Inhibition Of Interleukin Research Articles

Direct M2 macrophage co-culture overrides viscoelastic hydrogel mechanics to promote fibroblast activation.

Fibroblast activation drives fibrotic diseases such as pulmonary fibrosis. However, the complex interplay of how tissue mechanics and macrophage signals combine to influence fibroblast activation is not well understood. Here, we use hyaluronic acid hydrogels as a tunable cell culture system to mimic lung tissue stiffness and viscoelasticity. We applied this platform to investigate the influence of macrophage signaling on fibroblast activation. Fibroblasts cultured on stiff (50 kPa) hydrogels mimicking fibrotic tissue exhibit increased activation as measured by spreading as well as type I collagen and cadherin-11 expression compared to fibroblasts cultured on soft (1 kPa) viscoelastic hydrogels mimicking normal tissue. These trends were unchanged in fibroblasts cultured with macrophage-conditioned media. However, fibroblasts directly co-cultured with M2 macrophages show increased activation, even on soft viscoelastic hydrogels that normally suppress activation. Inhibition of interleukin 6 (IL6) signaling does not change activation in fibroblast-only cultures but ameliorates the pro-fibrotic effects of M2 macrophage co-culture. These results underscore the ability of direct M2 macrophage co-culture to override hydrogel viscoelasticity to promote fibroblast activation in an IL6-dependent manner. This work also highlights the utility of using hydrogels to deconstruct complex tissue microenvironments to better understand the interplay between microenvironmental mechanical and cellular cues.

An unexpected role of IL10 in mesoderm induction and differentiation from pluripotent stem cells: Implications in zebrafish angiogenic sprouting, vascular organoid development, and therapeutic angiogenesis

Mesoderm induction is a crucial step for vascular cell specification, vascular development and vasculogenesis. However, the cellular and molecular mechanisms underlying mesoderm induction remain elusive. In the present study, a chemically-defined differentiation protocol was used to induce mesoderm formation and generate functional vascular cells including smooth muscle cells (SMCs) and endothelial cells (ECs) from human induced pluripotent stem cells (hiPSCs). Zebrafish larvae were used to detect an in vivo function of interleukin 10 (IL10) in mesoderm formation and vascular development. A three dimensional approach was used to create hiPSC-derived blood vessel organoid (BVO) and explore a potential impact of IL10 on BVO formation. A murine model hind limb ischemia was applied to investigate a therapeutic potential of hiPSC-derived cells treated with or without IL10 during differentiation. We found that IL10 was significantly and specifically up-regulated during mesoderm stage of vascular differentiation. IL10 addition in mesoderm induction media dramatically increased mesoderm induction and vascular cell generation from hiPSCs, whereas an opposite effect was observed with IL10 inhibition. Mechanistic studies revealed that IL10 promotes mesoderm formation and vascular cell differentiation by activating signal transducer and activator of transcription 3 signal pathway. Functional studies with an in vivo model system confirmed that knockdown of IL10 using morpholino antisense oligonucleotides in zebrafish larvae caused defective mesoderm formation, angiogenic sprouting and vascular development. Additionally, our data also show IL10 promotes blood vessel organoid development and enhances vasculogenesis and angiogenesis. Importantly, we demonstrate that IL10 treatment during mesoderm induction stage enhances blood flow perfusion recovery and increases vasculogenesis and therapeutic angiogenesis after hind limb ischemia. Our data, therefore, demonstrate a regulatory role for IL10 in mesoderm formation from hiPSCs and during zebrafish vascular development, providing novel insights into mesoderm induction and vascular cell specifications.

Christensenella minuta protects and restores intestinal barrier in a colitis mouse model by regulating inflammation

Christensenella minuta DSM 22607 has recently been suggested as a potential microbiome-based therapy for inflammatory bowel disease (IBD) because it displays strong anti-inflammatory effects both in vitro and in vivo. Here, we aimed to decipher the mechanism(s) underlying the DSM 22607-mediated beneficial effects on the host in a mouse model of chemically induced acute colitis. We observed that C. minuta plays a key role in the preservation of the epithelial barrier and the management of DNBS-induced inflammation by inhibiting interleukin (IL)-33 and Tumor necrosis factor receptor superfamily member 8 (Tnfrsf8) gene expression. We also showed that DSM 22607 abundance was positively correlated with Akkermansia sp. and Dubosiella sp. and modulated microbial metabolites in the cecum. These results offer new insights into the biological and molecular mechanisms underlying the beneficial effects of C. minuta DSM 22607 by protecting the intestinal barrier integrity and regulating inflammation.

Rotation or change of biotherapy after TNF blocker treatment failure for axial spondyloarthritis: the ROC-SpA study, a randomised controlled study protocol

IntroductionAxial spondyloarthritis (axSpA) is a chronic inflammatory disease characterised by inflammatory low back pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as a first treatment in axSpA. In case of inadequate...

Safety and Efficacy of Bimekizumab in Patients with Psoriatic Arthritis: 2-Year Results from Two Phase 3 Studies.

Psoriatic arthritis (PsA) is a chronic inflammatory disease requiring long-term treatment. Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and sustained clinical efficacy for up to 1year for patients with PsA. Here, we report the longer-‍term safety and efficacy of bimekizumab up to 2years. BE OPTIMAL (biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (prior inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160mg every 4weeks in patients with PsA. BE OPTIMAL included a reference arm (adalimumab 40mg every 2weeks); patients switched to bimekizumab at week 52 with no washout between treatments. BE OPTIMAL week 52 and BE COMPLETE week 16 completers were eligible for the BE VITAL open-label extension. Efficacy outcomes are reported to week 104/100 (BE OPTIMAL/BE COMPLETE). A total of 710/852 (83.3%) bDMARD-naïve and 322/400 (80.5%) TNFi-IR patients completed week 104/100. Up to 104weeks, patients treated with bimekizumab in BE OPTIMAL and BE COMPLETE had treatment-emergent adverse event incidence rates (exposure-adjusted incidence rate/100 patient-years) of 179.9 (95% CI 166.9, 193.7) and 100.3 (89.2, ‍112.4), respectively. The proportion of patients achieving efficacy outcomes (≥ 50% improvement from baseline in American College of Rheumatology [ACR] response criteria, 100% improvement from baseline in Psorisis Area and Severity Index [PASI], minimal disease activity [MDA]) was sustained in all patients from week 52 to week 104/100. Bimekizumab was well tolerated for up to 2years of treatment and no new safety signals were observed. Sustained clinical efficacy was observed up to 2years in bDMARD-naïve and TNFi-IR patients with active PsA. Patients switching from adalimumab to bimekizumab demonstrated further improvement in skin and nail symptoms, and sustained efficacy in joint symptoms. BE OPTIMAL (NCT03895203), BE COMPLETE (NCT03896581), BE VITAL (NCT04009499).

Head-to-head studies on psoriasis and psoriatic arthritis

Given the ever-increasing number of approved therapies for the treatment of psoriasis (PsO) and psoriatic arthritis (PsA), head-to-head (H2H) comparative studies are essential. These are aimed primarily at acomparative analysis of treatment effectiveness. In both PsO and PsA, biological disease-modifying antirheumatic drugs (bDMARD) have been shown to be superior to conventional therapies in H2H studies. In PsO interleukin 17 (IL-17) and IL-23 inhibitors proved superiority compared to tumor necrosis factor (TNF) inhibitors (etanercept and adalimumab) in several studies. Ustekinumab was more effective than etanercept, but less effective than IL-17 and IL-23 inhibitors. Only afew H2H studies have been published on the treatment of PsA. In the Spirit H2H study ixekizumab was superior to adalimumab using acombined endpoint of arthritis and psoriasis response (ACR-50 and PASI-100). When looking at arthritic symptoms only (ACR-20), secukinumab was not significantly superior to adalimumab in the EXCEED study but was superior in terms of the effect on skin involvement (PASI90). Other H2H studies focused on the treatment of enthesitis (ECLIPSA study), the efficacy of Janus kinase (JAK) inhibition (SELECT-PSA-1) or the additional administration of methotrexate to bDMARD treatment (MUST study). The H2H data have been incorporated into the treatment guidelines and have led to IL-17 and IL-23 inhibition being preferred over TNF inhibition in cases of relevant skin involvement in PsA.

JAK2/mTOR inhibition fails to prevent acute GVHD despite reduced Th1/Th17 cells: final phase 2 trial results

AbstractOur phase 1 graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib (PAC; recommended phase 2 dose: 100 mg orally twice a day on day 0 to +70) plus sirolimus and tacrolimus (SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits interleukin 6 (IL-6) receptor activity and pathogenic T helper cell 1 (Th1)/Th17 differentiation in preclinical models and the phase 1 trial. Herein, we report on our completed phase 2 trial of PAC/SIR/TAC after 8/8 human leukocyte antigen matched alloHCT. This single-arm phase 2 trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed percentage phosphorylated STAT3 (pSTAT3)+ CD4+ T cells at day +21 (primary end point: percentage pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II to IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T-cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n = 28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary end point, reducing percentage pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of regulatory T cells to Th1 and Th17 cells with PAC/SIR/TAC at recommended phase 2 dose PAC compared with dose level 1 PAC. The cumulative incidence of grade II to IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46% vs 43%). Although PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.

Long-term renal outcome of Cryopyrin-associated periodic syndrome (CAPS) under anti-Interleukin-1 therapy

Cryopyrin-associated periodic syndromes (CAPS) are orphan hereditary auto-inflammatory diseases with various phenotypes, including chronic kidney disease (CKD). Current therapies inhibit interleukin-1 (IL-1) to achieve clinical and serological remission; however, the effect on kidney involvement remains unclear. The objective of this study was to investigate the long-term efficacy of anti-IL-1 treatment with special emphasis on renal outcome. We retrospectively analysed clinical, genetic and laboratory data of patients with CAPS under anti-IL-1 therapy from a single-centre university outpatient clinic. Patients with CAPS (n = 28) were followed for a median of 11 (IQR 8.5–13) years. Four patients at various ages (19%), bearing the most common CAPS mutation R260W, had significant CKD at presentation. All affected patients were related; however, other family members with the same genetic variant did not develop CKD. While anti-IL-1 therapy was effective in lowering symptom burden and inflammatory parameters in all CAPS patients, two of the four individuals with significant CKD had persistent proteinuria and worsening kidney function. None of the patients without renal affection at therapy initiation developed relevant CKD in the follow-up period. We showed that in patients with CAPS: (1) CKD is a common complication; (2) renal involvement shows familial predisposition beyond the mutational status and is independent of age; (3) anti-IL-1 therapy results in sustained improvement of inflammatory parameters and symptom load and (4) may prevent development of CAPS-associated CKD but not affect kidney involvement when already present. Overall, early therapy initiation might sufficiently prevent renal disease manifestation and attenuate progression.

The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection

PurposeVibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. MethodsAn increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. ResultsIn mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival (p = 0.014), reduced the serum creatinine (p = 0.002), urea nitrogen (p = 0.030), aspartate aminotransferase (p = 0.029), and alanine aminotransferase (p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1β: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1β, IL-6, TNF-α in liver (IL-1β: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1β: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid (p = 0.225), liver (p = 0.186), or kidney (p = 0.637). ConclusionBergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.

Anti-rheumatoid arthritis potential of Acorus calamus L. extract by interleukin-17 inhibition: Molecular insights through an in silico study

Context: Interleukin-17 (IL-17) is a pro-inflammatory cytokine that plays a crucial role in immunity and inflammation. Aims: To evaluate the potential therapeutic effects of two compounds, magnosalicine and neotatarine, derived from the ethanolic extract of Acorus calamus L. rhizome, against IL-17. Methods: Utilizing LC/MS analysis combining molecular docking simulations, drug likeness, ADME and toxicity analysis. This study explored the molecular interactions and binding affinities of identified compounds from A. calamus with crucial residues of IL-17, including Tyr62, Pro63, Ile66, Gln94, Ile96, Leu97, and Leu99. Results: The results revealed that magnosalicine and neotatarine exhibited remarkable binding affinities of -10.16 kcal/mol and -9.53 kcal/mol, respectively, indicating their strong interactions with IL-17. Moreover, both compounds displayed superior binding energies compared to other extract constituents. Interestingly, this study highlighted that all terpenoid compounds from the A. calamus rhizome extract were capable of interacting with these key residues of IL-17, resembling the interactions observed with the natural ligand (RMK) and methotrexate. Meanwhile, the analysis results revealed a safer ADME and toxicity profile for neotatarine compared to magnolalicine. Conclusions: This research unveils the promising potential of neotatarine as candidates for further exploration in therapeutic interventions targeting IL-17-related pathways. These findings shed light on the molecular insights of Acorus calamus L. compounds, providing valuable information for developing novel treatments for IL-17-associated disorders.

E068 Achievement of low disease activity over 52 weeks in patients with active axial spondyloarthritis on bimekizumab treatment: results from the phase 3 studies BE MOBILE 1 and BE MOBILE 2

Abstract Background/Aims The recommended treatment target for axial spondyloarthritis (axSpA) is remission/low disease activity (LDA) according to Ankylosing Spondylitis Disease Activity Score (ASDAS) levels (ASDAS<2.1); however, remission is difficult to achieve for many patients. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) remains commonly used in clinical practice to assess disease activity, although limited data exist to validate cut-offs. Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. BKZ has demonstrated consistent and sustained efficacy up to Week (Wk)52 in the BE MOBILE 1 and 2 phase 3 studies, including achievement of LDA according to ASDAS by > 50% of patients with non-radiographic (nr-)axSpA and radiographic (r-)axSpA. Here, we report achievement of LDA, as assessed by either ASDAS<2.1, BASDAI<4, or both, to Wk52 with BKZ across the spectrum of axSpA in two phase 3 studies. Methods BE MOBILE 1 (NCT03928704) and BE MOBILE 2 (NCT03928743) comprised a 16-wk placebo (PBO)-controlled and 36-wk maintenance period. BE MOBILE 1 (nr-axSpA) patients met Assessment of SpondyloArthritis international Society (ASAS) classification criteria and had objective inflammation (MRI and/or elevated C-reactive protein). BE MOBILE 2 (r-axSpA) patients met modified New York and ASAS classification criteria. All patients had active disease (BASDAI≥4 and spinal pain≥4 [BASDAI item 2]) at baseline. Patients were randomised to subcutaneous BKZ 160 mg every 4 weeks (Q4W) or PBO. Patients randomised to PBO switched to BKZ from Wk16 (‘PBO/BKZ-switchers’). The proportion of patients that achieved LDA to Wk52, as defined by either ASDAS<2.1, BASDAI<4, or both, are presented (non-responder imputation). Results Overall, 254 patients with nr-axSpA (BKZ: 128/PBO: 126) and 332 with r-axSpA (BKZ: 221/PBO: 111) were randomised. Most had high (ASDAS≥2.1-≤3.5) or very high (ASDAS>3.5) disease activity at baseline (nr-axSpA: BKZ: 99.2%/PBO: 97.6%; r-axSpA: BKZ: 98.6%/PBO: 100%). At Wk16, a greater proportion of BKZ vs PBO-treated patients achieved ASDAS<2.1 (nr-axSpA: BKZ: 46.1%/PBO: 19.8%; r-axSpA: BKZ: 42.1%/PBO: 17.1%), BASDAI<4 (nr-axSpA: BKZ: 52.3%/PBO: 31.7%; r-axSpA: BKZ: 55.7%/PBO: 41.4%) and both (nr-axSpA: BKZ: 43.8%/PBO: 19.0%; r-axSpA: BKZ: 41.6%/PBO: 17.1%). Results were sustained/improved across continuous BKZ-treated patients and PBO/BKZ-switchers to Wk52, with achievement of ASDAS<2.1 (nr-axSpA: BKZ: 53.9%/switchers: 47.6%; r-axSpA: BKZ: 50.2%/switchers: 61.3%), BASDAI<4 (nr-axSpA: BKZ: 60.2%/switchers: 54.0%; r-axSpA: BKZ: 65.6%/switchers: 68.5%) and both (nr-axSpA: BKZ: 49.2%/switchers: 45.2%; r-axSpA: BKZ: 49.8%/switchers: 58.6%). Achievement of BASDAI<4 was consistently higher than ASDAS<2.1, regardless of treatment arm. Conclusion Across the full axSpA disease spectrum, BKZ resulted in rapid achievement of LDA vs PBO to Wk16, as assessed by ASDAS<2.1, BASDAI<4, or both; improvements continued to Wk52. Most patients achieving ASDAS<2.1 also achieved BASDAI<4. These data suggest ASDAS<2.1 is a more stringent criterion for LDA, relevant for consideration of BKZ in the context of a potential treat-to-target approach for axSpA in daily practice. Disclosure X. Baraliakos: Consultancies; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB Pharma ; grant/research support from: Novartis and UCB Pharma. Member of speakers’ bureau; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. Other; Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. S. Ramiro: Grants/research support; AbbVie, Galapagos, MSD, Novartis, Pfizer and UCB Pharma; Consultant for AbbVie, Eli Lilly, Novartis, Pfizer, Sanofi and UCB Pharma. M. Magrey: Consultancies; AbbVie, BMS, Eli Lilly, Novartis, Pfizer and UCB Pharma. Grants/research support; AbbVie, BMS and UCB Pharma. M. Rudwaleit: Consultancies; AbbVie, Eli Lilly, Novartis and UCB Pharma. Member of speakers’ bureau; AbbVie, Boehringer Ingelheim, Chugai, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma. N. Haroon: Consultancies; AbbVie, Eli Lilly, Janssen, Novartis and UCB Pharma. C. Fleurinck: Other; Employees of UCB Pharma. U. Massow: Other; Employees of UCB Pharma. N. de Peyrecave: Other; Employees of UCB Pharma. T. Vaux: Other; Employees of UCB Pharma. H. Marzo-Ortega: Consultancies; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Honoraria; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Grants/research support; Janssen, Novartis and UCB Pharma. V. Navarro-Compán: Consultancies; AbbVie, Eli Lilly, Galapagos, MoonLake, MSD, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, Eli Lilly, Fresenius Kabi, Janssen, MSD, Novartis, Pfizer and UCB Pharma. Grants/research support; AbbVie and Novartis.

E067 Bimekizumab maintained efficacy responses through 52 weeks in biologic disease-modifying antirheumatic drugnaïve patients with psoriatic arthritis who were responders at week 16: results from BE OPTIMAL, a phase 3, activereference study

E067 Bimekizumab maintained efficacy responses through 52 weeks in biologic disease-modifying antirheumatic drugnaïve patients with psoriatic arthritis who were responders at week 16: results from BE OPTIMAL, a phase 3, activereference study

P167 Bimekizumab achieved sustained improvements in efficacy outcomes in patients with axial spondyloarthritis, regardless of prior tumour necrosis factor inhibitor treatment: week 52 pooled results from the phase 3 studies BE MOBILE 1 and BE MOBILE 2

Abstract Background/Aims Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL17A. In the phase 3 BE MOBILE 1 and 2 studies, BKZ treatment resulted in rapid and sustained improvements in efficacy outcomes through 52 weeks (wks) in patients with active nonradiographic axial spondyloarthritis (nr-axSpA) and radiographic (r)axSpA (i.e., ankylosing spondylitis [AS]). Here, we assess the efficacy of BKZ in tumour necrosis factor inhibitor (TNFi)-naïve or -inadequate responder (IR) patients with active nr-axSpA and raxSpA through Wk52. Methods In BE MOBILE 1 (nr-axSpA; NCT03928704) patients met Assessment of SpondyloArthritis international Society (ASAS) classification criteria and in BE MOBILE 2 (r-axSpA; NCT03928743) patients fulfilled modified New York and ASAS criteria. Patients were randomised to receive subcutaneous BKZ 160mg every 4wks (Q4W) or placebo (PBO) then BKZ 160mg Q4W from Wk16. This post-hoc analysis reports pooled mean efficacy data, including disease activity, MRI inflammation, physical function, and quality of life (QoL), through Wk52, stratified by TNFi status (naïve/IR). TNFi-IR patients were defined as those who experienced intolerance, or IR, to prior treatment given at an approved dose for ≥12wks. Results This pooled analysis included 505 TNFi-naïve and 81 TNFi-IR patients. 302/505 (59.8%) TNFi-naïve and 47/81 (58.0%) TNFi-IR patients were randomised to BKZ. Higher proportions of BKZ-randomised patients vs PBO achieved Wk16 ASAS40 (TNFinaïve: 46.0% vs 23.2%, TNFi-IR: 44.7% vs 14.7%; multiple imputation) and AS Disease Activity Score (ASDAS) <2.1 or low disease activity (47.9% vs 20.3%, 30.2% vs 15.6%; observed case). In continuous BKZ-treated patients, responses increased to Wk52 (ASAS40: 59.9%, 55.3%; ASDAS<2.1: 62.0%, 54.1%). Greater reductions from baseline in ASDAS-CRP and MRI inflammation by Wk16 were achieved with BKZ vs PBO in both TNFi-naïve/-IR patients; in continuous BKZ-treated patients this was sustained or further improved through 52wks. Comparable improvements in physical function, nocturnal spinal pain and ASQoL were observed through 52wks with BKZ in TNFinaïve/-IR patients (Table). Conclusion Across the full axSpA disease spectrum, BKZ treatment resulted in clinically relevant improvements in key efficacy outcomes vs PBO, including suppression of inflammation and improvements in physical function and QoL, regardless of prior TNFi exposure. Improvements were sustained to Wk52. Disclosure M. Magrey: Consultancies; AbbVie, BMS, Eli Lilly, Novartis, Pfizer and UCB Pharma. Grants/research support; AbbVie, BMS and UCB Pharma. M. Van de Sande: Consultancies; AbbVie, Novartis and UCB Pharma. Member of speakers’ bureau; Janssen, Novartis and UCB Pharma. Grants/research support; Eli Lilly, Novartis and UCB Pharma. M. Breban: Consultancies; Novartis and UCB Pharma. Grants/research support; MSD. F. Van den Bosch: Consultancies; AbbVie, Amgen, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, Amgen, Janssen, Merck, Novartis, Pfizer and UCB Pharma. C. Fleurinck: Other; Employee of UCB Pharma. U. Massow: Other; Employee of UCB Pharma. N. de Peyrecave: Other; Employee of UCB Pharma. T. Vaux: Other; Employee of UCB Pharma. X. Baraliakos: Consultancies; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. Grants/research support; Novartis and UCB Pharma. Other; Paid instructor for AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. H. Marzo-Ortega: Consultancies; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Honoraria; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Grants/research support; Janssen, Novartis and UCB Pharma.

The cost-effectiveness of a bimekizumab versus IL-17A inhibitors treatment-pathway in patients with active axial spondyloarthritis in Scotland

Objective To estimate the cost-effectiveness of a treatment-pathway initiated with bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A, in patients with axial spondyloarthritis (axSpA) compared with IL-17Ai's, ixekizumab, and secukinumab, from the NHS Scotland perspective. Methods The axSpA treatment-pathway was modeled using a decision tree followed by a lifetime Markov model. The pathway included first- and second-line biologic disease-modifying antirheumatic drugs (bDMARD), followed by best supportive care (bDMARD, nonbiologic). Bimekizumab followed by any bDMARD (“BKZ”) was compared with IL-17Ai’s: secukinumab 150 mg followed by a blend (“SEC”) of dose up-titration to secukinumab 300 mg and any bDMARD, or ixekizumab followed by any bDMARD (“IXE”). Transition to the next therapy was triggered by Bath Ankylosing Spondylitis Disease Activity Index-50% (BASDAI50) non-response or any-cause discontinuation. A published network meta-analysis provided efficacy data. EuroQoL-5-dimensions utilities were derived by mapping from Ankylosing Spondylitis Disease Activity Score. Costs included disease management (linked to functional limitations), biologics acquisition (list prices), administration and monitoring (NHS 2021/22). Discounting was 3.5%/year. Probabilistic results from patients with non-radiographic axSpA and ankylosing spondylitis were averaged to reflect the axSpA disease spectrum. Scenario and sensitivity analyses were performed. Results The incremental cost-effectiveness ratio (ICER) of BKZ was £24,801/quality-adjusted life-year (QALY) vs. SEC (95% credible interval £24,163–£25,895). BKZ had similar costs (Δ -£385 [−£15,239–£14,468]) and QALYs (Δ 0.039 [−0.748–0.825]) to IXE, with £1,523 (£862–£2,222) net monetary benefit. Conclusions remained unchanged in most scenarios. Results’ drivers included BASDAI50 response rate and disease management cost. Limitations Results were based on list prices. Data concerning up-titration to secukinumab 300 mg was scarce. Conclusions The bimekizumab treatment-pathway represents a cost-effective option across the axSpA disease spectrum in Scotland. Bimekizumab is cost-effective compared to a secukinumab-pathway that includes dose up-titration, and has similar costs and QALYs to an ixekizumab-pathway.

RNA-Based Anti-Inflammatory Effects of Membrane Vesicles Derived from Lactiplantibacillus plantarum.

Bacteria generally release extracellular membrane vesicles (MVs), which are nanoparticles that play important roles in bacterial-bacterial and bacterial-host communication. As probiotics, lactic acid bacteria provide diverse health benefits to their hosts. In this study, we found that the Gram-positive lactic acid bacteria Lactiplantibacillus plantarum subsp. plantarum NBRC 15891 produce high amounts of MVs (LpMVs), and that LpMVs inhibit interleukin (IL)-8 production induced by lipopolysaccharide in intestinal epithelial HT29 cells. Heat- or UV-killed bacterial cells did not exhibit anti-inflammatory effects, and there was no uptake of these bacterial cells; contrarily, LpMVs were taken up into the cytoplasm of HT29 cells. Small RNAs extracted from LpMVs also suppressed IL-8 production in HT29 cells, suggesting that RNAs in the cytoplasm of bacterial cells are encapsulated in the MVs and released from the cells, which may be delivered to HT29 cells to exert their anti-inflammatory effects. In addition, administration of LpMVs to mice with dextran sodium sulfate-induced colitis alleviated colitis-induced weight loss and colon length shortening, indicating that LpMV intake is likely to be effective in preventing or ameliorating colitis.

Bimekizumab Versus Secukinumab Continuous Maintenance of PASI 90 and PASI 100 Responses through One Year in Patients with Moderate to Severe Plaque Psoriasis: Post-HOC Results from the BE RADIANT Phase 3b Trial

Introduction: Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL‑17A.[1] Secukinumab (SEC) is a widely used monoclonal IgG1 antibody that targets IL-17A. BE RADIANT was the first phase 3 study to compare inhibition of IL-17A and IL-17F with inhibition of IL-17A alone. Patient (pt) surveys have confirmed that maintaining a long-lasting response is a key treatment goal for patients who have already achieved skin clearance.[2,3] Here, we assess the efficacy of BKZ vs SEC in continuously maintaining an improvement of ≥90% in the Psoriasis Area and Severity Index (PASI 90), and PASI 100 responses, at every visit from Week (Wk)16 to Wk48 of treatment in pts with moderate to severe plaque psoriasis. Procedure/study: BE RADIANT was a phase 3b, randomized trial, consisting of a 48-week double-blinded, active comparator-controlled period followed by an open-label extension.[4] Pts were randomized 1:1 to BKZ 320 mg every 4 wks (Q4W) or SEC (weekly to Wk4 then Q4W). At Wk16, BKZ-randomized pts either continued to receive BKZ 320 mg Q4W or switched to BKZ 320 mg every 8 wks (Q8W). This analysis includes pts who achieved PASI 90 or 100 at Wk16 and continued to receive study medication at Wk16 or later, reported with BKZ dose groups pooled. We report the proportion of responders who continued to achieve their response at every study visit up to and including Wk48. Missing data were imputed as non-response. Results: At baseline, 373 pts were randomized to BKZ, and 370 were randomized to SEC. At Wk16, 319/373 (85.5%) BKZ-randomized and 273/370 (73.8%) SEC-randomized pts achieved PASI 90; 230/373 (61.7%) and 180/370 (48.6%) achieved PASI 100. PASI 90 was continuously maintained at each study visit from Wk16–Wk48 by 242/319 (75.9%) BKZ-treated and 177/273 (64.8%) SEC-treated Wk16 responders. PASI 100 was continuously maintained through Wk48 by 139/230 (60.4%) BKZ-treated and 93/180 (51.7%) SEC-treated Wk16 responders. Conclusion: A higher proportion of pts treated with BKZ continuously maintained their Wk16 PASI 90 and PASI 100 responses at every visit during the first treatment year compared to SEC. Funding: UCB Pharma. Medical writing support: Costello Medical.

Bimekizumab Efficacy through Year 1 in Patients with Moderate to Severe Plaque Psoriasis Who Had Not Achieved a PASI 90 Response by Week 16: A Pooled Analysis from Four Phase 3/3B Trials

Introduction: Psoriasis Area and Severity Index (PASI) is a commonly used tool for evaluating skin clearance; patients with ≥90% reduction from baseline PASI (PASI 90) have a level of skin clearance that has been associated with improved quality of life.1 Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A.2 High PASI 90 response rates have been observed with BKZ, maintained through three years, across four phase 3/3b trials and an open-label extension (OLE).3–7 Here, we evaluate PASI response through Year 1 in patients who had not had a PASI 90 response during at least one visit up to and including Week 16, in four phase 3/3b trials of BKZ in moderate to severe plaque psoriasis. 
 Methods: Data were pooled from the double-blinded 52-week BE VIVID,3 56-week BE READY,4 56-week BE SURE,5 phase 3 trials, and the 48-week double-blind period of the BE RADIANT6 phase 3b trial. Included patients were randomized to BKZ 320 mg every 4 weeks (Q4W) to Week 16 and then received either BKZ 320 mg Q4W or Q8W maintenance dosing until end of Year 1 (Week 52 for BE VIVID; Week 48 for other trials). Results are reported as observed case (OC).
 Results: Of the 1,362 patients randomized to BKZ across four phase 3/3b trials, 92.6% (n=1,261) had a PASI 90 response during at least one visit up to and including Week 16 while 7.1% (n=97) had not. PASI response was unavailable for 4 patients. The median (minimum, maximum) percent change from baseline PASI among the 97 patients without a PASI 90 response by Week 16 was −77.3 (−89.7, +20.0) at Week 16 (n=78) and −92.9 (−100, +90.7) at Year 1 (n=51).
 Overall, 61.9% (60/97) of patients without a PASI 90 response by Week 16 completed their respective phase 3/3b trials and entered an OLE. By Year 1, 55.0% (33/60) achieved PASI 90 during at least one visit.
 Conclusion: While the vast majority (92.6%) of patients treated with BKZ had a PASI 90 response during at least one visit up to Week 16, a large proportion of patients without a PASI 90 response by Week 16 who completed the phase 3/3b trials and entered an OLE had a PASI 90 response during at least one visit up to Year 1 (55.0%).

CHF6297: a novel potent and selective p38 MAPK inhibitor with robust anti-inflammatory activity and suitable for inhaled pulmonary administration as dry powder.

Inhibition of p38 mitogen-activated protein kinase (MAPKs) is a potential therapeutic approach for the treatment of acute and chronic pulmonary inflammatory conditions. Here, we report the in vitro and in vivo characterization of the anti-inflammatory effects of CHF6297, a novel potent and selective p38α inhibitor designed for inhalation delivery as a dry powder formulation. CHF6297 has been proven to inhibit p38α enzymatic activity with sub-nanomolar potency (IC50 = 0.14 ± 0.06nM), with >1,000-fold selectivity against p38γ and p38δ. In human peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharides (LPS), as well as in human bronchial epithelial cells (BEAS2B) stimulated with TNF-α or cigarette smoke extract (CSE), CHF6297 inhibited interleukin (IL)-8 release with low nanomolar potency. CHF6297 administered to rats by using a nose-only inhalation device as a micronized dry powder formulation blended with lactose dose-dependently inhibited the LPS-induced neutrophil influx in the bronchoalveolar lavage fluid (BALF). CHF6297 administered intratracheally to rats dose-dependently counteracted the IL-1β (0.3mg/kg)-induced neutrophil influx (ED50 = 0.22mg/kg) and increase in IL-6 levels (ED50 = 0.82mg/kg) in the BALF. In mice exposed to tobacco smoke (TS), CHF6297, administered intranasally (i.n.) for 4 days at 0.03 or 0.3mg/kg, dose-dependently inhibited the corticosteroid-resistant TS-induced neutrophil influx in the BALF. In a murine house dust mite (HDM) model of asthma exacerbated by influenza virus A (IAV) (H3N3), CHF6297 (0.1mg/kg, i.n.) significantly decreased airway neutrophilia compared to vehicle-treated IAV/HDM-challenged mice. When CHF6297, at a dose ineffective per se (0.03mg/kg), was added to budesonide, it augmented the anti-inflammatory effects of the steroid. Overall, CHF6297 effectively counteracted lung inflammation in experimental models where corticosteroids exhibit limited anti-inflammatory activity, suggesting a potential for the treatment of acute exacerbations associated with chronic obstructive pulmonary disease (COPD) and asthma, acute lung injury (ALI), and viral-induced hyperinflammation.

Mental health outcomes in patients with moderate to severe psoriasis treated with bimekizumab: Analysis of phase 2/3 randomized trials

Patients with psoriasis have increased risk of suicidal ideation and behavior (SIB) and depression. Bimekizumab, a biologic that inhibits interleukin (IL)-17A and IL-17F, received Food and Drug Administration approval in 2023 for moderate to severe plaque psoriasis, following 2021 European Medicines Agency approval. To report SIB and depression in patients with moderate to severe psoriasis treated in bimekizumab clinical trials. Mental health changes, including neuropsychiatric events, were actively monitored across 9 bimekizumab clinical trials in psoriasis phase 2/3 trials. The patient-reported electronic Columbia-Suicide Severity Rating Scale (measuring SIB) and Patient Health Questionnaire-9 (measuring depression) were administered, monitored by an independent Neuropsychiatric Adjudication Committee. Throughout 7166 patient-years (PY) of bimekizumab exposure, the adjudicated SIB rate was 0.13/100PY; SIB ranges for the general psoriasis population and patients receiving anti-IL-17A/anti-IL-23 therapies are 0.09 to 0.54/100PY and 0.09 to 0.19/100PY, respectively. At week 16, 92.9% vs 81.1% of bimekizumab- vs placebo-treated patients had no/minimal depression. Newonset positive electronic Columbia-Suicide Severity Rating Scale responses and mean Patient Health Questionnaire-9 scores were low for bimekizumab-treated patients. Patient exclusion for significant/severe prespecified SIB/depression history. The long-term adjudicated SIB rate with bimekizumab was low and within ranges reported in the general psoriasis patient population and psoriasis patients treated with anti-IL-17A/anti-IL-23 biologics. Screening/monitoring questionnaires reported low SIB and depression levels.

Newcastle disease virus suppresses antigen presentation via inhibiting IL-12 expression in dendritic cells.

As a potential vectored vaccine, Newcastle disease virus (NDV) has been subject to various studies for vaccine development, while relatively little research has outlined the immunomodulatory effect of the virus in antigen presentation. To elucidate the key inhibitory factor in regulating the interaction of infected dendritic cells (DCs) and T cells, DCs were pretreated with the NDV vaccine strain LaSota as an inhibitor and stimulated with lipopolysaccharide (LPS) for further detection by enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunoblotting, and quantitative real-time polymerase chain reaction (qRT-PCR). The results revealed that NDV infection resulted in the inhibition of interleukin (IL)-12p40 in DCs through a p38 mitogen-activated protein kinase (MAPK)‍-dependent manner, thus inhibiting the synthesis of IL-12p70, leading to the reduction in T cell proliferation and the secretion of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-6 induced by DCs. Consequently, downregulated cytokines accelerated the infection and viral transmission from DCs to T cells. Furthermore, several other strains of NDV also exhibited inhibitory activity. The current study reveals that NDV can modulate the intensity of the innate‍‒‍adaptive immune cell crosstalk critically toward viral invasion improvement, highlighting a novel mechanism of virus-induced immunosuppression and providing new perspectives on the improvement of NDV-vectored vaccine.