with idiopathic pulmonary fibrosis (IPF) have a higher prevalence of coronary artery disease and this could have an impact on their outcomes. We investigated the predictive ability of coronary artery calcification, assessed by routine CT, which may predict the presence of coronary artery disease. METHODS: The study cohort consisted of patients with IPF and with left heart catheterization data plus CT scans from July 2003 to July 2008. Grades of coronary calcification on CT were compared with left heart catheterization determination of coronary artery disease. RESULTS: There were 57 patients in whom left heart catheterization review demonstrated significant coronary artery disease in 28.1% (16/57), mild disease in 40.3% (23/57) and none in 31.6% (18/57). The median time interval between the catheterization and the reviewed CT scan was 39 days. The sensitivity of moderate to severe calcification for significant coronary artery disease was 81%, while the specificity was 85%, with an associated odds ratio of 25.2 (4.64-166, P < 0.005). There was excellent agreement among three radiologists in the grading of coronary calcification. CONCLUSIONS: Coronary calcification, as assessed by routine CT of the chest, has very good performance characteristics in predicting underlying significant coronary artery disease in patients with IPF. The routine availability of this study enables the ready screening for coronary artery disease in IPF patients.

Does 1-minute walk test predict results of 6-minute walk test in patients with idiopathic pulmonary fibrosis?

BACKGROUND: The six-minute walk test (6MWT) is a readily available tool used to evaluate functional capacity in patients with idiopathic pulmonary fibrosis (IPF). However, it is often logistically challenging to perform in the context of a busy clinical practice. We sought to investigate if the 1MWT distance (1MWD) predicts the 6MWT distance (6MWD), and if an abbreviated walk could accurately predict outcomes in IPF patients. METHODS: Baseline demographics and pulmonary function testing of IPF patients evaluated at a tertiary referral center between 2010 and 2017 were collected. 6MWT variables at baseline as well as 1 and 6 minutes were collected. Time to death, lung transplantation, or most recent follow-up was ascertained. RESULTS: There were 177 patients, the majority of whom (80%) were male. The mean age was 67 ± 9 years and mean FVC was 64 ± 18% predicted. Forty eight (27%) patients used oxygen supplementation during the 6MWT. The median 6MWD was 366 meters (IQR: 268-471) while the median 1MWD was 65 meters (IQR: 46-81). Stratified by the median, 89 patients were "High Walkers" based on the 6MWD ≥ 366m (HW6) and 88 patients were "Low Walkers" (LW6). HW6 had a higher FVC% (70 ± 15 vs 57 ± 18, p= 0.001), higher DLCO% (45 ± 12 vs 34 ± 14, p= 0.001) and higher 1MWD (83 ± 28 vs 47 ± 16, m p= 0.001). Median transplant-free survival was better in HW6 vs LW6 (27 ± 16 vs 22 ± 18 months, log rank p= 0.018). There was a strong correlation between the 1MWD and the 6MWD (r= 0.91, Spearman's correlation, p < 0.0001). Also, the transplant-free survival curves stratified by 1MWD were very similar to the curves for 6MWD, showing a lower survival in the LW1 cohort (log rank p= 0.009). CONCLUSION: The 1MWD obtained during the first minute of a 6MWD shows a strong correlation to total 6MWD and retains its ability to predict transplant-free survival. 1MWT may serve as a practical substitute for the more cumbersome 6MWT. Our findings require further validation prospectively in larger cohorts of IPF patients.

Abnormal Ventilation-Perfusion Scan Is Associated with Pulmonary Hypertension in Sickle Cell Adults.

Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality. Chronic thromboembolic PH (CTEPH) is an important complication and contributor to PH in SCD but is likely underappreciated. Guidelines recommend ventilation-perfusion (V/Q) scintigraphy as the imaging modality of choice to exclude CTEPH. Data on V/Q scanning are limited in SCD. Our objective was to compare the performance of V/Q scanning with that of CT pulmonary angiography (CTPA) and to report clinical outcomes associated with abnormal V/Q findings. Methods: Laboratory data, echocardiography, 6-min-walk testing, V/Q scanning, CTPA, and right heart catheterization (RHC) were prospectively obtained. High-probability and intermediate-probability V/Q findings were considered to be abnormal. Included for analysis were 142 SCD adults (aged 40.1 ± 13.7 y, 83 women, 87% hemoglobin SS) in a stable state enrolled consecutively between March 13, 2002, and June 8, 2017. Results: V/Q results were abnormal in 65 of 142 patients (45.8%). CTPA was positive for pulmonary embolism in 16 of 60 (26.7%). RHC confirmed PH (mean pulmonary artery pressure ≥ 25 mmHg) in 46 of 64 (71.9%), of whom 34 (73.9%) had abnormal V/Q findings. Among those without PH by RHC (n = 18), 2 of 18 patients had abnormal V/Q findings. Thirty-three patients had a complete dataset (V/Q scanning, CTPA, and RHC); 29 of 33 had abnormal RHC findings, of whom 26 had abnormal V/Q findings, compared with 11 who had abnormal CTPA findings. There was greater concordance between V/Q findings and RHC (κ-value = 0.53; P < 0.001) than between CTPA and RHC (κ-value = 0.13; P = 0.065). The sensitivity and specificity for V/Q scanning was 89.7% and 75.0%, respectively, whereas CTPA had sensitivity of 37.3% and specificity of 100%. Abnormal V/Q finding swere associated with hemodynamic severity (mean pulmonary artery pressure, 35.2 ± 9.6 vs. 26.9 ± 10.5 mm Hg, P = 0.002; transpulmonary gradient, 21.5 ± 9.7 vs. 12.16 ± 11 mmHg, P = 0.005; and pulmonary vascular resistance, 226.5 ± 135 vs. 140.7 ± 123.7 dynes⋅s⋅cm-5, P = 0.013) and exercise capacity (6-min-walk distance, 382.8 ± 122.3 vs. 442.3 ± 110.6 m, P < 0.010). Thirty-four deaths were observed over 15 y. All-cause mortality was higher in the abnormal-V/Q group (21 [61.8%]) than in the normal-V/Q group (13 [38.2%]) (log-rank test, P = 0.006; hazard ratio, 2.54). Conclusion: V/Q scanning is superior to CTPA in detecting thrombotic events in SCD. Abnormal V/Q findings are associated with PH, worse hemodynamics, lower functional capacity, and higher mortality. Despite high sensitivity in detecting CTEPH, V/Q scanning is underutilized. We recommend the use of V/Q scanning in the evaluation of dyspnea in adult SCD patients given the important implications toward management.

Identifying Clinical and Research Priorities in Sickle Cell Lung Disease. An Official American Thoracic Society Workshop Report.

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality.Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1) acute chest syndrome, 2) lower airways disease and pulmonary function, 3) sleep-disordered breathing and hypoxia, and 4) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus.Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation.Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

Riociguat use in sickle cell related chronic thromboembolic pulmonary hypertension: A case series.

Adults with sickle cell disease can develop pulmonary hypertension from a multitude of etiologies. Classified as WHO Group 5, there are no therapies approved for the treatment of sickle cell disease-pulmonary hypertension. Thromboembolic disease is prevalent in sickle cell disease and can lead to pulmonary hypertension. The only approved medical therapy for chronic thromboembolic pulmonary hypertension is riociguat. We report the experience, safety and tolerability of riociguat use in a series of sickle cell disease patients with chronic thromboembolic pulmonary hypertension.

Spironolactone-induced degradation of the TFIIH core complex XPB subunit suppresses NF-κB and AP-1 signalling.

Aims: Spironolactone (SPL) improves endothelial dysfunction and survival in heart failure. Immune modulation, including poorly understood mineralocorticoid receptor (MR)-independent effects of SPL might contribute to these benefits and possibly be useful in other inflammatory cardiovascular diseases such as pulmonary arterial hypertension. Methods and results: Using human embryonic kidney cells (HEK 293) expressing specific nuclear receptors, SPL suppressed NF-κB and AP-1 reporter activity independent of MR and other recognized nuclear receptor partners. NF-κB and AP-1 DNA binding were not affected by SPL and protein synthesis blockade did not interfere with SPL-induced suppression of inflammatory signalling. In contrast, proteasome blockade to inhibit degradation of xeroderma pigmentosum group B complementing protein (XPB), a subunit of the general transcription factor TFIIH, or XPB overexpression both prevented SPL-mediated suppression of inflammation. Similar to HEK 293 cells, a proteasome inhibitor blocked XPB loss and SPL suppression of AP-1 induced target genes in human pulmonary artery endothelial cells (PAECs). Unlike SPL, eplerenone (EPL) did not cause XPB degradation and failed to similarly suppress inflammatory signalling. SPL combined with siRNA XPB knockdown further reduced XPB protein levels and had the greatest effect on PAEC inflammatory gene transcription. Using chromatin-immunoprecipitation, PAEC target gene susceptibility to SPL was associated with low basal RNA polymerase II (RNAPII) occupancy and TNFα-induced RNAPII and XPB recruitment. XP patient-derived fibroblasts carrying an N-terminal but not C-terminal XPB mutations were insensitive to both SPL-mediated XPB degradation and TNFα-induced target gene suppression. Importantly, SPL treatment decreased whole lung XPB protein levels in a monocrotaline rat model of pulmonary hypertension and reduced inflammatory markers in an observational cohort of PAH patients. Conclusion: SPL has important anti-inflammatory effects independent of aldosterone and MR, not shared with EPL. Drug-induced, proteasome-dependent XPB degradation may be a useful therapeutic approach in cardiovascular diseases driven by inflammation.

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

BACKGROUND: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.