Search

Background: Anti-tumor necrosis factor (TNF) monoclonal antibodies, especially infliximab (IFX) and adalimumab (ADA), are considered the first-line treatment for active Crohn's disease (CD). However, the predictive role of therapeutic drug monitoring (TDM) of serum anti-TNF in monitoring the treatment of inflammatory bowel disease (IBD) remains controversial. Objectives: To explore the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram. Design: Cross-sectional study. Methods: The simplified endoscopic activity score for CD (SES-CD), Crohn's disease activity index (CDAI), laboratory parameters, and the serum trough levels of IFX and ADA were assessed. Results: The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. Furthermore, the receiver operating characteristic curve revealed that an optimal level of IFX (4.80 μg/mL) and ADA (8.80 μg/mL) exhibited the best performance in predicting endoscopic response. Concomitantly, we developed a novel nomogram prediction model based on the results of multivariate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram showed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort. Conclusion: This study demonstrates a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. Importantly, the TDM- and laboratory marker-based nomogram may be used to evaluate the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients. Plain language summary: Therapeutic drug monitoring-based nomogram predicts primary endoscopic response in Crohn's disease The present study established a therapeutic drug monitoring-based nomogram, which exhibits an exceptional predictive value, remarkable accuracy, and discrimination. This algorithmic nomogram holds the potential to enhance clinicians' comprehension of the underlying mechanisms contributing to individual patients' failure in achieving expected efficacy. Such approach is crucial for optimizing therapy options and facilitating biologic switching in refractory Crohn's disease. [ABSTRACT FROM AUTHOR]

Neutrophils participate in the pathogenesis of ulcerative colitis (UC) through regulating the intestinal homeostasis. Several inflammatory diseases are reported to be regulated by proline‐rich tyrosine kinase 2B (PTK2B). However, the role of PTK2B in regulating the function of neutrophils and the pathogenesis of UC remains unknown. In this study, the mRNA and protein levels of PTK2B in the colonic tissues from UC patients were measured by using quantitative real‐time polymerase chain reaction (qRT‐PCR), western blotting, and immunohistochemistry. TAE226, a PTK2B inhibitor, was used to inhibit the activity of PTK2B in neutrophils, and then, the pro‐inflammatory factors were analyzed by using qRT‐PCR and ELISA. To determine the role of PTK2B in intestinal inflammation, a dextran sulfate sodium (DSS)‐induced colitis model was established in PTK2B gene knockout (PTK2B KO) and wild‐type (WT) mice. We found that compared with healthy donor controls, the expression level of PTK2B was significantly elevated in inflamed mucosa from UC patients. In addition, expression of PTK2B was positively correlated with the severity of disease. Pharmacological inhibition of PTK2B could markedly reduce the generation of reactive oxygen species (ROS), myeloperoxidase (MPO), and antimicrobial peptides (S100a8 and S100a9) in neutrophils. The vitro study showed that tumor necrosis factor (TNF)‐α is involved in promoting the expression of PTK2B in neutrophils. As expected, UC patients treated with infliximab, an anti‐TNF‐α agent, showed significantly reduced level of PTK2B in neutrophils, as well as in the intestinal mucosa. Of note, compared with DSS‐treated WT mice, DSS‐treated PTK2B KO mice showed more severe colitis symptoms. Mechanistically, PTK2B could enhance neutrophil migration by regulating CXCR2 and GRK2 expression via the p38 MAPK pathway. Additionally, mice treated with TAE226 exhibited the same effects. In conclusion, PTK2B is involved in the pathogenesis of UC by promoting the migration of neutrophils and inhibiting mucosal inflammation, highlighting PTK2B as a new potential therapeutic target to treat UC. [ABSTRACT FROM AUTHOR]

Background and Aims Non-invasive biomarkers in sera of patients with inflammatory bowel disease [IBD] are not currently available for rapidly and accurately diagnosing the disease. We aimed to investigate and validate the potential roles of anti-paratuberculosis-nocardia polypeptide antibodies [anti-pTNP] in the diagnosis of IBD. Methods Serum samples were collected from 502 patients with diagnosed Crohn's disease [CD], 141 patients with ulcerative colitis [UC], and 109 healthy donors. The levels of anti-pTNPs and anti- Saccharomyces cerevisiae antibodies [ASCAs] were determined by enzyme-linked immunosorbent assay. The effects of each variable on the diagnosis were analysed by receiver operating characteristic [ROC] analysis. We also performed an estimate study by first developing a clinical prediction model, with external validation in CD patients from nine IBD medical centres in China. Results The levels of anti-pTNPs in sera of CD patients were higher than those in UC patients and healthy donors. The positive rates of anti-pTNPs were significantly higher in ileal CD patients than in ileocolonic and colonic CD patients, and the levels of anti-pTNP IgG in perianal patients were significantly higher than those in non-perianal CD patients. Of note, anti-pTNPs and perianal diseases were important predictors for active stage of CD patients. Discriminative ability to predict active CD patients was 0.918 (95% confidence interval [CI]:0.886–0.949). Conclusions Anti-pTNP functions as a novel biological marker for diagnosing CD and can be used to assess disease severity, particularly in those with lesion locations in the terminal ileum and stricturing and perianal diseases. A validated prediction model reveals that anti-pTNPs are useful for estimating the likelihood of active CD. [ABSTRACT FROM AUTHOR]

Rho-associated kinase (ROCK) has been found to be involved in the pathogenesis of a variety of autoimmune diseases, but the role of ROCK in inflammatory bowel disease (IBD) is still elusive. In this study, we demonstrated that the levels of ROCK2, but not ROCK1, activity were significantly upregulated in peripheral blood mononuclear cells (PBMC) and inflamed mucosa from IBD patients using a ROCK activity assay, and that ROCK2 activity in intestinal mucosa was positively correlated with disease severity. Stimulation with TNF markedly upregulated ROCK2 activity in IBD CD4 + T cells through NF-κB signaling. Blockade of ROCK2 activity using Slx-2119 significantly suppressed proinflammatory cytokines in inflamed mucosa from IBD patients including IFX-unresponsive CD patients, and inhibited IBD CD4 + T cells to differentiate into Th1 and Th17 cells through downregulating phosphorylated Stat1 and Stat3, but promoted Treg cell differentiation through upregulating phosphorylated Stat5. Furthermore, oral administration of Slx-2119 markedly ameliorated intestinal mucosal inflammation in TNBS-induced colitis in mice and decreased proinflammatory cytokines productions in inflamed colon. Our data indicate that ROCK2 plays a critical role in inducing mucosal T cell activation and inflammatory responses in IBD and that inhibition of ROCK2 activity might serve as a novel therapeutic approach in the management of IBD. [ABSTRACT FROM AUTHOR]

Background:Inflammatory bowel disease (IBD), composed of Crohn’s disease (CD) and ulcerative colitis (UC), is an inflammatory autoimmune disease. CD99 has been reported to participate in migration of leukocytes and T cell activation. However, the roles of CD99 in IBD are obscure. Materials and methods:CD99 expression was examined in peripheral blood mononuclear cells (PBMCs) and inflamed mucosa from IBD patients by qRT-PCR. Serum TNF-α and IL-17A levels were detected by ELISA. Correlations of CD99 expression with TNF-α, IL-17A, Crohn’s disease activity index (CDAI), simple endoscopic score for CD (SES-CD), Mayo index, and Truelove grading were performed by Pearson’s correlation. Results:CD99 expression was increased in PBMCs and inflamed mucosa from active CD and UC patients, and CD99 expression was also increased in the inflamed mucosa compared with unaffected control from the same patients. Serum TNF-α and IL-17A levels were increased in active CD or UC patients, and positively correlated with CD99 expression in PBMCs (CD:r = .402,p = .009;r = .350,p = .025. UC:r = .289,p = .028;r = .322,p = .014). Moreover, CD99 expression in inflamed mucosa was correlated with CDAI, SES-CD, Mayo index, and Truelove grading (r = .410,p = .012;r = .341,p = .005;r = .366,p = .002;r = .312,p = .011). Conclusion:CD99 expression is increased in patients with active IBD, and positively correlated with disease activity. Therefore, CD99 expression can be used as an index to evaluate the activity of IBD. [ABSTRACT FROM PUBLISHER]