Introduction Smoked tobacco is a leading risk factor for cardiopulmonary disease. Pipe and cigar use remains common among US adults, yet its risks remain insufficiently understood.Methods We analysed data from five pooled cohorts with adults enrolled from 1971 to 2011 with follow-up through 2018. Pipe/cigar use was defined by baseline self-report. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were measured by spirometry. All-cause mortality, coronary heart disease mortality and hospitalisation, respiratory-related mortality, and chronic obstructive pulmonary disease (COPD) mortality and hospitalisation were classified via adjudication or validated algorithms. Associations were estimated with linear mixed models and Fine-Gray subdistribution hazards models adjusted for sociodemographic and clinical factors.Results Among 22 823 participants (mean (SD) age 48.0 (15.7) years; 44.9% male sex; 70.5% white, 25.4% black, 2.4% Hispanic/Latino), 2621 (11.5%) reported ever pipe/cigar use, including 518 (2.3%) exclusive users without cigarette history. Compared with never tobacco users (n=9931), exclusive pipe/cigar use was associated with faster decline in FEV1 (3.36 mL/year; 95% CI 1.99 to 4.72), FVC (3.73 mL/year; 95% CI 2.05 to 5.42) and FEV1/FVC (0.031 per year; 95% CI 0.008 to 0.054). Exclusive users had higher all-cause mortality (adjusted HR (aHR) 1.24; 95% CI 1.08 to 1.41), COPD hospitalisation/mortality (aHR 2.02; 95% CI 1.41 to 2.90) and preserved ratio impaired spirometry (aHR 1.83; 95% CI 1.24 to 2.71).Conclusion Pipe and cigar use was associated with accelerated lung function decline and increased mortality and cardiopulmonary events, including among never cigarette users. These findings underscore the need for prevention and cessation efforts targeting non-cigarette tobacco.

Introduction Anifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using longitudinal transcriptomic and proteomic analyses of the 52-week, randomised, phase 3 TULIP-1 and TULIP-2 trials. Methods Patients with moderate to severe SLE were enrolled in TULIP-1 and TULIP-2 and received intravenous anifrolumab or placebo alongside standard therapy. Whole-blood expression of 18 017 genes using genome-wide RNA sequencing (RNA-seq) (pooled TULIP; anifrolumab, n=244; placebo, n=258) and 184 plasma proteins using Olink and Simoa panels (TULIP-1; anifrolumab, n=124; placebo, n=132) were analysed. We compared treatment groups via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA-seq and longitudinal linear mixed effect models for gene counts and protein levels. Results Compared with placebo, anifrolumab modulated >2000 genes by week 24, with overlapping results at week 52 and 41 proteins by week 52. IFNAR1 blockade with anifrolumab downregulated multiple type I and II IFN-induced gene modules/pathways and type III IFN-lambda protein levels, and impacted apoptosis-associated and neutrophil extracellular trap-associated transcriptional pathways, innate cell activating chemokines and receptors, proinflammatory cytokines and B-cell activating cytokines. In silico deconvolution of RNA-seq data indicated an increase from baseline of mucosal-associated invariant and gamma delta T cells and a decrease of monocytes following anifrolumab treatment. Discussion Type I IFN blockade with anifrolumab modulated multiple inflammatory pathways downstream of type I IFN signalling, including apoptotic, innate and adaptive mechanisms that play key roles in SLE immunopathogenesis.

Introduction Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. Methods Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. Results Among 8252 adults (mean age 56.710.3 years, 58.1%women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (-2.44 units, 95%CI -4.42 to -0.45), though to a lesser extent than exclusive use of cigarettes (-6.01 units, 95%CI -6.01 to -4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95%CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). Conclusion Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

BACKGROUND:Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic esophagitis are unclear. METHODS:In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients 12 to 65 years of age with symptomatic and histologically active eosinophilic esophagitis in a 1:1 ratio to receive subcutaneous benralizumab (30 mg) or placebo every 4 weeks. The two primary efficacy end points were histologic response (≤6 eosinophils per high-power field) and the change from baseline in the score on the Dysphagia Symptom Questionnaire (DSQ; range, 0 to 84, with higher scores indicating more frequent or severe dysphagia) at week 24. RESULTS:A total of 211 patients underwent randomization: 104 were assigned to receive benralizumab, and 107 were assigned to receive placebo. At week 24, more patients had a histologic response with benralizumab than with placebo (87.4% vs. 6.5%; difference, 80.8 percentage points; 95% confidence interval [CI], 72.9 to 88.8; P<0.001). However, the change from baseline in the DSQ score did not differ significantly between the two groups (difference in least-squares means, 3.0 points; 95% CI, -1.4 to 7.4; P = 0.18). There was no substantial between-group difference in the change from baseline in the Eosinophilic Esophagitis Endoscopic Reference Score, which reflects endoscopic abnormalities. Adverse events were reported in 64.1% of the patients in the benralizumab group and in 61.7% of those in the placebo group. No patients discontinued the trial because of adverse events. CONCLUSIONS:In this trial involving patients 12 to 65 years of age with eosinophilic esophagitis, a histologic response (≤6 eosinophils per high-power field) occurred in significantly more patients in the benralizumab group than in the placebo group. However, treatment with benralizumab did not result in fewer or less severe dysphagia symptoms than placebo. (Funded by AstraZeneca; MESSINA ClinicalTrials.gov number, NCT04543409.).

Introduction: Autoimmune encephalitis is a rare immune-related adverse event of PD-1 inhibitors, nivolumab and pembrolizumab. Autoimmune hypophysitis can also be seen with the use of these agents. The relationship between these two phenomena is currently unknown. Case report: We describe a 79-year-old man with anterior scalp melanoma who received adjuvant nivolumab therapy. Sixteen weeks after the completion of nivolumab therapy, the patient presented to the hospital with altered mental status, anterograde amnesia, and symptoms of nausea and vomiting. The patient's encephalopathy was associated with confabulations. Workup identified increased CSF protein without increased cellularity, along with decreased serum cortisol and ACTH levels. This was consistent with encephalitis and central adrenal insufficiency. Management and outcome: The patient had a robust clinical response to steroids, with resolution of mental status changes and normalization of blood pressure. He continues to receive maintenance steroid therapy without any further symptoms six months later. Conclusions: We report herein a unique case of encephalopathy in the setting of nivolumab use for the treatment of melanoma. The condition resembled Korsakoff psychosis seen in the setting of alcoholism and was associated with central adrenal insufficiency. A prompt response to steroids was both diagnostic and therapeutic in our case, suggesting the resolution of autoimmune phenomena related to nivolumab.

The type I interferon (IFN) signaling pathway is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Anifrolumab is a monoclonal antibody that targets the type I IFN receptor subunit 1. Anifrolumab is approved in several countries for patients with moderate to severe SLE receiving standard therapy. The approved dosing regimen of anifrolumab is a 300-mg dose administered intravenously every 4 weeks; this was initially based on the results of the Phase 2b MUSE and further confirmed in the Phase 3 TULIP-1 and TULIP-2 trials, in which anifrolumab 300-mg treatment was associated with clinically meaningful improvements in disease activity with an acceptable safety profile. There have been several published analyses of the pharmacokinetic and pharmacodynamic profile of anifrolumab, including a population-pharmacokinetic analysis of 5 clinical studies of healthy volunteers and patients with SLE, in which body weight and type I IFN gene expression were significant covariates identified for anifrolumab exposure and clearance. Additionally, the pooled Phase 3 SLE population has been used to evaluate how serum exposure may be related to clinical responses, safety risks, and pharmacodynamic effects of the 21-gene type I IFN gene signature (21-IFNGS). The relevance of 21-IFNGS with regard to clinical efficacy outcomes has also been analyzed. Herein, the clinical pharmacokinetics, pharmacodynamics, and immunogenicity of anifrolumab as well as results of population-pharmacokinetics and exposure-response analyses are reviewed.

Introduction Nivolumab is an immune checkpoint inhibitor used in the treatment of several malignancies. A number of immune-related endocrinopathies have been linked to its use. Case report We report a unique case of a 74-year-old man with well-controlled diabetes mellitus type 2 and metastatic mucosal anorectal melanoma who presented with diabetic ketoacidosis after receiving his third cycle of nivolumab 240 mg intravenous (IV) every 2 weeks. He was found to have autoantibodies against glutamic acid decarboxylase 65. Genotyping for human leukocyte antigens showed the presence of DQB1*02:01 and DRB1*03:01. Management and outcome His presentation was complicated by acute renal failure. He required aggressive fluid resuscitation and insulin supplementation to reverse severe acid-base disturbance and multiple electrolyte abnormalities. After an 8-week interruption, the patient restarted nivolumab without any further evidence of adverse events over the next 12 weeks. He continues to require insulin replacement therapy. Discussion and conclusion Development of type 1 diabetes with the use of immune checkpoint inhibitors has been increasingly reported in the literature. The exact mechanism for autoimmune diabetes precipitated by nivolumab is yet to be elucidated. Patient education about the symptoms of diabetes and regular glucose monitoring cannot be overemphasized. Testing for antibodies against glutamic acid decarboxylase 65, insulin receptors, and islet cells may also prove useful. Human leukocyte antigen DQ and DR haplotyping prior to immune checkpoint inhibitor treatment might help determine susceptibility toward developing type 1 diabetes, and provide opportunities for earlier recognition, intervention, and possibly prevention.

Objective Lupus nephritis (LN) is diagnosed by biopsy, but longitudinal monitoring assessment methods are needed. Here, in this preliminary and hypothesis-generating study, we evaluate the potential for using urine proteomics as a non-invasive method to monitor disease activity and damage. Urinary biomarkers were identified and used to develop two novel algorithms that were used to predict LN activity and chronicity.Methods Baseline urine samples were collected for four cohorts (healthy donors (HDs, n=18), LN (n=42), SLE (n=17) or non-LN kidney disease biopsy control (n=9)), and over 1 year for patients with LN (n=42). Baseline kidney biopsies were available for the LN (n=46) and biopsy control groups (n=9). High-throughput proteomics platforms were used to identify urinary analytes ≥1.5 SD from HD means, which were subjected to stepwise, univariate and multivariate logistic regression modelling to develop predictive algorithms for National Institutes of Health Activity Index (NIH-AI)/National Institutes of Health Chronicity Index (NIH-CI) scores. Kidney biopsies were analysed for macrophage and neutrophil markers using immunohistochemistry (IHC).Results In total, 112 urine analytes were identified from LN, SLE and biopsy control patients as both quantifiable and overexpressed compared with HDs. Regression analysis identified proteins associated with the NIH-AI (n=30) and NIH-CI (n=26), with four analytes common to both groups, demonstrating a difference in the mechanisms associated with NIH-AI and NIH-CI. Pathway analysis of the NIH-AI and NIH-CI analytes identified granulocyte-associated and macrophage-associated pathways, and the presence of these cells was confirmed by IHC in kidney biopsies. Four markers each for the NIH-AI and NIH-CI were identified and used in the predictive algorithms. The NIH-AI algorithm sensitivity and specificity were both 93% with a false-positive rate (FPR) of 7%. The NIH-CI algorithm sensitivity was 88%, specificity 96% and FPR 4%. The accuracy for both models was 93%.Conclusions Longitudinal predictions suggested that patients with baseline NIH-AI scores of ≥8 were most sensitive to improvement over 6–12 months. Viable approaches such as this may enable the use of urine samples to monitor LN over time.

Purpose Lupus nephritis (LN) confers poor prognosis, and there is a lack of effective non-invasive tests to assess disease activity and treatment response. We previously showed that a set of six urinary biomarkers (NGAL, KIM-1, MCP-1, adiponectin, hemopexin, ceruloplasmin) is sensitive and specific in adult patients with active LN, using renal biopsy as reference. In pediatric patients, Renal Activity Index for Lupus (RAIL) is effective in distinguishing inactive vs active LN and can differentiate LN treatment responders from non-responders. We hypothesized that the same would be true in adult patients. Methods Urine samples were obtained at baseline, Week 12, 24 and 48 from 131 biopsy proven active Class III and IV adult patients with LN participating in a phase 2 trial (NCT02547922). Urine samples were also taken at baseline from a subset of 59 patients with renal BILAG scores C, D or E, from a phase 3 trial with active non-renal systemic lupus erythematosus (SLE; NTCT02446912); RAIL biomarkers were assayed using single-plex assays. Clinical characteristics comparisons and Wilcoxon rank sum test comparing urinary biomarkers between studies were performed, and RAIL score was calculated. Receiver operator characteristic (ROC) analyses were conducted assessing the ability of RAIL scores to distinguish patients with renal activity and involvement. In the LN trial, longitudinal creatinine-standardized RAIL (RAIL_cr) scores were compared between non-responders and patients with complete renal response (CRR), partial renal response (PRR) and urine protein/creatinine ratio (UPCR) decrease >50% (UPCR50). CRR was defined as 24h UPCR ≤0.7 mg/mg, estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, or a decrease ≥20%, no treatment discontinuation, and no restricted medication use. For PRR, improvement in 24h UPCR to <1.0 mg/mg (if baseline UPCR ≤3 mg/mg) and to ≤3.0 mg/mg (if baseline UPCR >3 mg/mg) and >50% improvement was required. Results Among 131 LN patients, 42.8% were white, 83.2% were female with a median age of 34 years. At baseline, median (interquartile range) proteinuria, eGFR (mg/min/1.73m2), and RAIL_cr scores were 2.62 (1.53, 4), 91.8 (63.1, 125) and 5.59 (4.31, 6.47), respectively. In the SLE study (n=59), 76.3% were white, 93.2% were female with a median age of 36 years. Median non-renal Systemic Lupus Erythematosus Disease Activity Index 2000 score was 12. RAIL biomarker concentrations and median RAIL_cr scores were higher in the LN group than the SLE group (P<0.001). ROC analyses, including RAIL score, showed an area under the curve of 0.8 with an odds ratio of log-transformed RAIL 2.027. In the LN trial at Weeks 12/24/52, there were 25/31/41 patients with CRR, 39/54/60 with PRR, and 40/73/77 with UPCR50, respectively. RAIL_cr scores significantly differentiated responders at Weeks 12, 24, and 48 using a Wilcoxon rank sum Test (Figure 1). Conclusion RAIL_cr identifies adult SLE patients with active renal disease. Longitudinal RAIL_cr scores differentiate responders and non-responders to LN treatment. RAIL_cr has novel clinical utility as a noninvasive biomarker signature to monitor treatment response over time.

AIMSThe aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF).METHODS AND RESULTSData were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking.CONCLUSIONLung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

Background Lupus nephritis (LN) confers a poor prognosis, with lack of effective laboratory tests to diagnose and evaluate therapies. We have demonstrated that the RAIL score, based on a set of six urinary biomarkers ( NGAL, KIM-1, MCP-1, adiponectin, hemopexin, ceruloplasmin) is sensitive and specific in adult patients with active LN, using renal biopsy as reference. 1,2 RAIL has been shown in the pediatric population to be effective in distinguishing inactive vs active LN with no effect from mycophenolate mofetil (MMF) treatment. A comparable study has not been conducted in an adult population. Objectives To assess the ability of RAIL to discriminate patients with active LN vs active non-renal SLE and to evaluate if RAIL performance varies by MMF treatment using urine samples from adult LN patients. Methods Urine samples were obtained at baseline in two clinical trials: a phase 2 study in adult patients with biopsy-proven active Class III and IV LN ( NCT02547922 ) and a subset of patients from the phase 3 trial in adults with active non-renal SLE ( NCT02446912 ) who had baseline renal BILAG scores C, D, or E. RAIL biomarkers were assayed using single-plex assays. Patient demographics and clinical characteristics were compared between studies. Wilcoxon rank sum test was performed comparing the urinary biomarkers between the two studies and RAIL score was then calculated. Receiver operating characteristic (ROC) analyses were conducted assessing the ability for RAIL scores to distinguish patients with renal activity and involvement. Results Comparison of the patient demographic, clinical characteristics, and biomarkers is in the Table 1. Wilcoxon rank sum test showed the six urinary biomarkers were significantly different between two groups of patients as demonstrated (Table 1). Each of the RAIL biomarker concentrations and the creatinine-adjusted median score were higher in the active LN group than the SLE group ( P <0.001). ROC analyses including RAIL score showed an area under the ROC curve of 0.8 (Figure 1), with odds ratio of log-transformed RAIL 2.027 (95% CI [1.587, 2.589]). There were no significant interactions between RAIL and MMF. RAIL remained significant after adjusting for estimated glomerular filtration rate (eGFR), which was not statistically significant. Table 1. Study Demographics and Biomarkers Variables LN study (N=131) SLE study (N=59) Observed N Observed Median (IQR) or % Observed N Observed Median (IQR) or % Demographics Age 131 34 (25, 42) 59 36 (28, 44) Sex, Female 109 83.21% 55 93.22% Race, White 56 42.75% 45 76.27% Ethnicity, Hispanic or Latino 61 46.56% 9 15.25% OCS use, yes 127 97.69% 57 96.61% MMF use, yes 95 72.52% 21 35.59% Spot UPCR (mg/mg) 128 2.13 (1.22, 4.04) 59 1.11 (0.55, 2.61) eGFR 130 91.8 (63.1, 125) 59 98.06 (81.91, 116.54) Non-renal SLEDAI-2K score 130 4 (4, 6) 59 12 (9, 13) Renal SLEDAI-2K score 130 4 (4, 8) 59 0 (0, 0) Biomarkers NGAL (ng/mL) 128 33.33 (17.55, 56.7) 58 19.47 (11.37, 42.05) MCP-1 (pg/mL) 128 658.24 (271.58, 1049.95) 58 275.62 (106.09, 481.99) Ceruloplasmin (ng/mL) 128 93.55 (44.5, 311.25) 58 47.2 (13.05, 231.25) Adiponectin (ng/mL) 128 42.45 (16.71, 139.64) 58 9.33 (3.35, 25.51) Hemopexin (ng/mL) 128 1876.8 (745.07, 4743.4) 58 513.4 (236.36, 1388.74) KIM-1 (pg/mL) 128 1673.5 (772.5, 2767) 58 864 (394, 1480) Creatinine (mg/mL) 128 0.7 (0.46, 1.3) 58 0.99 (0.46, 1.74) Adult RAIL score (creatinine adjusted ) 128 5.59 (4.31, 6.47 ) 58 3.57 (2.78, 4.47 ) eGFR, estimated glomerular filtration rate; IQR, interquartile range; KIM, kidney injury molecule; LN, lupus nephritis; MCP, monocyte chemotactic protein; MMF, mycophenolate mofetil; NGAL, neutrophil gelatinase-associated lipocalin; OCS, oral corticosteroid; SLEDAI-2K, SLE Disease Activity Index 2000; UPCR, urine protein/creatinine ratio. Conclusion The analyses performed suggest that creatinine-corrected RAIL discriminates between active LN and non-renal adult SLE, with RAIL scores not influenced by MMF use. References [1]Brunner HI. Arthritis Care Res (Hoboken ). 2016;68:1003–11. [2]Gulati G. Lupus . 2017;26:927–36. Acknowledgements Writing assistance by Kelly M. Hunter, PhD (Fishawack). This study was sponsored by AstraZeneca. Disclosure of Interests Ellen Cody: None declared, Hermine Brunner Speakers bureau: Novartis, Pfizer, GSK, Consultant of: AbbVie, Astra Zeneca-Medimmune, Biogen, Boehringer, Bristol Myers Squibb, Celgene, Lilly,EMD Serono, Idorsia, Cerocor, Janssen, GSK, F. Hoffmann-La Roche, Merck, Novartis, R-Pharm, Sanofi, Grant/research support from: Pfizer, Bin Huang: None declared, Tingting Qiu: None declared, Prasad Devarajan Speakers bureau: Reata, Alnylam, Dicerna, Consultant of: BioPorto Inc, Madhu Ramaswamy Shareholder of: AstraZeneca, Employee of: AstraZeneca, Dominic Sinibaldi Shareholder of: AstraZeneca, Employee of: AstraZeneca, Philip Z Brohawn Shareholder of: AstraZeneca, Employee of: AstraZeneca, Jacob Knagenhjelm Shareholder of: AstraZeneca, Employee of: AstraZeneca, Frederick Jones Shareholder of: AstraZeneca, Employee of: AstraZeneca, Raj Tummala Shareholder of: AstraZeneca, Employee of: AstraZeneca, Catharina Lindholm Employee of: AstraZeneca, Wendy White Shareholder of: AstraZeneca, Employee of: AstraZeneca

This study aimed to elucidate the pharmacokinetic/pharmacodynamic and pharmacodynamic/efficacy relationships of anifrolumab, a type I interferon receptor antibody, in patients with moderate to severe systemic lupus erythematosus. Data were pooled from the randomized, 52‐week, placebo‐controlled TULIP‐1 and TULIP‐2 trials of intravenous anifrolumab (150 mg/300 mg, every 4 weeks for 48 weeks). Pharmacodynamic neutralization was measured with a 21‐gene type I interferon gene signature (21‐IFNGS) in patients with high IFNGS. The pharmacokinetic/pharmacodynamic relationship was analyzed graphically and modeled with a nonlinear mixed‐effects model. British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response rates were compared across 21‐IFNGS neutralization quartiles. Overall, 819 patients received ≥1 dose of anifrolumab or placebo, of whom 676 were IFNGS high. Over 52 weeks, higher average anifrolumab serum concentrations were associated with increased median 21‐IFNGS neutralization, which was rapid and sustained with anifrolumab 300 mg (>80%, weeks 12‐52), lower and delayed with anifrolumab 150 mg (>50%, week 52), and minimal with placebo. The proportion of patients with week 24 anifrolumab trough concentration exceeding the IC 80 (3.88 μg/mL) was greater with anifrolumab 300 mg vs anifrolumab 150 mg (≈83% vs ≈27%), owing to the higher estimated median trough concentration (15.6 vs 0.2 μg/mL). BICLA response rates increased with 21‐IFNGS neutralization; more patients had a BICLA response in the highest vs lowest neutralization quartiles at week 52 (58.1% vs 37.6%). In conclusion, anifrolumab 300 mg every 4 weeks rapidly, substantially, and sustainably neutralized the 21‐IFNGS and was associated with clinical efficacy, supporting this dosing regimen in patients with systemic lupus erythematosus.

We characterized the population pharmacokinetics of anifrolumab, a type I interferon receptor-blocking antibody. Pharmacokinetic data were analyzed from the anifrolumab (intravenous [IV], every 4 weeks) arms from 5 clinical trials in patients with systemic lupus erythematosus (SLE) (n =664) and healthy volunteers (n = 6). Population pharmacokinetic modeling was performed using a 2-compartment model with parallel linear and nonlinear elimination pathways. The impact of covariates (demographics, interferon gene signature [IFNGS, high/low], disease characteristics, renal/hepatic function, SLE medications, and antidrug antibodies) on pharmacokinetics was evaluated. Time-varying clearance (CL) was characterized using an empirical sigmoidal time-dependent function. Anifrolumab exposure increased more than dose-proportionally from 100 to 1000 mg IV every 4 weeks. Based on population pharmacokinetics modeling, the baseline median linear CL was 0.193 L/day in IFNGS-high patients and 0.153 L/day in IFNGS-low/healthy volunteers. After a year, median anifrolumab linear CL decreased by 8.4% from baseline. Body weight and IFNGS were significant pharmacokinetic covariates, whereas age, sex, race, disease activity, SLE medications, and presence of antidrug antibodies had no significant effect on anifrolumab pharmacokinetics. Anifrolumab at a concentration of 300 mg IV every 4 weeks was predicted to be below the lower limit of quantitation in 95% of patients approximate to 10 weeks after a single dose and approximate to 16 weeks after stopping dosing at steady state. To conclude, anifrolumab exhibited nonlinear pharmacokinetics and time-varying linear CL; doses >= 300 mg IV every 4 weeks provided sustained anifrolumab concentrations. This study provides further evidence to support the use of anifrolumab 300 mg IV every 4 weeks in patients with moderate to severe SLE.

OBJECTIVE:Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). In the present study, we evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers in comparison to placebo. METHODS:Study subjects comprised patients with moderate-to-severe SLE who were enrolled in phase IIb of the MUSE trial (A Phase II, Randomized Study to Evaluate the Efficacy and Safety of MEDI-546 in Subjects with Systemic Lupus Erythematosus), with healthy individuals as controls. Blood samples were collected from SLE patients (n = 305) and healthy controls (n = 10-20) before the initiation of treatment (baseline) and from SLE patients after they had been treated with 300 mg of anifrolumab (n = 99) or placebo (n = 102). Baseline IFN gene signature test status was determined, and the IFN gene signature (21-gene panel) was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa assay. NET complexes, cholesterol efflux capacity (CEC), and glycoprotein acetylation (GlycA) and other lipid parameters were assessed in plasma. RESULTS:Formation of NET complexes and levels of tumor necrosis factor (TNF) and interleukin-10 (IL-10) were correlated with extent of type I IFN pathway activity. NET complexes and IL-10 levels were up-regulated in SLE patients compared to healthy controls (P < 0.008). The cardiometabolic disease markers CEC and GlycA were also found to be dysregulated in patients with SLE (P < 0.001 versus healthy controls). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC compared to baseline (P < 0.05) whereas no improvements were seen with placebo. Levels of TNF and IL-10 were reduced with anifrolumab compared to placebo (P < 0.05). CONCLUSION:These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibition of this pathway could decrease cardiovascular risk in individuals with SLE.

Importance Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. Objective To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. Design, Setting, and Participants The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). Exposures Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. Main Outcomes and Measures Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. Results Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]). Conclusions and Relevance In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.