Reduction In Inflammatory Biomarkers Research Articles

Baricitinib and Pulse Steroids Combination Treatment in Hyperinflammatory COVID-19: A Rheumatological Approach in the Intensive Care Unit.

Hyperinflammatory Coronavirus disease 2019 (COVID-19) and rapidly-progressive interstitial lung diseases (RP-ILD) secondary to inflammatory myopathies (IIM) present important similarities. These data support the use of anti-rheumatic drugs for the treatment of COVID-19. The aim of this study was to compare the efficacy of combining baricitinib and pulse steroids with the Standard of Care (SoC) for the treatment of critically ill COVID-19 patients. We retrospectively enrolled consecutive patients admitted to the Intensive Care Unit (ICU) with COVID-19-pneumonia. Patients treated with SoC (dexamethasone plus remdesivir) were compared to patients treated with baricitinib plus 6-methylprednisolone pulses (Rheuma-group). We enrolled 246 patients: 104/246 in the SoC and 142/246 in the Rheuma-group. All patients presented laboratory findings suggestive of hyperinflammatory response. Sixty-four patients (26.1%) died during ICU hospitalization. The mortality rate in the Rheuma-group was significantly lower than in the SoC-group (15.5 vs. 40.4%, p < 0.001). Compared to the SoC-group, patients in the Rheuma-group presented significantly lower inflammatory biomarker levels after one week of treatment. Higher ferritin levels after one week of treatment were strongly associated with mortality (p < 0.001). In this large real-life COVID-19 cohort, baricitinib and pulse steroids led to a significant reduction in mortality, paralleled by a prompt reduction in inflammatory biomarkers. Our experience supports the similarities between hyperinflammatory COVID-19 and the IIM-associated RP-ILD.

Impact of sleeve gastrectomy on the periodontal status of patients with and without type 2 diabetes: a 1-year prospective real-world study.

Periodontitis is a chronic inflammatory disease potentially associated with obesity and type 2 diabetes (T2D). Sleeve gastrectomy (SG) has shown substantial effect on weight loss and treatment of T2D. However, there is no direct evidence comparing the impact of SG on the periodontal status of patients with and without T2D. To determine the impact of SG on the periodontal status of patients with and without T2D in a real-world setting. In a prospective and two-armed cohort design, participants who were scheduled for SG at an affiliated hospital between April 2022 and December 2022 were approached for eligibility. After a clinical evaluation and oral examination, those with periodontitis were included and further divided into the DM group (diabetic) and the Control group (non-diabetic) with a 1-year follow-up after surgery. The primary outcome was the periodontal status of patients at 12 months after SG. The secondary outcomes included weight loss, diabetes remission, and alterations in inflammatory markers for up to 1 year after SG. Fifty-seven and 49 patients were included in the DM and the Control group, respectively. Before surgery, patients in the DM group had further worsened periodontal condition compared with those in the Control group. Accompanied by weight loss and glucose reduction, patients in both groups demonstrated significant decreases in plaque index (PLI) and bleeding index (BI) with no alterations in probing depth or clinical attachment loss for up to 1 year after SG. Even patients in the DM group achieved less TWL% (32.79 ± 6.20% vs. 37.95 ± 8.34, P<0.01), their periodontal condition had more substantial improvement with no significant difference in PLI and BI between groups at 1 year after SG. We also observed a significant reduction in the levels of high sensitive C-reactive protein and interleukin-6 in both groups at 1 year after SG. Both patients with and without T2D demonstrated improved periodontal status for up to 1 year after SG. Patients with T2D achieved less weight loss but a more substantial improvement in periodontal condition. The significant reduction in inflammatory biomarkers contributed to the improvement of periodontal status after SG.

Impact of the SGLT2-inhibitor empagliflozin on inflammatory biomarkers after acute myocardial infarction – a post-hoc analysis of the EMMY trial

BackgroundSGTL2-inhibitors are a cornerstone in the treatment of heart failure, but data on patients with acute myocardial infarction (AMI) is limited. The EMMY trial was the first to show a significant reduction in NTproBNP levels as well as improved cardiac structure and function in post-AMI patients treated with Empagliflozin compared to placebo. However, data on the potential impact of SGLT2-inhibitors on inflammatory biomarkers after AMI are scarce.Materials and methodsThe EMMY trial is an investigator-initiated, multicentre, double-blind, placebo-controlled trial, which enrolled patients after AMI, receiving either 10 mg Empagliflozin once daily or placebo over a period of 26 weeks on top of standard guideline-recommended therapy starting within 72 h after percutaneous coronary intervention. In this post-hoc subgroup analysis of the EMMY trial, we investigated inflammatory biomarkers of 374 patients. The endpoints investigated were the mean change in inflammatory biomarkers such as high-sensitive c-reactive protein (hsCRP), interleukin-6 (IL-6), neutrophils, leukocytes, neutrophile/lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) from baseline to 26 weeks.ResultsBaseline median (interquartile ranges) IL-6 was 17.9 pg/mL (9.0-38.7), hsCRP 18.9 mg/L (11.2–37.1), neutrophil count 7.9 x G/L (6.2–10.1), leukocyte count 10.8 x G/L (9.1–12.8) and neutrophile/lymphocyte ratio (NLR) of 0.74 (0.67–0.80). At week 26, a significant mean reduction in inflammatory biomarkers was observed, being 35.1 ± 3.2% (p < 0.001) for IL-6, 57.4 ± 0.7% (p < 0.001) for hsCRP, 26.1 ± 0.7% (p < 0.001) for neutrophils, 20.5 ± 0.6% (p < 0.001) for leukocytes, 10.22 ± 0.50% (p < 0.001) for NLR, and − 2.53 ± 0.92% for PLR (p = 0.006) with no significant difference between Empagliflozin and placebo treatment.ConclusionTrajectories of inflammatory biomarkers showed a pronounced decline after AMI, but Empagliflozin treatment did not impact this decline indicating no central role in blunted systemic inflammation mediating beneficial effects.

Anti-inflammatory effects of dexamethasone in COVID-19 patients: Translational population PK/PD modeling and simulation.

Dexamethasone (DEX) given at a dose of 6 mg once-daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID-19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti-inflammatory effects in COVID-19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed-effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID-19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL-6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL-6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti-inflammatory compounds as well as drug combinations in the treatment of cytokine storms.

Weighted Gene Co-Expression Network Analysis Identifies a Functional Guild and Metabolite Cluster Mediating the Relationship between Mucosal Inflammation and Adherence to the Mediterranean Diet in Ulcerative Colitis.

Diet influences the pathogenesis and clinical course of inflammatory bowel disease (IBD). The Mediterranean diet (MD) is linked to reductions in inflammatory biomarkers and alterations in microbial taxa and metabolites associated with health. We aimed to identify features of the gut microbiome that mediate the relationship between the MD and fecal calprotectin (FCP) in ulcerative colitis (UC). Weighted gene co-expression network analysis (WGCNA) was used to identify modules of co-abundant microbial taxa and metabolites correlated with the MD and FCP. The features considered were gut microbial taxa, serum metabolites, dietary components, short-chain fatty acid and bile acid profiles in participants that experienced an increase (n = 13) or decrease in FCP (n = 16) over eight weeks. WGCNA revealed ten modules containing sixteen key features that acted as key mediators between the MD and FCP. Three taxa (Faecalibacterium prausnitzii, Dorea longicatena, Roseburia inulinivorans) and a cluster of four metabolites (benzyl alcohol, 3-hydroxyphenylacetate, 3-4-hydroxyphenylacetate and phenylacetate) demonstrated a strong mediating effect (ACME: -1.23, p = 0.004). This study identified a novel association between diet, inflammation and the gut microbiome, providing new insights into the underlying mechanisms of how a MD may influence IBD. See clinicaltrials.gov (NCT04474561).

Combined training improves the diagnostic measures of sarcopenia and decreases the inflammation in HIV-infected individuals.

BackgroundHIV‐related sarcopenia is an emerging health issue that often remains undiagnosed and can lead to reduced quality of life, independence, and premature death if untreated. This study investigated the effects of a 6 month combined training (resistance plus aerobic exercise) (CT) intervention on diagnostic measures of sarcopenia, including grip strength, appendicular lean mass index (ALMI), and gait speed.MethodsForty participants were randomized into either a CT group (n = 20; age = 38.3 ± 4.9 years) or a control group (CON; n = 20; age = 37.9 ± 5.1 years). Participants in the CT group performed three supervised sessions per week for 6 months, consisting of weekly reverse linear periodized resistance training followed by 20 min aerobic training. Participants in the CON group were instructed to continue with their current lifestyle habits. Assessments were completed at baseline and after 6 months. Statistical analyses were performed using a two‐way analysis of covariance (ANCOVA) adjusted for sex and preintervention values. Primary outcomes included grip strength, ALMI, and gait speed. Secondary outcomes were changes in levels of pro‐inflammatory cytokines (IL‐6 and TNF‐α), IGF‐1, and myostatin. Associations were explored between changes in inflammatory markers (IL‐6 and TNF‐α), gait speed, and ALMI with grip strength.ResultsA significant increase in ALMI was found for CT compared with CON (0.29 ± 0.13 kg/m2 vs. −0.11 ± 0.14 kg/m2, respectively; P < 0.001). Significant improvements in grip strength (7.86 ± 8.50 kg for CT vs. −1.58 ± 2.47 kg for CON) and gait speed (0.16 ± 0.07 m/s2 for CT vs. −0.06 ± 0.52 m/s2 for CON; both P < 0.001) were also observed in CT compared with CON. Reduction in inflammatory biomarkers was found in CT compared with CON (IL‐6; TNF‐α, both P < 0.001). An increase in IGF‐1 (74.36 ± 56.64 pg/mm3 for CT vs. 7.19 ± 99 pg/mm3 for CON; P < 0.001) and a decrease in myostatin (−158.90 ± 62.03 pg/mm3 for CT vs. −43.33 ± 146.60 pg/mm3 for CON; P < 0.001) was found following CT compared with the CON group. Change in grip strength was correlated with changes in IL‐6 (r = −0.65, P < 0.001), TNF‐α (r = −0.63, P < 0.001), gait speed (r = 0.63, P < 0.001), and ALMI (r = 0.54, P = 0.001), but not IGF‐1 and myostatin. No adverse events were recorded, and compliance with the CT exercise sessions was high (>85%).ConclusionsCombined training appears to be an effective means to counteract sarcopenia and improve various inflammatory markers and growth hormones in people living with HIV.

Adapted Tango to improve blood inflammatory markers in middle‐aged African‐American female caregivers of persons with Alzheimer's disease: A clinical trial

AbstractBackgroundAlzheimer’s disease (AD) is a devastating, progressive neurodegenerative disease resulting in memory loss and a severe reduction in ability to perform activities of daily living. Ethnicity‐related genetic factors promoting the development of dementias among African Americans (AA) and increased risk among females for developing AD indicates that AA female with a parent with AD are at great risk for developing dementias.MethodThis phase I study assessed the impact of a 12 week, 20‐lesson adapted Argentine Tango intervention (N=24) vs. a no‐contact control group (N=10) on measures of cognition, motor and psychosocial performance, and plasma inflammatory markers in middle‐aged (45‐65 years) AA females who are at increased risk for AD by virtue of parental history.ResultSome females (n=17) were also caregivers, and thus the impact of the program on caregiving burden was examined in this subset. Preliminary analysis of efficacy was conducted with significance tests on biomarkers and key measures of balance, strength, and cognition, including visuospatial and executive function. After 12 weeks, Tango participants had significantly decreased inflammatory cytokine levels: IL‐7 (p=.003), IFN‐γ (p=.011), and TNFα (p=.011), compared to controls. Participants in Tango improved on the Fullerton Advanced Balance Scale, which measures both dynamic and static balance (p=.023), the 30 second chair stand, which assesses functional lower body strength in older adults (p=.018), and inhibition of the color word interference test, which measures to ability to inhibit cognitive interference (p=0.031). Large effects were noted for the Tango group from pre to postintervention in the Trails B test score, which measures executive control and functioning. Other non‐significant, yet large effects were noted in gait speed, spatial cognition, and executive function. Moderate effects were noted in caregiving burden measures among the subset of caregivers.ConclusionThese data show substantial cognitive and motor improvements and reduction in inflammatory biomarkers through a non‐pharmacologic and affordable intervention among a small cohort of AA females with a parental history of AD.

GM6 attenuates Alzheimer's disease pathology through a reduction in fibrinogen levels and by regulation of Aβ, p-tau and inflammation.

Alzheimer's disease (AD) is characterized by cerebral amyloid-b (Ab) deposition, vascular alterations, tau pathology, microglia activation, and inflammation. Vascular dysfunction and amyloid burden are independent and equal predictors of cognitive decline in the elderly, with an additive adverse effect on cognition. Fibrinogen, a blood coagulation protein, is deposited in the AD brain; co-localizes with amyloid plaques, pericyte loss, dystrophic neurites, and activated microglia; and its increased concentrations in plasma and cerebrospinal fluid correlate with brain atrophy in AD patients. GM6 is a derivative of motoneuronotrophic factor (MNTF) which functions as a regulator of key biomarkers and acts upon multiple extracellular receptors to modulate a series of signaling pathways. This study evaluates the effects of GM6 on fibrinogen levels in two animal models of AD. APP and h-tau transgenic mice were treated with GM6 daily for up to 4 months and examined for changes in fibrinogen, Aβ peptide levels, plaques, inflammation, phosphorylated tau (p-tau) as well as behavioral changes associated with disease progression. Fibrinogen levels were determined by ELISA and western blot analysis. When we studied APP transgenic mice treated with GM6 compared to placebo, fibrinogen levels were significantly decreased (75%) along with diminished Aβ peptide levels, attenuation of plaque load, and a reduction in inflammatory biomarkers. In another study of the p-tau formation in the h-tau mice treated with GM6 compared to placebo, again a reduction in fibrinogen was observed along with reduction in p-tau and inflammation biomarker levels. In both transgenic mice, behavioral changes were attenuated with GM6 treatment. In both APP and h-tau mice, inflammation cytokines TNF-α, IL-1β, IL-6, and TGF-β were reduced by 80-90% as previously reported. In conclusion, to counter the additive adverse effect on cognition from vascular dysfunction and amyloid burden, GM6 may be a feasible approach to attenuate Alzheimer's disease pathology through a reduction in fibrinogen levels and by regulation of Ab, p-tau and inflammation.

The Effectiveness of Extra Virgin Olive Oil and the Traditional Brazilian Diet in Reducing the Inflammatory Profile of Individuals with Severe Obesity: A Randomized Clinical Trial.

We analyzed the effectiveness of two nutritional interventions alone and together, EVOO and the DieTBra, on the inflammatory profile of severely obese individuals. This study was an RCT with 149 individuals aged from 18 to 65 years, with a body mass index ≥ 35 kg/m2, randomized into three intervention groups: (1) 52 mL/day of EVOO (n = 50); (2) DieTBra (n = 49); and (3) DieTBra plus 52 mL/day of EVOO (DieTBra + EVOO, n = 50). The primary outcomes we measured were the-neutrophil-to-lymphocyte ratio (NLR) and the secondary outcomes we measured were the lymphocyte-to-monocyte ratio (LMR); leukocytes; and C reactive protein (CRP). After 12 weeks of intervention, DieTBra + EVOO significantly reduced the total leucocytes (p = 0.037) and LMR (p = 0.008). No statistically significant differences were found for the NLR in neither the intra-group and inter-group analyses, although a slight reduction was found in the DieTBra group (−0.22 ± 1.87). We observed reductions in the total leukocytes and LMR in the three groups, though without statistical difference between groups. In conclusion, nutritional intervention with DietBra + EVOO promotes a significant reduction in inflammatory biomarkers, namely leukocytes and LMR. CRP was reduced in EVOO and DieTBra groups and NLR reduced in the DieTBra group. This study was registered at ClinicalTrials.gov under NCT02463435.

Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study

ObjectivesThe goal of this study was to evaluate the effect of empagliflozin, in addition to optimal medical treatment, on epicardial adipose tissue (EAT), interstitial myocardial fibrosis, and aortic stiffness in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF). BackgroundSeveral randomized clinical trials have established the benefits of the inhibitors of the sodium-glucose cotransporter-2 receptor (SGLT2-i) in HFrEF, independent of their hypoglycemic effects. The mechanisms of the benefits of SGLT2-i in HFrEF have not been well defined. MethodsThis study was a secondary analysis of patients enrolled in the EMPA-TROPISM [ATRU-4] (Are the cardiac benefits of Empagliflozin independent of its hypoglycemic activity?) clinical trial. It was a double-blind, placebo-controlled randomized clinical trial investigating the effect of empagliflozin in nondiabetic patients with HFrEF. Patients underwent cardiac magnetic resonance at baseline and after 6 months. Interstitial myocardial fibrosis was calculated by using T1 mapping (extracellular volume). Aortic stiffness was calculated by using pulsed wave velocity, and EAT was measured from the cine sequences. ResultsEmpagliflozin is associated with significant reductions in EAT volume (–5.14 mL; 95% CI: –8.36 to –1.92) compared with placebo (–0.75 mL; 95% CI: –3.57 to 2.06; P < 0.05); this finding was paralleled by reductions in subcutaneous adipose tissue area (–5.33 cm2 [95% CI: –12.61 to 1.95] vs 9.13 cm2 [95% CI: –2.72 to 20.99]; P < 0.05). Empagliflozin-treated patients reported a reduction in extracellular volume (–1.25% [±0.56 95% CI] vs 0.24% [±0.57 95% CI]; (P < 0.01)]; specifically, empagliflozin reduced both matrix volume (–7.24 mL [95% CI: –11.59 to –2.91] vs 0.70 mL [95% CI: –0.89 to 2.29]; P < 0.001) and cardiomyocyte volume (–11.08 mL [95% CI: –19.62 to –2.55] vs 0.80 mL [95% CI: –1.96 to 3.55]; P < 0.05). Pulsed wave velocity was also significantly reduced in the empagliflozin group (–0.58 cm/s [95% CI: –0.92 to –0.25] vs 0.60 cm/s [95% CI: 0.14 to 1.06]; P < 0.01). Using proteomics, empagliflozin was associated with a significant reduction in inflammatory biomarkers. ConclusionsEmpagliflozin significantly improved adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers in nondiabetic patients with HFrEF. These results shed new light on the mechanisms of action of the benefits of SGLT2-i. (Are the “Cardiac Benefits” of Empagliflozin Independent of Its Hypoglycemic Activity [ATRU-4] [EMPA-TROPISM]; NCT03485222)

Study rationale and design of a study of EMPAgliflozin\u2019s effects in patients with type 2 diabetes mellitus and Coronary ARtery disease: the EMPA-CARD randomized controlled trial

BackgroundRecent trials have revealed that sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are effective against hyperglycemia and also reduce micro- and macro-vascular complications in patients with type 2 diabetes mellitus (T2DM). Most of the beneficial cardiovascular effects have been investigated in patients with heart failure and coronary artery disease (CAD). Yet, few human studies have been conducted to investigate the molecular mechanisms underlying these clinically beneficial effects in patients with CAD. Accordingly, the EMPA-CARD trial was designed to focus on the molecular effects of empagliflozin in patients with T2DM and CAD.MethodsIn this multicenter, triple-blind randomized controlled trial, patients with documented known T2DM and CAD will be recruited. They will be randomized on a 1:1 ratio and assigned into two groups of empagliflozin 10 mg/daily and placebo. The primary endpoint is the effect of empagliflozin on changes of plasma interleukin 6 (IL-6) after 26 weeks of treatment. The secondary endpoints will consist of changes in other inflammatory biomarkers (Interleukin 1-beta and high-sensitive C-reactive protein), markers of oxidative stress, platelet function, and glycemic status.DiscussionThe EMPA-CARD trial mainly tests the hypothesis that SGLT2 inhibition by empagliflozin may improve inflammatory status measured as reduction in inflammatory biomarkers in patients with T2DM and CAD. The results will provide information about the underlying mechanisms of SGLT2 inhibition that mediate the beneficial effects of this medication on clinical outcomes.Trial registrationIranian Registry of Clinical Trials. www.IRCT.ir, Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.

A Pilot randomized clinical trial of adapted tango to improve cognition and psychosocial function in African American women with family history of Alzheimer's disease (ACT trial)

Alzheimer's disease (AD) is a devastating, progressive neurodegenerative disease resulting in memory loss and a severe reduction in the ability to perform activities of daily living. Ethnicity-related genetic factors promoting the development of dementias among African Americans (AA) and increased risk among women for developing AD indicates that AA women with a parental history of AD are at great risk for developing AD. This phase I study assessed the impact of a 12 week, 20-lesson adapted Argentine Tango intervention (n = 24) to a no-contact control group (n = 10) on measures of plasma inflammatory markers, cognition, and motor and psychosocial performance in middle-aged AA woman at increased risk for AD by virtue of parental history. Some woman (n = 16) were also caregivers; thus, the impact of the intervention on caregiving burden was examined in this subset. Preliminary analysis of efficacy was conducted with significance tests on biomarkers and key measures of cognition, including visuospatial and executive function, balance, and strength. After 12 weeks, Tango participants had significantly decreased inflammatory cytokine, including reductions in IL-7 (p = 0.003), IFN-γ (p = 0.011), TNFα (p = 0.011), and MCP-1 (p = 0.042) compared to controls. Large effects were noted for the Tango group on tests of executive functioning (d = 0.89), and inhibition (p = 0.031). Participants in Tango improved in dynamic and static balance (p = 0.018) and functional lower body strength (p = 0.023). Secondary assessment revealed trends favoring the intervention group were noted in spatial cognition and executive function. Moderate effects were noted in caregiving burden measures among the subset of caregivers. These data demonstrate substantial reductions in inflammatory biomarkers along with cognitive and motor improvements through a non-pharmacologic, affordable intervention among a small, well-characterized cohort of AA women with a parental history of AD.

Thromboembolism, Hypercoagulopathy, and Antiphospholipid Antibodies in Critically Ill Coronavirus Disease 2019 Patients: A Before and After Study of Enhanced Anticoagulation

Retrospective. Tertiary intensive care unit. Two cross-sectional cohorts of ICU-treated coronavirus disease 2019 patients were included before (cohort 1, n = 12) and after (cohort 2, n = 14) enhanced prophylactic anticoagulation strategy. Before and after study of enhanced anticoagulation. Thromboelastometry point-of-care coagulation tests were performed by thromboelastography (Tem International GmbH, Munich, Germany), standard blood tests were extracted from patient charts, and presence of antiphospholipid antibodies in plasma was measured. All patients were males on mechanical ventilation. In cohort 1 (low-molecular-weight heparin dose: 129 ± 53 U/kg/24 hr), 50% had pulmonary embolism, and thromboelastography analysis revealed hypercoagulation in a majority of patients and greater than 80% had detectable antiphospholipid antibodies. In the second cohort (enhanced low-molecular-weight heparin dose: 200 ± 82 U/kg/24 hr; p = 0.04 vs cohort 1), we found a nonsignificantly lower prevalence of pulmonary embolism (21%; p = 0.22), lower fibrinogen (6.3 ± 2.5 vs 8.7 ± 2.0; p = 0.02), reduced fibrinogen-dependent thromboelastography (p < 0.001), and lower inflammatory markers. In these two cross-sectional cohorts of ICU-treated coronavirus disease 2019 patients, thromboembolic complications, hypercoagulation, and antiphospholipid antibodies were common. A more aggressive anticoagulation regime was associated with a reduction in inflammatory biomarkers including plasma fibrinogen and a reduction in fibrinogen-dependent hypercoagulation, as indicated by thromboelastography analyses.

Anakinra in hospitalized patients with severe COVID-19 pneumonia requiring oxygen therapy: Results of a prospective, open-label, interventional study

ObjectiveThe aim of this study was to evaluate the efficacy of anakinra in patients who were admitted to hospital for severe COVID-19 pneumonia requiring oxygen therapy. MethodsA prospective, open-label, interventional study in adults hospitalized with severe COVID-19 pneumonia was conducted. Patients in the interventional arm received subcutaneous anakinra (100 mg twice daily for 3 days, followed by 100 mg daily for 7 days) in addition to standard treatment. Main outcomes were the need for mechanical ventilation and in-hospital death. Secondary outcomes included successful weaning from supplemental oxygen and change in inflammatory biomarkers. Outcomes were compared with those of historical controls who had received standard treatment and supportive care. ResultsA total of 69 patients were included: 45 treated with anakinra and 24 historical controls. A need for mechanical ventilation occurred in 14 (31%) of the anakinra-treated group and 18 (75%) of the historical cohort (p < 0.001). In-hospital death occurred in 13 (29%) of the anakinra-treated group and 11 (46%) of the historical cohort (p = 0.082). Successful weaning from supplemental oxygen to ambient air was attained in 25 (63%) of the anakinra-treated group compared with 6 (27%) of the historical cohort (p = 0.008). Patients who received anakinra showed a significant reduction in inflammatory biomarkers. ConclusionIn patients with severe COVID-19 pneumonia and high oxygen requirement, anakinra could represent an effective treatment option and may confer clinical benefit. Trial registration numberISRCTN74727214.

The Nutrient Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Feasibility Phase

The Mediterranean diet, characterized by increased consumption of extra virgin olive oil (EVOO), nuts, legumes, vegetables, fruits, fish, and whole grain products, has proven to be beneficial in diseases where chronic subclinical inflammation plays a key role (Calder et al., 2011). For example, the PREDIMED (Prevención con Dieta Mediterránea) study demonstrated that a Mediterranean diet supplemented with EVOO or nuts reduced the incidence of major cardiovascular events (Estruch et. al, 2010). The Mediterranean diet's anti-inflammatory properties are attributed to its richness in phenolic compounds and main nutrients, such as: fiber, monounsaturated fatty acids, n-3 polyunsaturated fatty acids, vitamins C and E, and carotenoids (Casas et al., 2017). Overproduction of pro-inflammatory cytokines like IL-6 and TNF-α is a characteristic feature of Myeloproliferative Neoplasm (MPN) and correlates with high symptom burden and may also play a role in disease progression (Craver et al., 2018). Therefore, reduction of inflammation at the early stages of disease through low-risk interventions such as diet could lessen symptom burden and potentially blunt disease progression. To date, this nutrition trial will be the first to study the effects of the Mediterranean dietary pattern in MPN patients. To initially assess the feasibility of a Mediterranean diet intervention among MPN patients, we developed a prospective interventional proof-of-concept study of 30 MPN patients randomized (1:1) to either a Mediterranean diet supplemented with EVOO or the United States Dietary Guidelines for Americans (USDA). Inclusion and exclusion criteria are listed in Table 1 and study schematic is shown in Figure 1. The primary endpoint for this study is adherence to a Mediterranean diet with our diet curriculum. Exploratory endpoints include reduction in inflammatory biomarkers, reduction in symptom burden, and change in the gut microbiome. All participants meet once at the start of the intervention period (week 3) with a dietician for one-on-one counseling to educate the participant on the central components of the Mediterranean diet or the US Dietary guidelines and tailor the diet to meet each participant's medical needs and or cultural preferences. Participants are emailed 10 weekly installments of educational materials on their respective diet. At weeks 3 and 9, participants in the Mediterranean diet arm are given 750ml of EVOO and participants in the USDA arm receive a $10 grocery gift card. Six unannounced surveys and 24-hour food recalls are collected throughout the duration of the 15-week study. Conformity with the Mediterranean dietary pattern is assessed by the 14-item Mediterranean diet adherence score. Symptom burden is assessed using the MPN symptom assessment form (MPN-SAF). Four biological sample data points are collected during the 15-week study which includes collection of blood, stool, and urine. Complete blood count, Comprehensive Metabolic Panel, Lipid Panel, hsCRP are measured, and plasma is stored for cytokine analysis. Urine is used to quantify urine total polyphenol excretion. Stool samples are used to measure changes in the gut microbiome with diet. Since opening in October 2018, we have screened 44 potential participants. Four did not meet the inclusion criteria, 8 participants did not respond to initial surveys, and thus, did not progress to the intervention phase and were not randomized. Of the 32 participants who were randomized, 2 withdrew due to family illness. Eighteen participants have completed the 15-week study and 12 participants are currently in the active intervention phase. Demographics of the 30 participants who have completed this study or are currently receiving active intervention are shown in Table 2. In summary, this is a feasibility study to evaluate if MPN patients can adhere to a Mediterranean diet when given written curriculum and verbal counseling, and to explore whether a diet rich in anti-inflammatory properties can improve MPN symptoms. Geography was a limitation for this study, participants who were not in Southern California found it difficult to arrange travel for in-person visits. Patients who self-referred were more responsive and engaged than those recruited from clinic. Subsequent trials will test the impact of diet in a larger group of MPN patients, likely with a remotely administered intervention to obviate the need for travel. Disclosures Scherber: Incyte: Consultancy; Blueprint: Other: Ad board; Gilead: Consultancy. Mesa:Genotech: Research Funding; Celgene: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte: Research Funding; Samus: Research Funding; Novartis: Consultancy; La Jolla Pharma: Consultancy; AbbVie: Research Funding; Sierra Onc: Consultancy. Fleischman:incyte: Speakers Bureau.

A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial)

Psoriasis is a T helper type 17 autoimmune disease associated with an increased risk cardiovascular events and mortality. Ustekinumab, an antibody to p40, blocks cytokines IL-12 and IL-23, and is a highly effective and safe treatment for psoriasis. We conducted a randomized double-blinded placebo-controlled trial to determine the effect of ustekinumab on aortic vascular inflammation (AVI) measured by imaging, and key biomarkers of inflammation, lipid, and glucose metabolism in the blood of patients with moderate-to-severe psoriasis. A total of 43 patients were randomized, and at week 12, ustekinumab-treated patients had a -18.65% (95% confidence interval= -29.45% to -7.85%) reduction in AVI, a reduction in inflammatory biomarkers, and an increase in apolipoprotein B lipoproteins compared with placebo. At week 12, placebo patients were crossed over such that all patients received ustekinumab for 52 weeks. At the end of 52 weeks of ustekinumab treatment, there was no change in AVI compared with baseline, inflammatory markers were reduced, and there were increases in selected measures of lipids and leptin. These results show that blockade of IL-12 and/or IL-23 may transiently reduce AVI, with more durable reduction in inflammatory cytokines associated with cardiovascular disease.

136-OR: Efficacy of Cenicriviroc (CVC) in Adults with NASH-Induced Liver Fibrosis

Background: Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of type 2 diabetes and can progress to advanced fibrosis (AF), associated with significant increase in morbidity and mortality. CVC is an oral C-C chemokine receptor 2/5 antagonist being evaluated to treat liver fibrosis in adults with NASH. This study describes antifibrotic effects seen in the Phase 2b CENTAUR study overall and those with AF (F3) specifically. Methods: Adults with confirmed NASH, nonalcoholic fatty liver disease activity score ≥4, and liver fibrosis Stages F1-3 (NASH CRN) received CVC 150 mg daily (Arm A) or placebo (PBO; Arm C) for 2 years; Arm B received PBO in Year (Y)1 and CVC in Y2. Liver biopsies were assessed blind at baseline (BL), Y1, and Y2 by a central pathologist. Improvement in fibrosis and serum inflammatory markers were assessed in subjects with evaluable biopsies at BL, Y1, and Y2 (modified intent-to-treat [mITT] population). Results: Of 289 adults randomized (mean age 54 years, mean BMI 33.9 kg/m2, 52.0% diabetes), 28.6% (36/126) vs. 19.0% (24/126) achieved ≥1-stage fibrosis improvement at Y1 in CVC vs. PBO arms (mITT) overall. Of 97 AF subjects at BL (mean age 57.8 years, mean BMI 34.1 kg/m2, 69.0% diabetes), 38.3% (18/47) vs. 28.0% (14/50) achieved this endpoint in CVC vs. PBO arms (mITT). Overall, 60.0% (18/30) in Arm A vs. 30.0% (3/10) in Arm C maintained benefit at Y2 (mITT). In AF subjects, 85.7% (12/14) in Arm A vs. 60.0% (3/5) in Arm C maintained benefit at Y2 (mITT). Greater reductions in hs-CRP, fibrinogen, IL-6, IL-8, and IL-1β were observed with CVC. In AF subjects, these changes were more pronounced. Overall and with AF, adverse events were comparable for CVC and PBO; no deaths occurred. Conclusion: CVC was well tolerated and provided antifibrotic benefit in adults with NASH and fibrosis, especially those with AF. Most subjects achieving ≥1-stage fibrosis improvement at Y1 maintained benefit at Y2, with reductions in inflammatory biomarkers, supporting the ongoing Phase 3 study of CVC in NASH. Disclosure N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. H. Landgren: Employee; Self; Allergan. A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc.

Tu1712 – Reduction in Inflammatory Biomarkers in a Phase 2 Study of Mirikizumab in the Treatment of Patients with Moderatelyto-Severely Active Ulcerative Colitis

Tu1712 – Reduction in Inflammatory Biomarkers in a Phase 2 Study of Mirikizumab in the Treatment of Patients with Moderatelyto-Severely Active Ulcerative Colitis

DOP52 Reduction in inflammatory biomarkers in a Phase 2 study of mirikizumab in patients with moderately to severely active ulcerative colitis

DOP52 Reduction in inflammatory biomarkers in a Phase 2 study of mirikizumab in patients with moderately to severely active ulcerative colitis

Novel PAradigm to improve Inflammatory burden in end stage Renal disease (rePAIR): study protocol for a randomized controlled trial

BackgroundGiven the importance of inflammation as a predictor of poor outcomes in End Stage Renal Disease (ESRD), reductions in inflammatory biomarkers have been proposed as a critical target in this population. This study targets chronic periodontitis, an oral inflammatory disease of microbial etiology causing persistent inflammation in ESRD. Unlike the previously reported episodic periodontal interventions, we propose to control periodontal inflammation with a continuous maintenance and oral health behavior modifications. We hypothesize that this strategy will improve systemic inflammation and oxidative stress, oral health and quality of life within the 6-month observation period.MethodsThe rePAIR (novel PAradigm to improve Inflammatory burden in ESRD) study is a pilot and feasibility, parallel-arm, and randomized controlled clinical trial that will recruit 72 ESRD subjects with periodontitis in a model of computerized block randomization. This trial aims to compare the effect of standard-of-care vs. repeated non-surgical periodontal therapy on systemic and oral inflammatory burden. This trial will recruit ESRD adult patients with periodontitis older than 21 years old with a minimum of 12 teeth and no history of periodontal treatment within a year. The trial will examine serum C-reactive protein (CRP) (primary outcome) as a biomarker of inflammation as well as interleukin-6 (IL-6), F2 isofurans and F2 isoprostanes (secondary outcomes) and compare their difference between groups from baseline to 6 months. The trial will also compare the difference between groups in patient-centered and clinical oral outcomes from baseline to 6 months.DiscussionThe trial follows a rigorous and transparent study design capturing elements such as pre-specified eligibility criteria, pre-specified primary and secondary outcomes, detailed intervention description to allow replication, intervention random allocation and concealment, blinding in outcome assessment, appropriate sample size calculations, explanation of interim analysis, as per CONSORT Guidelines. Further, gender diversity is secured not only at recruitment but also throughout the trial and during the analysis. Therefore, treatment response outcomes will be examined per gender category. In order to manage anticipated problems, the protocol has included alternative approaches.Trial registrationClinicalTrials.gov, NCT03241511. Registered on 7 August 2017.