Mirikizumab, approved for the treatment of moderately to severely active ulcerative colitis (UC), may be prescribed in a similar placement to ustekinumab in second-line settings. Payers may compare the economic value when making formulary decisions. This study estimated and compared the cost per remission of the second-line therapies mirikizumab versus ustekinumab in patients with UC.

An Excel-based analytic model was developed to estimate the cost per additional patient achieving clinical remission at the end of one year in biologic/Janus kinase inhibitor (JAKi)-experienced patients (second-line therapy) with UC from a United States commercial payer perspective. A network meta-analysis of published pivotal randomized clinical trials was used to derive the number needed to treat (NNT) for clinical response, clinical remission, and endoscopic remission/endoscopic improvement/mucosal healing for ustekinumab and mirikizumab in the study population. The model included the treatment cost (wholesale acquisition costs [WAC] and treatment administration costs) during the induction and maintenance phases. A scenario involving the availability of a ustekinumab biosimilar was also evaluated, assuming the NNT remained the same as ustekinumab but with a WAC set at 50% lower than its current WAC.

The costs per patient achieving clinical remission for mirikizumab vs. ustekinumab as a second-line therapy were $461,096 vs. $67,273 during induction and $501,456 vs. $1,079,189 during maintenance. The cost per clinical remission in case of dose escalation during maintenance was lower for mirikizumab vs. ustekinumab ($501,456 vs. $1,569,127). Considering the ustekinumab 130 mg IV biosimilar, the scenario resulted in a lower cost per clinical remission for mirikizumab vs. a ustekinumab biosimilar during the maintenance phase ($501,456 vs. $539,594).

Mirikizumab is projected to have a lower cost per remission during maintenance therapy than ustekinumab. Given the need for long-term treatment for this chronic condition, mirikizumab appears to be a cost-efficient treatment option.

Existing findings on outcomes of anti-tumor-necrosis-factor (TNF) therapy in patients with inflammatory bowel diseases (IBD) are largely based on retrospective studies. We aimed to investigate real-world outcomes of anti-TNF therapy and predictors thereof in a prospective IBD cohort.

In a Danish multicenter cohort of adult bio-naïve patients with IBD treated with anti-TNF, we assessed clinical response and remission to induction therapy using clinical disease activity scoring indices at Week 14. In patients who continued treatment beyond the induction period, we also assessed loss of response (LOR), drug withdrawal, and major IBD surgery during maintenance therapy.

This study included 774 patients (706 infliximab, 68 adalimumab) followed for a median duration of 125 weeks Clinical response was achieved in 209/331 (67.4%) of ulcerative colitis (UC) and 125/197 (74.0%) of Crohn's disease (CD) patients, while 143/331 (46.1%) UC and 81/197 (47.9%) CD patients achieved clinical remission. In 294 UC and 309 CD patients received maintenance therapy, while 86/294 (29.3%) UC and 78/309 (25.2%) CD patients experienced LOR. Active smoking and less severe disease activity predicted favorable outcomes in UC, while short disease duration, colonic disease, nonstricturing behavior, and concomitant immunomodulator therapy predicted favorable outcomes in CD.

Clinical response was achieved in 2 in 3 UC and 3 in 4 CD patients, meanwhile, one-third of UC and one-fourth of CD patients experienced LOR despite the short disease duration in this study. Several clinical features were associated with outcomes and may be useful predictors of anti-TNF treatment response.

Adoptive transfer of regulatory T cells (Tregs) has been proposed as a next-generation treatment approach for the treatment of various inflammatory or autoimmune disorders(Amini et al., 2022; Bluestone et al., 2023, 2015; Dall'Era et al., 2019; Chandran et al., 2017; Laukova and Glatman Zaretsky, 2023; Voskens et al., 2023; Canavan et al., 20161-8), inclusive of inflammatory bowel diseases (IBD). Identification of the appropriate Treg populations as donor sources for effective cell therapy is of great importance. We have recently identified specialized Tregs that localize within the hematopoietic stem cell (HSC) microenvironments(Fujisaki et al., 2011; Hirata et al., 2018, 2019, 2015; Kakiuchi et al., 2021a, 2021b; Furuhashi et al., 20259-16) of bone marrow (BM), termed HSC niches. These BM niche Tregs exhibit robust anti-inflammatory and pro-regenerative effects and render HSCs immune privileged. The transfer of BM niche Tregs exhibits high therapeutic effects against BM transplantation and injury(Hirata et al., 2018; Kakiuchi et al., 2021b10, 14). Yet, the treatment effects of transferred BM niche Tregs in non-BM disease settings remain unknown.

We investigated the therapeutic effects of transfer of BM niche Tregs for IBD using mouse models of experimental colitis. To identify the key effector molecule of niche Tregs, we further examined the roles of cell-surface ectoenzyme CD39 expressed at high levels by BM niche Tregs.

Mouse colitis was induced by administering dextran sulfate sodium salt. Subsequently, the mice received intravenous injections of BM niche Tregs, BM non-niche Tregs, lymph node Tregs, or vehicle alone. We compared these treatment effects on clinical scores, histopathological features and profiles of immune cells. We also tested how targeted deletion of CD39 in the adoptively transferred Tregs impacted experimental outcomes.

The transfer of as few as 1.5 × 104 BM niche Tregs per mouse ameliorated clinical and histopathological features of the mouse colitis far better than the transfer of other Tregs. The transfer of BM niche Tregs inhibited the generation of Th17 cells and promoted the regeneration and recovery of the colon tissue. Targeted deletion of CD39 in Tregs abrogated therapeutic effects of transferred BM niche Tregs.

We show robust therapeutic effects of the transfer of BM niche Tregs in the experimental model of colitis. Donor niche Tregs mediate anti-inflammatory and pro-regenerative effects via Treg CD39. Our work suggests the transfer of BM niche Tregs is a promising approach to treat colitic disorders and boost tissue regeneration.

Superior efficacy of subcutaneous infliximab (CT-P13 SC) over placebo for maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC) was demonstrated in the randomized LIBERTY-CD and LIBERTY-UC studies. The current post hoc analysis compared outcomes with CT-P13 SC by baseline immunosuppressant use.

Patients with moderately to severely active CD or UC randomized to the CT-P13 SC maintenance arm of the 54-week LIBERTY trials at week 10 and who were treated in the open-label extension (weeks 56-102) were included. Pharmacokinetic, efficacy, biomarker, safety, and immunogenicity endpoints were evaluated by baseline immunosuppressant use (monotherapy vs combination therapy).

A total of 192 patients with CD (monotherapy, n = 126; combination therapy, n = 66) and 237 patients with UC (monotherapy, n = 180; combination therapy, n = 57) were included. In both studies, efficacy outcomes were generally comparable between monotherapy and combination therapy at week 54 or week 102. Serum concentrations were generally higher, and antidrug antibody-positive conversion rates were lower, with combination therapy relative to monotherapy. In combined analyses of CD and UC, comparable safety profiles were observed between monotherapy and combination therapy.

Despite some differences in pharmacokinetics and immunogenicity between CT-P13 SC received alone or in combination with immunosuppressants in patients with CD or UC, efficacy outcomes at week 54 or week 102 were generally comparable. The overall safety profile and incidence of systemic injection reactions were also comparable between monotherapy and combination therapy.

Ulcerative colitis (UC) is characterized clinically by intestinal inflammation and gut microbiota dysbiosis. The consumption of biologics, although effective in inflammation control, may lead to adverse effects and is inconvenient for at-home administration. Goat milk-derived extracellular vesicles (GMEVs) have been proposed as a supplement to prevent intestinal inflammation. However, their therapeutic potential for colitis remains elusive. This study aimed to explore the preventive effect of GMEVs on colitis and its underlying mechanisms through the microbiota-immune axis using a dextran sodium sulfate (DSS)-induced colitis mouse model. We found that a pre-treatment of 20 mg/kg/d GMEVs effectively prevented body weight loss, colon shortening, the depletion of colonic goblet cells, and the disappearance of crypts, while enhancing the intestinal mucosal barrier. Consistent with these phenotypes, GMEV pre-treatment increased levels of IL-22 and IL-10 and decreased levels of IL-1β, TNF-α, IL-6, and iNOS. However, GMEVs themselves had no effect on normal mice. Paralleling the alleviation of intestinal inflammation, GMEV pre-treatment also restored the reduction in unclassified Muribaculaceae, Dubosiella, and Lactobacillus and suppressed the expansion of Alistipes and Proteobacteria following DSS treatment. Additionally, GMEV intake significantly downregulated the expression of proteins in the NF-κB signaling pathway induced by DSS. In summary, GMEVs could prevent colitis by regulating intestinal inflammation, the intestinal mucosal barrier, gut microbiota, organ damage, and the immune microenvironment. This study demonstrated that GMEVs have potential application prospects for UC prevention.

Elective switching from intravenous (IV) to subcutaneous (SC) infliximab (IFX) has shown efficacy in patients with inflammatory bowel disease (IBD). However, long-term outcomes for patients not in remission remain unclear.

We evaluated the effectiveness of SC IFX switching in both remission and non-remission patients.

This study was a retrospective multicentre study conducted across five tertiary hospitals in Korea.

Patients with IBD who switched to SC IFX between January 2021 and January 2023 were included. Clinical remission was defined as a Crohn's Disease Activity Index of <150 or a partial Mayo score of <2. Biochemical remission was defined as faecal calprotectin of <250 µg/g and C-reactive protein of <0.5 mg/dL. We investigated the treatment persistence rate of SC IFX and trends in pharmacokinetics, clinical indices and biomarkers over 1 year of follow-up, analysing the data based on the baseline remission state.

Among 127 patients included, 90 (70.9%) were in clinical remission, and 37 (29.1%) were not at the time of switching. The one-year treatment persistence rate was 92.1%, with no significant difference between the clinical remission and non-remission groups (p = 0.139). Persistence was also unaffected by baseline biochemical remission status. IFX pharmacokinetics and biomarkers improved significantly in both clinical groups over 12 months (p < 0.005). Disease activity indices remained stable in the remission group and decreased in the non-remission group after switching. Previous biologics exposure was the only significant predictor of treatment persistence (hazard ratio, 5.634; 95% confidence interval, 1.357-23.384; p = 0.017). Adverse events related to SC IFX occurred in 15.7% of patients. The optimal SC IFX cutoff levels associated with clinical and biochemical remission were 11 and 17 μg/mL, respectively.

Switching from IV to SC IFX during maintenance therapy demonstrated high treatment persistence and safety, irrespective of clinical and biochemical remission status.

Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease primarily affecting the colorectal mucosa. The disease is characterized by a relapsing-remitting course and is currently incurable. Its pathogenesis is multifactorial, involving genetic predisposition, environmental triggers, immune dysregulation, and alterations in gut microbiota. The appendix plays a role in modulating intestinal immunity and maintaining microbial homeostasis. Left-sided colitis with appendiceal orifice inflammation (AOI) or periappendiceal erythematous patch (PARP) is a common endoscopic finding in UC. However, whether AOI in UC patients requires intervention remains debated.

Here, we report a rare case of a UC with AOI.

By means of cholangioscope-assisted endoscopic retrograde appendicitis therapy (ERAT), copious purulent secretions were discovered and flushed out of the appendiceal cavity, resulting in clinical remission and endoscopic mucosal healing of UC.

Our case indicates that there may be some correlation between the appendix and the pathogenesis of ulcerative colitis. For refractory left-sided UC patients with AOI, ERAT-based management of appendiceal lumen inflammation may benefit patients.

Inflammatory Bowel Disease (IBD) is an autoimmune disease characterized by chronic relapsing inflammation of the intestinal tract. Gut microbiota (GM) and CD4+T cells are important in the development of IBD. A lot of studies have shown that GM and their metabolites like short-chain fatty acids, bile acids and tryptophan can be involved in the differentiation of CD4+T cells through various mechanisms, which in turn regulate the immune homeostasis of the IBD patients. Therefore, regulating CD4+T cells through GM may be a potential therapeutic direction for the treatment of IBD. Many studies have shown that Traditional Chinese Medicine (TCM) formulas and some herbal extracts can affect CD4+T cell differentiation by regulating GM and its metabolites. In this review, we mainly focus on the role of GM and their metabolites in regulating the differentiation of CD4+T cells and their correlation with IBD. We also summarize the current research progress on the regulation of this process by TCM.

Inflammatory bowel disease (IBD) represents a group of chronic inflammatory disorders of the gastrointestinal tract. Despite substantial advances in our understanding of IBD pathogenesis, the currently available therapeutic options remain limited in their efficacy and often come with significant side effects. Therefore, there is an urgent need to explore novel approaches for the management of IBD. One promising avenue of investigation revolves around the use of histone deacetylase (HDAC) inhibitors, which have garnered considerable attention for their potential in modulating gene expression and curbing inflammatory responses. This review emphasizes the pressing need for innovative drugs in the treatment of IBD, and drawing from a wealth of preclinical studies and clinical trials, we underscore the multifaceted roles and the therapeutic effects of HDAC inhibitors in IBD models and patients. This review aims to contribute significantly to the understanding of HDAC inhibitors' importance and prospects in the management of IBD, ultimately paving the way for improved therapeutic strategies in this challenging clinical landscape.

Background/Objectives: A bidirectional association between inflammatory bowel disease (IBD) and periodontitis has been observed, yet their causal relationship remains unclear. This study aimed to investigate the potential causal links between these two inflammatory conditions through comprehensive genetic and molecular analyses. Methods: We conducted a bidirectional Mendelian randomization (MR) analysis integrated with bioinformatics approaches. The causal relationships were primarily evaluated using inverse variance weighting (IVW), complemented by multiple sensitivity analyses to assess the robustness of the findings. Additionally, we performed differential gene expression analysis using RNA sequencing data to identify co-expressed genes and shared inflammatory mediators between IBD and periodontitis, followed by pathway enrichment analysis. Results: Bidirectional MR analysis revealed significant causal associations between IBD and periodontitis (p-value < 0.05). Sensitivity analyses demonstrated the consistency of these findings, with no evidence of significant heterogeneity or horizontal pleiotropy (p-value > 0.05). Integrated bioinformatics analysis identified key immune regulators, particularly interleukin 1 beta (IL1B) and C-X-C motif chemokine receptor 4 (CXCR4), and inflammatory signaling pathways, including tumor necrosis factor (TNF-α) and interleukin 17 (IL17), as potential molecular mechanisms underlying the bidirectional relationship between these conditions. Conclusions: Our findings provide genetic evidence supporting a bidirectional causal relationship between IBD and periodontitis. Transcriptomic analysis revealed shared pathological mechanisms and identified crucial immune regulatory factors common to both diseases. These insights enhance our understanding of the molecular interplay between IBD and periodontitis, potentially informing new therapeutic strategies for both conditions.

Cytokine therapy utilizes cytokines to enhance the immune system to fight diseases. These strategies rely on advanced knowledge, including the communication between cytokines and their receptors. In situ, cytokine-receptor interactions are typically analyzed by co-localization using immunolabeling. Our study compared co-localization using the Proximity Ligation Assay (PLA), a recently developed in situ protein-protein interaction technique. In an inflamed porcine lung model, we demonstrated the efficacy of PLA in detecting interactions between tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2. Additionally, the CD163 receptor was identified as a novel partner of TNF. Furthermore, the combination of immunolabeling and PLA offered additional insights, particularly, the internalization of TNF following its binding with CD163 in macrophages. Our work focused on in situ interactions of TNF with macrophages TNF receptors and suggested exciting perspectives for further understanding and application of cytokine-based therapies.

Death ligands (DLs), particularly tumor necrosis factor alpha (TNF-α), FAS ligand (FASL), and TNF-related apoptosis-inducing ligand (TRAIL), collectively termed TFT, are pivotal members of the TNF superfamily. While traditionally linked to apoptosis, TFT proteins have emerged as key regulators of various non-apoptotic processes. This review summarizes the non-apoptotic functions of TFT in cancer and explores the intricate crosstalk signaling pathways and their impact on nuclear factor kappa B (NF-κB) signaling, inflammation, and pro-tumorigenic function. It also highlights the potential connections and hurdles that exist in translating synthetic lethality strategies involving DLs into clinical applications. Lastly, it discusses the challenges and opportunities associated with TFT-targeted therapeutic strategies for both malignant and non-malignant diseases.

Patients with very early-onset inflammatory bowel disease (VEO-IBD), with an age of onset < 6 years, can present with severe manifestations and may require biologic therapy. Infliximab and adalimumab are approved for induction and maintenance in pediatric IBD patients but are licensed only above the age of 6 years. Effectiveness and safety data on adalimumab in this patient population are lacking. We assessed the therapeutic response to help close this gap.

This retrospective study involved 30 sites worldwide. Demographic, clinical, and laboratory data were collected from patients with VEO-IBD who commenced adalimumab therapy before the age of 6 years.

Seventy-eight patients (37 Crohn's disease, 26 ulcerative colitis, and 15 with IBD-unclassified) were included. Median age of IBD onset was 2.6 (1.3-4.1) years, with 30 (38.5%) patients diagnosed at age <2 years. Median age at adalimumab initiation was 4.2 (2.8-5.1) years. Adalimumab was used as second-line biologic therapy in 45 (57.7%) patients after infliximab. The median time to last follow-up was 63 (22-124) weeks. Significant improvement in clinical scores, CRP, fecal calprotectin, and weight Z-score were observed by Week 52. Adalimumab durability rates were 61.9%, 48.1%, and 35.6% after 1, 2, and 3 years, respectively. Drug discontinuation rates were not dependent on IBD type, age, prior anti-TNF exposure, or concomitant immunomodulatory treatment. Four (5.1%) patients developed serious infections, including 1 patient with TTC7A deficiency who died following adenovirus sepsis.

Adalimumab therapy is a viable therapeutic option in patients with VEO-IBD with an acceptable safety profile.

We present Enterocytozoon bieneusi infection in four patients with autoimmune diseases undergoing prolonged monoclonal antibody therapies. Two patients suffered from inflammatory bowel disease and received anti-TNF therapies, whereas two other patients suffered from systemic lupus erythematosus with renal involvement and received anti-CD20 or anti-BLyS protein therapies. Three out of four patients consulted for diarrhea with abdominal pain without intestinal inflammation or bleeding at the time of sampling. The fourth patient did not declare intestinal troubles. Microsporidia genotype detected in this study were S9, C, Wildboard3 with one patient harboring 2 genotypes S6 and EBCMAP-038. Management of microsporidia infection included albendazole and reduction of immunosuppression treatment, but no specific treatment was implemented in two other patients. In conclusion, microsporidia infection occurs in patients with autoimmune diseases undergoing prolonged monoclonal antibody therapies. Diagnosis should be carefully assessed in this population and a thorough benefit-risk analysis is essential prior to initiating therapeutic interventions.

Lipid Nanoparticles (LNPs) recently emerged as an invaluable RNA delivery platform. With many LNP-based therapeutics in the pre-clinical and clinical pipelines, there is extensive research dedicated to improving LNPs. These efforts focus mainly on the tolerability and transfectability of new ionizable lipids and RNAs, or modulating LNPs biodistribution with active targeting strategies. However, most formulations follow the well-established lipid proportions used in clinically approved products. Nevertheless, investigating the effects of LNPs composition on their biodistribution can expand the toolbox for particle design, leading to improved delivery strategies. Herein, a new LNPs (30-n-LNPs) formulation with increasing amounts of phospholipids is investigated as a possible mRNA delivery system for treating Inflammatory Bowel Diseases. Compared to LNPs with benchmark composition (b-LNPs), n-LNPs containing 30% distearoylphosphatidylcholine (DSPC) are well tolerated following intravenous administration and display natural targeting toward the inflamed colon in dextran sodium sulfate (DSS)-colitis bearing mice, while de-targeting clearing organs such as the liver and spleen. Using interleukin-10-encoding mRNA as therapeutic cargo, n-LNPs demonstrated a reduction of pathological burden in colitis-bearing mice. n-LNPs represent a starting point to further investigate the influence of LNPs composition on systemic biodistribution, ultimately opening new therapeutic modalities in different pathologies.

Hypercoagulability has been shown to act as an important component of ulcerative colitis (UC) pathogenesis and disease activity, and is strongly correlated with the occurrence of venous thromboembolism (VTE). This study aimed at providing novel therapeutic clues for hypercoagulable active UC.

The coagulation score model was developed using VTE cohorts, and the predictive performance of this model was evaluated by coagulation subtypes of UC patients, which were clustered by the unsupervised method. Subsequently, the response of UC of distinct coagulation types, as identified by the coagulation scoring model, to different biological agents was evaluated. Immunoinflammatory cells and molecules that were associated with hypercoagulable active UC were explored by employing gene set variation analysis, single-sample gene set enrichment analysis, univariate logistic regression analysis, and immunohistochemistry.

A coagulation scoring model was established, which includes five key coagulation factors (ARHGAP35, CD46, BTK, C1QB, and F2R), and accurately distinguished the coagulation subtypes of UC. When comparing anti-TNF-α agents with other biological agents after determining the model, especially golimumab, it showed more effective treatment for hypercoagulable active UC. CXCL8 has been identified as playing an important role in the tightly interconnected network between the immune-inflammatory system and coagulation system in UC. Immunohistochemical analysis showed that the expression of CXCL8, BTK, C1QB, and F2R was upregulated in active UC.

Anti-TNF-α agents have significant therapeutic effects on hypercoagulable active UC, and the strong association between CXCL8, hypercoagulation, and disease activity provides a novel therapeutic insight into hypercoagulable active UC.

Tumor necrosis factor (TNF) inhibitors have been used extensively to treat various autoimmune diseases. However, there are ongoing debates about the risk of inflammatory central nervous system (CNS) disease events following TNF inhibitor therapy, as well as uncertainty about how this risk varies across different autoimmune diseases or TNF-blocking agents.

To evaluate the risk of inflammatory CNS diseases after anti-TNF initiation and assess the difference in risk among different types of underlying autoimmune diseases or TNF inhibitors.

Separate searches were conducted across PubMed, Embase, and the Cochrane Library from inception until March 1, 2024.

Observational studies assessing the association between anti-TNF therapy and inflammatory CNS diseases relative to a comparator group.

Study eligibility assessment and data extraction were independently conducted by 2 investigators following PRISMA guidelines. The risk ratio (RR) was used as the effect measure of the pooled analysis.

The primary outcome was the risk of incident inflammatory CNS events after anti-TNF therapy for autoimmune diseases. Secondary analyses were performed based on different types of underlying autoimmune diseases and TNF inhibitors.

Eighteen studies involving 1 118 428 patients with autoimmune diseases contributing more than 5 698 532 person-years of follow-up were analyzed. The incidence rates of new-onset inflammatory CNS events after initiating TNF inhibitors ranged from 2.0 to 13.4 per 10 000 person-years. Overall, exposure to TNF inhibitors was associated with a 36% increased risk of any inflammatory CNS disease compared to conventional therapies (RR, 1.36; 95% CI, 1.01-1.84; I2, 49%), mainly attributed to demyelinating diseases (RR, 1.38; 95% CI, 1.04-1.81; I2, 31%). Secondary analyses revealed a similar risk of inflammatory CNS diseases across different types of underlying autoimmune diseases (rheumatic diseases: RR, 1.36; 95% CI, 0.84-2.21; inflammatory bowel disease 1.49; 95% CI, 0.93-2.40; P for subgroup = .74) and TNF inhibitors (anti-TNF monoclonal antibodies vs etanercept: RR, 1.04; 95% CI, 0.93-1.15; I2, 0%).

Compared to conventional therapies, exposure to TNF inhibitors was associated with a 36% increased risk of inflammatory CNS diseases, irrespective of background autoimmune disease or TNF inhibitor type.

Except for some surgical techniques, up to 1940 the clinical course of inflammatory bowel disease was determined by its own natural history: most medical interventions even worsened prognosis. The empyrical introduction of salazopyrine early in the 1940s, pioneered by Nanna Svartz in Sweden, was followed relatively soon by the incorporation of corticosteroids during the 1950s. However, it took both a long time to reach patients, and quality scientific evidence to better establish their indications built up very slowly.

Since 2015, an infliximab biosimilar, CT-P13, has been approved for commercial use in many countries, easing the economic burden borne by society and patients. Many clinical trials investigating CT-P13 for the treatment of IBD have been conducted and reported that it may be a substitute for infliximab. However, the differences between the efficacy of CT-P13 and infliximab-originator require further elucidation.

Data on the rates of clinical response, clinical remission, and mucosal healing of IBD were pooled for random-effects model meta-analysis using Stata MP 17. A total of 30 studies were included.

The pooled risk of clinical remission rate of patients with Crohn's disease and ulcerative colitis who were naïve to biologics at 08-14 weeks were 0.66 (95% CI, 0.58-0.75) and 0.48 (95% CI, 0.43-0.54), respectively, and at 100-104 weeks were 0.66 (95% CI, 0.49 to 0.84) and 0.71 (95% CI, 0.62 to 0.79) respectively. The pooled risk of clinical remission rate of patients with Crohn's disease and ulcerative colitis who were transitioned from the original agent at 24-32 weeks were 0.84 (95% CI, 0.77-0.92) and 0.78 (95% CI, 0.63-0.93), respectively, and at 48-54 weeks were 0.72 (95% CI, 0.62 to 0.82) and 0.78 (95% CI, 0.71 to 0.86) respectively. The pooled rates for mucosal healing in ulcerative colitis were 0.56 (95% CI: 0.46 to 0.67) at 08-14 weeks, and 0.64 (95% CI: 0.42 to 0.85) at 48-54 weeks. RCT studies showed no significant change in efficacy after switching, whether Crohn's disease or ulcerative colitis.

CT-P13 is effective in short and long-term periods. The application of CT-P13 for the management of IBD was promising.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.

Exosome therapy has garnered significant attention due to its natural delivery capabilities, low toxicity, high biocompatibility, and potential for personalised treatment through engineering modifications. Recent studies have highlighted the ability of tumour cell-derived exosomes (TDEs) to interact with immune cells or modify the immune microenvironment to suppress host immune responses, as well as their unique homing ability to parental cells. The core question of this study is whether this immunomodulatory property of TDEs can be utilised for the immunotherapy of inflammatory diseases. In our experiments, we prepared exosomes derived from murine colon cancer cells CT26 (CT26 exo) using ultracentrifugation, characterised them, and conducted proteomic analysis. The therapeutic potential of CT26 exo was evaluated in our dextran sulphate sodium salt (DSS)-induced inflammatory bowel disease (IBD) mouse model. Compared to the control and 293 T exo treatment groups, mice treated with CT26 exo showed a reduction in the disease activity index (DAI) and colon shortening rate, with no noticeable weight loss. Haematoxylin and eosin (H&E) staining of colon paraffin sections revealed reduced inflammatory infiltration and increased epithelial goblet cells in the colons of CT26 exo-treated group. Furthermore, we conducted preliminary mechanistic explorations by examining the phenotyping and function of CD4+ T cells and dendritic cells (DCs) in the colonic lamina propria of mice. The results indicated that the ameliorative effect of CT26 exosomes might be due to their inhibition of pro-inflammatory cytokine secretion by colonic DCs and selective suppression of Th17 cell differentiation in the colon. Additionally, CT26 exo exhibited good biosafety. Our findings propose a novel exosome-based therapeutic approach for IBD and suggest the potential application of TDEs in the treatment of inflammatory diseases.

The treatment of Crohn's disease (CD) has received widespread attention in clinical practice, but there is currently a lack of quantitative evaluation of the literature published in this field. This study aimed to describe the development trends and research hotspots of CD treatment through bibliometric analysis.

Publications related to CD treatment published from 2004 to 2023 were searched in the WoSCC. Microsoft Office Excel 2021 was used for the analysis and visualization of the annual number of publications. CiteSpace was used to visualize the collaboration networks of authors, institutions, and countries, as well as to construct a reference timeline visualization map and identify keywords with the strongest citation bursts.

The bibliometric analysis included 25,608 publications between 2004 and 2023. The most productive year was 2021. The United States of America (n = 7,891) and the University of California System (n = 939) are the country and institution with the most published papers, respectively. Among the 97,564 authors, Peyrin-Biroulet, Laurent (n = 424) published the most articles. The core journals were Inflammatory Bowel Diseases, Journal of Crohns and Colitis, Alimentary Pharmacology and Therapeutics, etc. The timeline view showed that "#5 JAK Inhibitor" was the most recent topic. The keywords that burst and persist from 2020 to 2023 include "ustekinumab" and "vedolizumab".

An increasing number of researchers are dedicating their efforts to exploring the treatment of CD, with the United States making the largest contribution to this field. Currently, the research hotspots predominantly involve drug therapy including ustekinumab, vedolizumab, and JAK inhibitors. Our study provides valuable information for scholars studying CD treatment.

Patient satisfaction has been positively associated with adherence which is expected to impact outcomes. Although vital for successful implementation of biosimilar medicines, little is known about the patient perspective of transition.

The aim of this study was to investigate clinical outcomes and patient experience of transitioning between reference adalimumab and a biosimilar (SB5).

iBaSS is a phase IV single-centre, prospective, randomised, single-blind, cross-over study in adult subjects with Crohn's disease. Participants, stable on adalimumab before consent, received 24 weeks of treatment with both reference adalimumab and SB5. The primary outcome was the proportion of patients maintaining baseline clinical status throughout each treatment period, with patients' perspective of disease control and treatment satisfaction assessed as secondary outcomes.

A total of 112 participants, representative of the heterogeneous patient populations encountered in routine clinical practice, were enrolled. A similar proportion of participants maintained baseline clinical status through each treatment period: 81.8% with reference adalimumab and 79.5% with SB5. Patient reported outcomes (IBD-Control questionnaire (SB5: 15.5; reference adalimumab 15) and TSQM), adverse events and therapeutic drug monitoring remained consistent through both treatment periods, although a higher median injection pain VAS score was noted with SB5 (53/100 versus 6/100 with reference adalimumab). The number of switches undertaken in the study did not impact serum drug concentration or immunogenicity.

This study, mimicking real world adalimumab transition, demonstrates that patients undertaking brand transition can be expected to have consistent clinical and satisfaction outcomes.

Number 2018-004967-30.

Crohn's disease (CD) is a debilitating gastrointestinal disease with complex etiology. Although effective, recipients of anti-tumor necrosis factor (TNF) agents may experience primary or secondary nonresponse, necessitating alternative treatments. This study is intended to compare the short-term effectiveness of ustekinumab and vedolizumab in treating CD after failure of multiple lines of anti-TNF therapy using real-world data.

A retrospective study was conducted at a tertiary hospital in Dammam, Saudi Arabia, including adults (≥18 years old) with CD who did not respond to anti-TNF therapy. Primary endpoints were clinical improvement per the Harvey-Bradshaw Index (HBI) scores and remission at 12 weeks on an ordinal outcome scale. Secondary endpoints included clinical, biochemical, and endoscopic remission; clinical response; corticosteroid-free days; and cumulative steroid dose. Proportional odds and logistic regression Bayesian models were used to analyze outcomes, and the probability of treatment effectiveness was calculated from the posterior distribution.

The study included 101 patients (ustekinumab, n = 71 and vedolizumab, n = 30) with a median age of 32 years (IQR: 26.0-38.0); 54.4% were male. At 12 weeks, the HBI endpoint showed an adjusted odds ratio (aOR) = 0.60 (95% confidence interval [CI]: 0.25-1.31), favoring ustekinumab, with a 75% probability of treatment effectiveness over vedolizumab. The clinical ordinal scale had an aOR = 0.61 (95% CI: 0.26-1.35) with a 73% probability of effectiveness for ustekinumab. Ustekinumab was also associated with favorable outcomes in secondary endpoints, reaching up to a 90% probability of effectiveness.

In CD patients with anti-TNF failure, ustekinumab was more effective than vedolizumab in the short term. These real-world insights contribute to understanding CD management but require validation in larger prospective studies and randomized controlled trials.

QingChang-XiaoPi Decoction (QCXPY), a Chinese herbal prescription, has been employed in the treatment of ulcerative colitis (UC) in China. However, its molecular mechanism of action in UC remains unclear.

To elucidate the therapeutic effects of QCXPY against UC and reveal its mechanism of action.

We conducted a single-arm observation to evaluate the clinical efficacy of QCXPY in patients with mild-to-moderate UC. Inclusion and exclusion criteria were established to ensure the eligibility of participants, with a focus on excluding patients with specific conditions or complications that could confound the results.

The expression of inflammatory factors in patients' serum was detected using a Luminex assay. The main components of QCXPY were identified using UHPLC-Q-TOF-MS. Network pharmacology was employed to predict potential therapeutic targets and their mechanisms of action. The efficacy of QCXPY was evaluated using a dextran sulfate sodium (DSS)-induced mouse model. Disease activity index (DAI), histopathological score, cytokine detection by ELISA, T-helper 17 (Th17) cell proportion by flow cytometry, expression of the IL-23/IL-17 axis, and changes in the levels of its downstream effectors were detected by immunohistochemistry, immunofluorescence, and western blotting.

QCXPY could alleviate the symptoms of diarrhea, abdominal pain, abdominal distension, and purulent stool in patients with mild-to-moderate UC. Moreover, it reduced the expression of IL-6, IL-17, and IL-23 in serum; alleviated DSS-induced experimental colitis in mice; reduced DAI, pathological scores, and the expressions of IL-6, IL-17, and IL-23 in colon tissue; and decreased the proportion of pathogenic Th17 cells and the expression of STAT3 and phospho-STAT3.

This study confirmed for the first time that QCXPY could alleviate intestinal symptoms, reduce the levels of serum inflammatory factors, and improve the quality of life of patients with mild-to-moderate UC. Its mechanism of action may involve reducing the secretion of inflammatory cytokines, moderating the pathogenicity of Th17 cells, and inhibiting STAT3 phosphorylation, thereby alleviating intestinal inflammation in UC.

This study sought to explore the effect of electroacupuncture (EA) intervention at Zusanli (ST36) acupoint on modulating the NLRP3 inflammasome pathway for treating inflammatory bowel disease (IBD).

C57BL/6 mice were administrated with 3% dextran sulfate sodium (DSS) to construct the IBD model. DSS mice were then administrated with EA (10 Hz, 1.5 mA) at ST36 for 7 days or intragastric administration of sulfasalazine (SASP) each day during the entire course. The control group animals were administered with distilled water. Then, partial least squares discriminant analysis revealed differences in the relative content of metabolites. The pathological changes of colon and spleen tissues were observed by H&E and immunohistochemistry (IHC) staining. qPCR determined the mRNA expression levels, while ELISA and western blot analysis determined the protein expression.

Compared with the control groups, DSS-induced decreases of body weight were reversed after EA stimulation at ST36 or SASP treatment. The DAI of DSS mice was significantly higher relative to the control groups, whereas the DAI of DSS mice were decreased after EA stimulation at ST36 or SASP treatment. The intestinal weight/length ratio increased significantly in DSS groups; however, EA at ST36 significantly improved the macroscopic/microscopic characteristics and the weight and length of the colon. EA reversed inflammation and leukocyte infiltration and normalized the elevated levels of IL-1β, IL-18, and NLRP3. Furthermore, EA improved the expression levels of ZO-1, occludin, and claudin 1, exhibiting normalization of the colon's tight junctions.

EA at Zusanli acupoint of colon tissue significantly improved the pathological phenotype, showing a therapeutic effect on IBD.

Tumor necrosis factor-α inhibitors (TNFis) are used for the treatment of inflammatory bowel disease (IBD). The aim of this study was to evaluate the association between neurological adverse events (AEs) and TNFi use.

Data of TNFis indicated for IBD were collected from the Food and Drug Administration Adverse Event Reporting System (FAERS) from the marketed date to the second quarter of 2023. The reporting odds ratio (ROR) and a Bayesian confidence propagation neural network were used to identify signals.

A total of 4,964 neurological AEs were reported in the IBD population. Infliximab had 3 signals, including demyelination [ROR (95% CI): 1.69 (1.33,2.15)], meningitis listeria [ROR (95% CI): 5.05 (3.52,7.25)], and optic neuritis [ROR (95% CI): 1.72 (1.3,2.26)]. The signals for adalimumab were gait disturbance [ROR (95% CI): 1.43 (1.32,1.56)] and muscular weakness [ROR (95% CI): 1.4 (1.27,1.55)]. A peripheral neuropathy signal was found for adalimumab [ROR (95% CI): 1.34 (1.18,1.53)] and certolizumab pegol [ROR (95% CI): 1.49 (1.07,2.08)]. However, there were no signals among neurological AEs for golimumab.

Neurological signals were detected for TNFi use, indicating that the risk of neurological AEs requires additional attention in clinical use of TNFis.

Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the tumor necrosis factor (TNF) promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and nonresponders.

We obtained mucosal biopsies from 200 participants (133 IBDs and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 nonresponders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency.

TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated intestinal epithelial cells from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF nonresponders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed 2 missense variants in DNA methyltransferase 1, 1 of which had reduced function in vivo.

Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.

The gastrointestinal tract is an immunologically rich organ, containing complex cell networks and dense lymphoid structures that safeguard this large absorptive barrier from pathogens, contribute to tissue physiology and support mucosal healing. Simultaneously, the immune system must remain tolerant to innocuous dietary antigens and trillions of normally beneficial microorganisms colonizing the intestine. Indeed, a dysfunctional immune response in the intestine underlies the pathogenesis of numerous local and systemic diseases, including inflammatory bowel disease, food allergy, chronic enteric infections or cancers. Here, we discuss group 3 innate lymphoid cells (ILC3s), which have emerged as orchestrators of tissue physiology, immunity, inflammation, tolerance and malignancy in the gastrointestinal tract. ILC3s are abundant in the developing and healthy intestine but their numbers or function are altered during chronic disease and cancer. The latest studies provide new insights into the mechanisms by which ILC3s fundamentally shape intestinal homeostasis or disease pathophysiology, and often this functional dichotomy depends on context and complex interactions with other cell types or microorganisms. Finally, we consider how this knowledge could be harnessed to improve current treatments or provoke new opportunities for therapeutic intervention to promote gut health.

Janus kinases (JAK) are enzymes involved in signaling pathways that activate the immune system. Upadacitinib, an oral small molecule, is the first JAK inhibitor approved by FDA and EMA for the treatment of moderately to severely active Crohn's disease (CD), following successful phase II and III trials. Compared to other JAK inhibitors, upadacitinib has a high selectivity toward JAK1. This characteristic could improve its efficacy and safety.

This review provides an overview of the available knowledge on the pharmacokinetics of upadacitinib as induction and maintenance therapy for CD.

The approval of newer targeted small molecules drug, including JAK inhibitors, marked a significant advancement in terms of effectiveness. In fact, the oral administration, the rapid absorption, the excellent bioavailability and the short serum time of maximum concentration are some of the advantages compared to biologics. The selective inhibition of JAK1 by upadacitinib allows for high efficacy while maintaining a reliable safety profile.

Inflammatory bowel disease (IBD) is a multifactorial chronic inflammation of the intestine and has become a global public health concern. A farnesoid X receptor (FXR) was recently reported to play a key role in hepatic-intestinal circulation, intestinal metabolism, immunity, and microbial regulation, and thus, it becomes a promising therapeutic target for IBD. In this study, we identified a series of nonbile acid FXR agonists, in which 33 novel compounds were designed and synthesized by the structure-based drug design strategy from our previously identified hit compound. Compound 33 exhibited a potent FXR agonistic activity, high intestinal distribution, good anti-inflammatory activity, and the ability to repair the colon epithelium in a DSS-induced acute enteritis model. Based on the results of RNA-seq analysis, we further investigated the therapeutic potential of the combination of compound 33 with 5-ASA. Overall, the results indicated that compound 33 is a promising drug candidate for IBD treatment.

Aims: The formation of anti-drug antibodies (ADAs) during anti-tumor necrosis factor (anti-TNF) therapy is reported to lead to reducing serum drug levels, which may bring about a loss of response to treatment. Previous research has suggested an association between specific antibiotic classes and ADA formation during anti-TNF therapy. However, there are few studies specifically examining this association in Chinese inflammatory bowel disease (IBD) patients. Therefore, our study aimed to evaluate the possible effect of antibiotic use on ADA formation to anti-TNF therapy in Chinese patients with IBD. Methods: A total of 166 patients with IBD, including 149 with Crohn's disease (CD) and 17 with ulcerative colitis (UC), were included in this retrospective analysis. These patients were initially treated with anti-TNF therapy (infliximab or adalimumab) after January 2018 and reviewed with available ADA levels before October 2023. After univariable analysis of all the variables, a multivariate Cox proportional hazards model was used to assess the association between antibiotic use and ADA development. Results: Among 166 IBD patients treated with infliximab (108/166, 65.1%) or adalimumab (58/166, 34.9%), 31 patients (18.7%) were measured as positive ADA levels. Cox proportional hazard model demonstrated an increased risk of ADA formation in IBD patients who used β-lactam-β-lactamase inhibitor combinations (BL-BLIs) (HR = 5.143, 95%CI 1.136-23.270, p = 0.033), or nitroimidazoles (HR = 4.635, 95%CI 1.641-13.089, p = 0.004) during 12 months before the ADA test. On the contrary, a reduced risk was noted in patients treated with fluoroquinolones (HR = 0.258, 95% CI 0.072-0.924, p = 0.037). Moreover, the median serum infliximab or adalimumab concentration in patients with positive ADA levels was significantly lower than that in patients with negative ADA levels (infliximab: 0.30 vs. 1.85 μg/mL, p < 0.0001; adalimumab: 0.45 vs. 7.55 μg/mL, p = 0.0121). Conclusion: ADA development is associated with various antibiotic classes. BL-BLIs and nitroimidazoles might increase the risk of ADA formation during anti-TNF therapy in Chinese IBD patients, while the treatment with fluoroquinolones could probably reduce such risk. There were certain limitations in the retrospective analysis of the study, therefore, the results are just for reference, and other studies are needed to further confirm our findings.