Effect Of Anti-inflammatory Treatment Research Articles

Efficacy and inflammatory levels (IL-6, IL-10) of adjuvant application of vitamin-A in the treatment of pediatric Mycoplasma pneumoniae pneumonia: a systematic review and meta-analysis.

The purpose of this study is to evaluate the efficacy of Vitamin A (VitA) as an adjuvant therapy for pediatric Mycoplasma Pneumoniae Pneumonia (MPP) through meta-analysis, and to investigate its impact on inflammation levels (IL-6, IL-10), in order to explore the role of VitA in pediatric MPP. Using a systematic literature search method, relevant research literature is searched, and RCT studies that meet the requirements are selected based on preset inclusion and exclusion criteria. Then, a quality evaluation was conducted on the included literature, and meta-analysis was used to calculate the combined effect values of mortality rate, hospital stay, lung rale disappearance time, cough duration, fever duration, IL-6 and IL-10 levels, and heterogeneity analysis was conducted. The levels of IL-6 and IL-10 represent the inflammatory levels in pediatric MPP patients, and exploring their changes has significant implications for the anti-inflammatory effect of treatment. A total of 10 RCT studies were included, with a total sample size of 1,485, including 750 cases in the control group and 735 cases in the observation group. The meta-analysis results of this study showed that there was a significant difference in the total clinical efficacy of using VitA adjuvant therapy compared to the control group without VitA [OR = 3.07, 95%CI = (2.81, 4.27)], P < 0.05. However, there was no significant difference in the adverse reaction rate between the use of VitA as an adjuvant therapy and the control without VitA [OR = 1.17, 95%CI = (0.61, 2.27)], P > 0.05. At the same time, the hospitalization time [MSD = -0.86, 95% CI = (-1.61, -0.21)], lung rale disappearance time [MSD = -0.78, 95%CI = (-1.19,-0.51)], cough duration [MSD = -1.07, 95%CI = (-1.41, -0.71)], and fever duration [MSD = -0.47, 95%CI = (-0.72, -0.23)] using VitA as an adjuvant treatment were obviously lower. In addition, the meta-analysis outcomes also showed that the use of VitA adjuvant therapy can significantly reduce IL-6 [MSD = -1.07, 95%CI = (-1.81, -0.27)] and IL-10 [MSD = -0.13, 95%CI = (-0.31, 0.12)] levels. This indicates that the application of VitA in pediatric MPP also has the effect of reducing inflammatory response. Based on the meta-analysis results, VitA adjuvant therapy can significantly improve the clinical symptoms of pediatric MPP patients, shorten hospitalization time, promote the disappearance of lung rales, and alleviate cough and fever symptoms. In addition, VitA adjuvant therapy can effectively reduce inflammation levels, indicating its potential role in inhibiting inflammatory responses. In clinical practice, VitA adjuvant therapy for pediatric MPP can be promoted as a potential treatment option.

Swissped-RECOVERY: masked independent adjudication for the interpretation of non-randomised treatment in a two-arm open-label randomised controlled trial (methylprednisolone vs immunoglobulins) in Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) involving 10 secondary and tertiary paediatric hospitals in Switzerland

ObjectivesIn trials of acute severe infections or inflammations frequent administration of non-randomised treatment (ie, intercurrent event) in response to clinical events is expected. These events may affect the interpretation of...

Serial electrical impedance tomography course in different treatment groups; The MaastrICCht cohort

PurposeTo describe the effect of dexamethasone and tocilizumab on regional lung mechanics over admission in all mechanically ventilated COVID-19 patients. Materials and methodsDynamic compliance, alveolar overdistension and collapse were serially determined using electric impedance tomography (EIT). Patients were categorized into three groups; no anti-inflammatory therapy, dexamethasone therapy, dexamethasone + tocilizumab therapy. The EIT variables were (I) visualized using polynomial regression, (II) evaluated throughout admission using linear mixed-effects models, and (III) average respiratory variables were compared. ResultsVisual inspection of EIT variables showed a pattern of decreasing dynamic compliance. Overall, optimal set PEEP was lower in the dexamethasone group (−1.4 cmH2O, −2.6; −0.2). Clinically applied PEEP was lower in the dexamethasone and dexamethasone + tocilizumab group (−1.5 cmH2O, −2.6; −0.2; −2.2 cmH2O, −5.1; 0.6). Dynamic compliance, alveolar overdistension, and alveolar collapse at optimal set PEEP did not significantly differ between the three groups. ConclusionOptimal and clinically applied PEEP were lower in the dexamethasone and dexamethasone + tocilizumab groups. The results suggest that the potential beneficial effects of these therapies do not affect lung mechanics favorably. However, this study cannot fully rule out any beneficial effect of anti-inflammatory treatment on pulmonary function due to its observational nature.

A Prospective, Monocentric Case-Control Study on Uncontrolled Psoriasis as Independent Risk Factor for a Hypercoagulable State.

Chronic inflammatory diseases, including psoriasis, are associated with development of venous thromboembolism (VTE). The clot lysis profile (CLP) provides information on both the clotting tendency and fibrinolysis activity. We hypothesized that CLP in uncontrolled psoriasis patients is disturbed towards more clotting/less lysis compared to healthy controls (HC) and that successful psoriasis treatment could normalize the CLP. In this project, we aim to compare the CLP in patients with uncontrolled psoriasis with age- and sex-matched HC and investigate the effect of anti-inflammatory treatment on CLP. Patients with uncontrolled psoriasis [psoriasis area severity index (PASI) or body surface area (BSA) > 10] (n = 87) and HC (n = 87) were recruited at a tertiary dermatology department. Samples from patients were obtained before treatment and when disease control was obtained (PASI < 3). Amplitude, area under the curve (AUC) and 50% clot lysis time were determined. At baseline, psoriasis patients had higher median amplitude and AUC compared with HC (p < 0.0001). After correction for possible confounders (BMI, smoking behavior, psoriatic arthritis, arterial hypertension, diabetes and coronary artery disease), the increased amplitude in psoriasis patients compared to HC remained significant. Successful anti-inflammatory treatment resulted in a significant decrease in amplitude (p = 0.0365). This is the first prospective study comparing the CLP of psoriasis patients with that of HC. A significant increase in both amplitude and area under the curve, indicative of a hypercoagulable CLP, was observed in psoriasis patients compared to HC. After successful anti-inflammatory treatment, amplitude significantly decreased.

Quercetin attenuates Pseudomonas aeruginosa-induced acute lung inflammation by inhibiting PI3K/AKT/NF-κB signaling pathway.

Pseudomonas aeruginosa is an opportunistic pathogen that commonly causes infections in immunocompromised individuals with significant morbidity and mortality. Quercetin is a natural flavonoid abundantly present in fruits and vegetables, exerting potent anti-inflammatory effects in treatment of various diseases. However, the molecular mechanisms of quercetin in treatment of P. aeruginosa-induced acute lung inflammation are unclear. In this study, we exploited network pharmacology- and molecular docking-based approach to explore the potential mechanisms of quercetin against P. aeruginosa pneumonia, which was further validated via in vivo and in vitro experiments. The in vivo experiments demonstrated that quercetin alleviated the P. aeruginosa-induced lung injury by diminishing neutrophil infiltration and production of proinflammatory cytokines (IL-1β, IL-6, and TNF), which was associated with decreased mortality. Moreover, the quercetin-treated mice displayed decreased phosphorylation levels of PI3K, AKT, IκBα, and NF-κB p65 in lung tissues compared to non-drug-treated mice. Similarly, the in vitro study showed that the phosphorylation of these regulatory proteins and production of the proinflammatory cytokines were impaired in the quercetin-pretreated macrophages upon P. aeruginosa infection. Altogether, this study suggested that quercetin reduced the P. aeruginosa-induced acute lung inflammation by suppressing PI3K/AKT/NF-κB signaling pathway.

Effect of anti-inflammatory treatments on patient outcomes and concentrations of inflammatory modulators in the post-surgical and post-traumatic tibiofemoral joint setting: a narrative review.

There are several anti-inflammatory therapeutic options that can be used in the context of post-surgical and post-traumatic knee settings. Each of these options carries with it certain benefits, as well as potential issues depending on the duration and administration of each therapy. An understanding of how these anti-inflammatory drugs modulate various biomarkers of inflammation is also necessary in understanding how they can affect patient and objective outcomes following acute knee injury or surgery. This review covers the many traditional therapeutic options that have been used in treating knee injuries, as well as some natural therapeutics that have shown anti-inflammatory properties. A current review of the literature was conducted and synthesized into this narrative review. Many traditional anti-inflammatory therapeutics have been shown to be beneficial in both post-traumatic and post-surgical tibiofemoral joint settings at reducing inflammation and improving patient outcomes. However, many of these treatments have risks associated with them, which becomes problematic with prolonged, repeated administration. Natural anti-inflammatory compounds may also have some benefit as adjunctive treatment options in these settings. There are multiple different therapeutic options that can be used in acute knee settings, but the specific mechanism of injury or surgical context should be weighed when determining the best clinical approach.

Blood inflammatory markers and mortality in the US population: A Health and Retirement Survey (HRS) analysis.

A potential direct correlation between systemic inflammation and physiological aging has been suggested, along with whether there is a higher expression of inflammatory markers in otherwise healthy older adults. Cross-sectional data were extracted from the publicly available 2016 Health and Retirement Survey, a nationally representative survey of older adults in the United States. A subset of participants (n = 9934) consented to a blood draw at the time of recruitment and were measured for high sensitivity C-reactive protein (hs-CRP), Interleukin (IL-6, IL-10, IL-1RA), soluble tumor necrosis factor receptor (sTNFR-1) and transforming growth factor beta 1 (TGF-β1). We included 9,188 participants, representative of 83,939,225 nationally. After adjusting for sex and the number of comorbidities, there remained a significant positive correlation between age and ln (log adjusted) IL-6, and ln sTNFR-1, and a significant inverse correlation between age and ln IL-1RA, ln TGF-β1, and ln hs-CRP. Among the subset of participants who reported none of the available comorbidities (n = 971), there remained an independent correlation of age with ln IL-6 and ln sTNFR-1. After adjusting for age, sex, and number of reported comorbidities, there was a statistically significant correlation between increased ln IL-6, ln IL-10, ln sTNFR-1, and ln hs-CRP with death. This study highlights the existence of a correlation between serum biomarkers of inflammation and aging, not only in the whole population, but also in the smaller subset who reported no comorbidities, confirming the existence of a presence of low-grade inflammation in aging, even in healthy elders. We also highlight the existence of a correlation between inflammatory markers and overall mortality. Future studies should address a possible threshold of systemic inflammation where mortality significantly increases, as well as explore the effectiveness of anti-inflammatory treatments on morbidity and mortality in healthy aging subjects.

Cannabidiol attenuates inflammatory impairment of intestinal cells expanding biomaterial-based therapeutic approaches

Cannabis-based biomaterials have the potential to deliver anti-inflammatory therapeutics specifically to desired cells, tissues, and organs, enhancing drug delivery and the effectiveness of anti-inflammatory treatment while minimizing toxicity. As a major component of Cannabis, Cannabidiol (CBD) has gained major attention in recent years because of its potential therapeutic properties, e.g., for restoring a disturbed barrier resulting from inflammatory conditions. The aim of this study was to test the hypothesis that CBD has beneficial effects under normal and inflammatory conditions in the established non-transformed intestinal epithelial cell model IPEC-J2. CBD induced a significant increase in transepithelial electrical resistance (TER) values and a decrease in the paracellular permeability of [³H]-D-Mannitol, indicating a strengthening effect on the barrier. Under inflammatory conditions induced by tumor necrosis factor alpha (TNFα), CBD stabilized the TER and mitigated the increase in paracellular permeability. Additionally, CBD prevented the barrier-disrupting effects of TNFα on the distribution and localization of sealing TJ proteins. CBD also affected the expression of TNF receptors. These findings demonstrate the potential of CBD as a component of Cannabis-based biomaterials used in the development of novel therapeutic approaches against inflammatory pathogenesis.

Conjugation with Tris Decreases the Risk of Ketoprofen-Induced Mucosal Damage and Reduces Inflammation-Associated Methane Production in a Rat Model of Colitis.

We have designed a new compound from the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (Ket) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors, with the aim to reduce the gastrointestinal (GI) side effects of NSAID therapies. We investigated mucosal reactions in a standard rat model of colitis together with methane generation as a possible indicator of pro-inflammatory activation under this condition (approval number: V./148/2013). Whole-body methane production (photoacoustic spectroscopy) and serosal microcirculation (intravital videomicroscopy) were measured, and mucosal damage was assessed (conventional histology; in vivo laser-scanning endomicroscopy). Inflammatory markers were measured from tissue and blood samples. Colitis induced an inflammatory response, morphological colonic damage and increased methane output. Ket treatment lowered inflammatory activation and colonic mucosal injury, but macroscopic gastric bleeding and increased methane output were present. Ket-Tris reduced inflammatory activation, methane emission and colonic mucosal damage, without inducing gastric injury. Conjugation with Tris reduces the GI side effects of Ket and still decreases the inflammatory response in experimental colitis. Methane output correlates with the mucosal inflammatory response and non-invasively demonstrates the effects of anti-inflammatory treatments.

Spondyloarthritis mass cytometry immuno-monitoring: a proof of concept study in the tight-control and treat-to target TiCoSpA trial.

Mass cytometry (MC) immunoprofiling allows high-parameter phenotyping of immune cells. We set to investigate the potential of MC immuno-monitoring of axial spondyloarthritis (axSpA) patients enrolled in the Tight Control SpondyloArthritis (TiCoSpA) trial. Fresh, longitudinal PBMCs samples (baseline, 24, and 48 weeks) from 9 early, untreated axSpA patients and 7 HLA-B27+ controls were analyzed using a 35-marker panel. Data were subjected to HSNE dimension reduction and Gaussian mean shift clustering (Cytosplore), followed by Cytofast analysis. Linear discriminant analyzer (LDA), based on initial HSNE clustering, was applied onto week 24 and 48 samples. Unsupervised analysis yielded a clear separation of baseline patients and controls including a significant difference in 9 T cell, B cell, and monocyte clusters (cl), indicating disrupted immune homeostasis. Decrease in disease activity (ASDAS score; median 1.7, range 0.6-3.2) from baseline to week 48 matched significant changes over time in five clusters: cl10 CD4 Tnai cells median 4.7 to 0.02%, cl37 CD4 Tem cells median 0.13 to 8.28%, cl8 CD4 Tcm cells median 3.2 to 0.02%, cl39 B cells median 0.12 to 2.56%, and cl5 CD38+ B cells median 2.52 to 0.64% (all p<0.05). Our results showed that a decrease in disease activity in axSpA coincided with normalization of peripheral T- and B-cell frequency abnormalities. This proof of concept study shows the value of MC immuno-monitoring in clinical trials and longitudinal studies in axSpA. MC immunophenotyping on a larger, multi-center scale is likely to provide crucial new insights in the effect of anti-inflammatory treatment and thereby the pathogenesis of inflammatory rheumatic diseases. Key Points • Longitudinal immuno-monitoring of axSpA patients through mass cytometry indicates that normalization of immune cell compartments coincides with decrease in disease activity. • Our proof of concept study confirms the value of immune-monitoring utilizing mass cytometry.

Beneficiary Effects of Colchicine on Inflammation and Fibrosis in a Mouse Model of Kidney Injury

Introduction: Low-grade inflammation is seen in many chronic illnesses, including chronic kidney disease (CKD). We have recently reported on beneficiary effects of anti-inflammatory treatment in the interleukin (IL-) 1 pathway on anemia as well as CKD extent in a mouse model. Colchicine has been shown to have beneficiary effects in several inflammatory conditions through various mechanisms, including inhibition of tubulin polymerization as well as caspase-1-mediated IL-1 activation. Methods: Kidney injury (KI) was induced by administering an adenine diet to 8-week-old C57BL/6J mice treated with colchicine (Col) (30 µg/kg) or saline injections for 3 weeks, generating 4 groups: C, Ccol, KI, and KIcol. Results: KI animals had an increase in inflammation indices in the blood (neutrophils), liver, and kidneys (uromodulin, IL-6, pSTAT3). Increased kidney tubulin polymerization and caspase-1 in KI, as well as kidney Mid88 and IRAK4 (downstream of IL-1), were inhibited in KIcol. Kidney macrophage and polymorphonuclear infiltration (positive for F4/80 and MPO, respectively), the percentage of fibrotic area, and TGFβ mRNA levels were lower in KIcol versus KI. Conclusions: Colchicine inhibited tubulin polymerization and caspase-1 activation and attenuated kidney inflammation and fibrosis in a mouse model of adenine-induced KI. Given its reported safety profile for long-term anti-inflammatory therapy without increasing infection tendency, it may serve as novel therapeutic approach in CKD.

Single nucleotide polymorphisms contribute to treatment resistant depression: effect of anti-inflammatory treatment

Single nucleotide polymorphisms contribute to treatment resistant depression: effect of anti-inflammatory treatment

Coronary microvascular dysfunction in the context of long COVID-19: What is the effect of anti-inflammatory treatment? Author's reply.

Coronary microvascular dysfunction in the context of long COVID-19: What is the effect of anti-inflammatory treatment? Author's reply.

Coronary microvascular dysfunction in the context of long COVID-19: What is the effect of anti-inflammatory treatment?

Coronary microvascular dysfunction in the context of long COVID-19: What is the effect of anti-inflammatory treatment?

Abstract WP95: Combination Of Steroid And Anticoagulant Therapy To Treat Acute/subacute Severe Cerebral Venous Thrombosis

Introduction: Endovascular treatment combined with standard anticoagulant treatment often fails to improve functional outcomes of patients with severe cerebral venous thrombosis (CVT). Accumulating evidence suggests that inflammatory response plays a vital role in severe CVT pathogenesis and is strongly associated with a poor prognosis. Hypothesis: To investigate the efficacy and safety of steroids combined with anticoagulant therapy in acute/subacute severe CVT patients. Methods: Patients with first-episode acute/subacute CVT between January 2018 and June 2021 were enrolled. We retrospectively reviewed data of patients with acute/subacute severe CVT treated with and without 500mg methylprednisolone pulse therapy for 3 days. We compared functional outcomes and major adverse events 6 months after discharge between two groups using propensity score matching for the purpose of completion. Results: In this study, 248 patients with acute/subacute severe CVT were included, and 93 (37.50%) patients with severe CVT were treated with steroids. After propensity score matching, there were 85 patients each in the steroid and nonsteroid groups. Patients in the steroid group had lower mRS scores (0-2) (P=0.03) and a lower likelihood of residual headache (19.28% vs. 47.50%, P&lt;0.01) than patients in the nonsteroid group at the 6-month follow-up after discharge. Regarding steroid safety, the likelihood of CVT recurrence (6.02% vs. 6.25%, P=0.95), lower extremity deep venous thrombosis (3.61% vs. 1.25%, P=0.33), pulmonary embolism (1.20% vs. 1.25%, P=0.98), infection (1.20% vs. 1.25%, P=0.98), and mortality (2.35% vs. 5.88%, P=0.25) did not differ between both groups. Steroid treatment (OR: 4.685, 95% CI: 1.629-13.476, P=0.00) was independently associated with favorable outcomes in the matched cohort. During the follow-up period, patients treated with steroids did not experience spontaneous fractures, osteonecrosis, or gastroduodenal ulcers. Discussion: Steroid pulse therapy combined with anticoagulant therapy may be effective and safe for improving the prognosis of patients with acute/subacute severe CVT. These findings shed light on the potential ameliorative effects of anti-inflammatory treatments in acute/subacute severe CVT.

Glial Contributions to Lafora Disease: A Systematic Review.

Lafora disease (LD) is a neurodegenerative condition characterized by the accumulation of polyglucosan bodies (PBs) throughout the brain. Alongside metabolic and molecular alterations, neuroinflammation has emerged as another key histopathological feature of LD. To investigate the role of astrocytes and microglia in LD, we performed a systematic review according to the PRISMA statement. PubMed, Scopus, and Web-of-Science database searches were performed independently by two reviewers. Thirty-five studies analyzing the relationship of astrocytes and microglia with LD and/or the effects of anti-inflammatory treatments in LD animal models were identified and included in the review. Although LD has long been dominated by a neuronocentric view, a growing body of evidence suggests a role of glial cells in the disease, starting with the finding that these cells accumulate PBs. We discuss the potential meaning of glial PB accumulations, the likely factors activating glial cells, and the possible contribution of glial cells to LD neurodegeneration and epilepsy. Given the evidence for the role of neuroinflammation in LD, future studies should consider glial cells as a potential therapeutic target for modifying/delaying LD progression; however, it should be kept in mind that these cells can potentially assume multiple reactive phenotypes, which could influence the therapeutic response.

A plant-derived glucocorticoid receptor modulator with potency to attenuate the side effects of glucocorticoid therapy.

Continuous efforts have been made to move towards maintaining the beneficial anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. Here, we investigated the selective glucocorticoid receptor (GR) modulator-like properties of a plant-derived compound caesaldekarin e (CA-e). The therapeutic efficacy of CA-e was evaluated in several mouse models, including dextran sulfate sodium-induced colitis, ovalbumin-induced lung allergic inflammation, imiquimod-induced psoriasis-like skin inflammation and skin atrophy. The action of CA-e targeting the GR was analysed using molecular docking, cellular thermal shift assays and microscale thermophoresis. Other methods included DNA-protein pull-down assays and mass spectrometry. CA-e selectively inhibited positive GC response element ((+) GRE)-mediated direct transactivation while maintaining and even enhancing the anti-inflammatory effects of treatment with dexamethasone. CA-e, alone and in combination with dexamethasone, efficiently alleviated inflammation in several mouse models with milder side effects compared with dexamethasone alone. Mechanistically, CA-e inhibited the formation of dimers by binding to the dimerization interface located in the ligand-binding domain of GR and facilitated embryonic ectoderm development that is involved in the regulation of transcriptional repression to compete for binding to (+) GRE, eventually leading to the repression of (+) GRE-regulated genes. In addition, CA-e repressed NF-κB-dependent genes by enhancing the interaction between GR and p65. Our results reveal that CA-e is a novel GR modulator with strong potency to attenuate the side effects of GC therapy and can be used as a potential molecular tool for deciphering GR signalling.

The effect of anti-inflammatory treatment on depressive symptoms in spondyloarthritis: does the type of drug matter?

To investigate the effect of pharmacological treatment of SpA on depressive symptoms and explore whether this effect differs between drug classes. Data from the observational Assessment of SpondyloArthritis international Society Health Index Validation Study were used. Patients were assessed at baseline and after initiation of NSAIDs/conventional synthetic DMARDs (csDMARDs)/TNF inhibitors (TNFis). Depressive symptoms were assessed with the Hospital Anxiety and Depression Scale depression subscale [HADS-D; 0-21 (best-worst)]. Covariables included demographics and disease characteristics, including disease activity [Ankylosing Spondylitis Disease Activity Score (ASDAS)/BASDAI]. The change in HADS-D from baseline was compared between treatments (NSAIDs/csDMARDs/TNFis) with analysis of variance and multivariable regression analysis. A total of 304 patients were included; 102/45/157 initiated NSAIDs/csDMARDs/TNFis and 260 (85%) / 44 (15%) had axial/peripheral SpA. At baseline, the mean HADS-D was 6.9 (s.d. 4.2); 126 (42%) were possibly depressed (HADS-D ≥8) and 66 (22%) were probably depressed (HADS-D ≥11). At follow-up, depressive symptoms significantly improved in all treatment groups. In multivariable regression without disease activity measures, initiating TNFis compared with NSAIDs was associated with greater improvement in depressive symptoms [β = -1.27 (95% CI -2.23, -0.32)] and lower odds of possible depression at follow-up [odds ratio 0.47 (95% CI 0.23, 0.94)]. This association was attenuated after additional adjustment for disease activity (ASDAS/BASDAI) but not CRP. csDMARDs did not differ from NSAIDs regarding their effect on HADS-D. Between-drug class results were confirmed in axial SpA (axSpA), although less clear in peripheral SpA. Treatment of active SpA also improves depressive symptoms. Especially in axSpA, TNFis have a greater effect than NSAIDs, which is mainly explained by a stronger effect on disease activity. We found no evidence for a direct link between CRP-mediated inflammation and depressive symptoms in SpA.

S754 Impact of Mirikizumab Treatment on Health-Related Quality of Life in Patients With Crohn’s Disease: A Phase 2 Study Analysis Using the SF-36

Introduction: This analysis evaluated Mirikizumab (miri) effects on Short Form Health Survey (SF-36) in the Phase (Ph)2 randomised, double-blind, parallel, placebo (PBO)-controlled study in patients (pts) with moderately-to-severely active Crohn’s disease (CD). Methods: 12-Week(W) Induction: 191 pts were randomized 2:1:1:2 to 4 treatment arms: intravenous (IV) PBO, 200, 600, or 1000mg miri every 4 weeks (Q4W; W0, 4, and 8). 40-W Maintenance: For miri induction dose, pts achieving ≥1-point improvement in Simple Endoscopic Score for CD (SES-CD) at W12 were re-randomized 1:1 to double-blind maintenance treatment from W12 to W48: continuation of induction IV treatment assignment (IV-IV; N=41) or subcutaneous (SC) 300mg miri Q4W (IV-SC; N=46). Due to small sample sizes, maintenance IV arms and SC arms were pooled. W12 SES-CD non-improvers (N=30) and pts receiving PBO during induction (N=59) received IV 1000mg miri Q4W from W12 to W48. No statistical comparisons were made between miri treatment groups in the maintenance period. SF-36 was assessed at baseline and at W4,12,16, 24, 32, 44, and 52. Results: Statistically significant improvement in MCS was observed at W4 (600mg dose level) and at W12 (all dose levels), whereas statistically significant improvements in PCS were observed only at W12 (600 and 1000mg dose levels) compared to PBO (Table). Though statistical comparisons were not made between treatment groups during maintenance, comparison of mean changes in MCS and PCS suggest that improvements during induction were sustained or further numerically increased with miri maintenance treatment, even in induction SES-CD non-improvers (Table). Conclusion: These data show that miri treatment improves health related quality of life in pts with moderately to severely active CD and suggest an earlier impact on mental compared to physical wellbeing. Maintenance treatment effects were numerically consistent or increased compared to induction effects, even among more refractory pts. These findings will be validated in the ongoing miri Ph3 CD study (NCT03926130). Proinflammatory signals can induce anxiety and depressive symptoms; better understanding of how the effects of anti-inflammatory treatment on the gut-brain axis may improve mental and physical subjective wellbeing requires additional mechanistic studies. Table 1. - Effect of mirikizumab on SF-36 MCS and PCS Change from Baseline Mental Component Score (MCS) Physical Component Score (PCS) Induction Period PBO (N=64) 200 mg IV miri (N=31) 600 mg IV miri (N=32) 1000 mg IV miri (N=64) PBO (N=64) 200 mg IV miri (N=31) 600 mg IV miri (N=32) 1000 mg IV miri (N=64) W0 Baseline (Mean ± SD) 37.0 ± 13.2 35.2 ± 10.2 41.1 ± 10.4 40.4 ± 11.6 38.9 ± 8.3 38.4 ± 6.4 42.9 ± 7.8 39.5 ± 8.6 W4 CFBL (LSM ± SE) 1.9 ± 1.0 2.6 ± 1.4 5.2 ± 1.4* 3.1 ± 1.0 2.4 ± 0.7 3.3 ± 1.0 3.4 ± 1.0 4.2 ± 0.7 W12 CFBL (LSM ± SE) 2.3 ± 1.1 7.5 ± 1.6* 6.5 ± 1.6* 6.1 ± 1.2* 3.1 ± 0.8 4.7 ± 1.1 8.0 ± 1.1** 6.7 ± 0.8** Maintenance Period PBO-1000 mg IV miri (N=59) NI-1000 mg IV miri (N=30) All IV-IV miri (N=41) All IV-SC miri (N=46) PBO-1000 mg IV miri (N=59) NI-1000 mg IV miri (N=30) All IV-IV miri (N=41) All IV-SC miri (N=46) W0 Baseline (Mean ± SD) 37.2 ±13.0 38.0 ±11.2 42.0 ± 10.1 38.7 ±10.7 39.5 ± 8.1 40.8 ± 8.3 41.1 ± 8.5 38.1 ± 7.1 W24 CFBL (Mean ± SD) 7.4 ± 8.7 7.7 ± 11.7 7.0 ± 10.6 5.9 ± 13.1 6.8 ± 7.3 7.1 ± 7.8 9.6 ± 5.6 7.1 ± 8.3 W52 CFBL (Mean ± SD) 7.1 ± 10.6 7.3 ± 9.8 8.5 ± 11.3 11.5 ± 11.4 9.9 ± 7.2 7.1 ± 8.2 10.2 ± 8.7 10.7 ± 7.9 Abbreviations: CFBL = change from baseline; IV = intravenous; IV-IV = pooled maintenance IV treatment arms for patients at each miri induction dose level who achieved ≥1-point improvement in SES-CD at W12 who were re-randomized to continued induction IV treatment assignment during maintenance; IV-SC = pooled maintenance SC treatment arms for patients at each miri induction dose level who achieved ≥1-point improvement in SES-CD at W12 who were re-randomized to SC 300mg miri Q4W during maintenance; LSM = least squares mean; NI = SES-CD non-improver (a patient who received miri during induction who did not achieve a ≥1-point improvement in SES-CD at W12); PBO = placebo; SC = subcutaneous; SD = standard deviation; SE = standard error; W = week. For statistical comparisons across induction treatment groups, a mixed model for repeated measures was used. The model includes treatment, region, prior biologic CD therapy used, baseline, visit and baseline by visit, and treatment by visit.p-values versus PBO: *p< 0.05; ** p≤0.001. Bolded values are statistically different versus PBO.

18F]DPA-714 PET imaging for the quantitative evaluation of early spatiotemporal changes of neuroinflammation in rat brain following status epilepticus.

Most antiepileptic drug therapies are symptomatic and adversely suppress normal brain function by nonspecific inhibition of neuronal activity. In recent times, growing evidence has suggested that neuroinflammation triggered by epileptic seizures might be involved in the pathogenesis of epilepsy. Although the potential effectiveness of anti-inflammatory treatment for curing epilepsy has been extensively discussed, the limited quantitative data regarding spatiotemporal characteristics of neuroinflammation after epileptic seizures makes it difficult to be realized. We quantitatively analyzed the spatiotemporal changes in neuroinflammation in the early phase after status epilepticus in rats, using translocator protein (TSPO) positron emission tomography (PET) imaging, which has been widely used for the quantitative evaluation of neuroinflammation in several animal models of CNS disease. The second-generation TSPO PET probe, [18F]DPA-714, was used for brain-wide quantitative analysis of neuroinflammation in the brains of rats, when the status epilepticus was induced by subcutaneous injection of kainic acid (KA, 15 mg/kg) into those rats. A series of [18F]DPA-714 PET scans were performed at 1, 3, 7, and 15 days after status epilepticus, and the corresponding histological changes, including activation of microglia and astrocytes, were confirmed by immunohistochemistry. Apparent accumulation of [18F]DPA-714 was observed in several KA-induced epileptogenic regions, such as the amygdala, piriform cortex, ventral hippocampus, mediodorsal thalamus, and cortical regions 3 days after status epilepticus, and was reversibly displaced by unlabeled PK11195 (1 mg/kg). Consecutive [18F]DPA-714 PET scans revealed that accumulation of [18F]DPA-714 was focused in the KA-induced epileptogenic regions from 3 days after status epilepticus and was further maintained in the amygdala and piriform cortex until 7 days after status epilepticus. Immunohistochemical analysis revealed that activated microglia but not reactive astrocytes were correlated with [18F]DPA-714 accumulation in the KA-induced epileptogenic regions for at least 1 week after status epilepticus. These results indicate that the early spatiotemporal characteristics of neuroinflammation quantitatively evaluated by [18F]DPA-714 PET imaging provide valuable evidence for developing new anti-inflammatory therapies for epilepsy. The predominant activation of microglia around epileptogenic regions in the early phase after status epilepticus could be a crucial therapeutic target for curing epilepsy.