ABSTRACT
BACKGROUND: Infliximab (IFX) is the first-line treatment for patients with Crohn's disease (CD) and is noted for its relatively high cost. The therapeutic efficacy of IFX has noticeable individual differences. Known single-gene polymorphisms (SNPs) are inadequate for predicting non-response to IFX. In this study, we aimed to identify new genetic factors associated with IFX-therapy failure and to predict non-response to IFX by developing a multivariate predictive model. METHODS: In this retrospective study, we collected and analysed the data of Chinese patients with CD who received IFX therapy at one hospital between June 2013 and June 2019. Primary non-response (PNR) and non-durable response (NDR) were evaluated using a simple endoscopic score for CD (SES-CD). A total of 125 SNPs within 44 genes were genotyped. A multivariate logistic-regression model was established to predict non-response to IFX. An area-under-the-receiver-operating-characteristics curve (AUROC) was applied to evaluate the predictive model performance. RESULTS: Forty-two of 206 (20.4%) patients experienced PNR and 15 of 159 (9.4%) patients experienced NDR. Nine SNPs were associated with PNR (P < 0.05). A PNR predictive model was established, incorporating 2-week high-sensitivity C-reactive protein (hs-CRP), rs61886887, rs61740234, rs357291, rs2269330, and rs111504845, and the AUROC on training and testing data sets were 0.818 (P < 0.001) and 0.888 (P < 0.001), respectively. At week 14, hs-CRP levels ≥ 2.25 mg/L were significantly associated with NDR (AUROC = 0.815, P < 0.001). PNR-associated SNPs were not mutually associated with NDR, suggesting distinct mechanisms between PNR and NDR. CONCLUSION: Genetic polymorphisms are significantly associated with response to IFX among Chinese CD patients.
ABSTRACT
Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide, imposing a great burden on the healthcare system. Regrettably, effective CKD therapeutic strategies are yet available due to their elusive pathogenic mechanisms. CKD is featured by progressive inflammation and fibrosis associated with immune cell dysfunction, leading to the formation of an inflammatory microenvironment, which ultimately exacerbating renal fibrosis. Transforming growth factor ß1 (TGF-ß1) is an indispensable immunoregulator promoting CKD progression by controlling the activation, proliferation, and apoptosis of immunocytes via both canonical and non-canonical pathways. More importantly, recent studies have uncovered a new mechanism of TGF-ß1 for de novo generation of myofibroblast via macrophage-myofibroblast transition (MMT). This review will update the versatile roles of TGF-ß signaling in the dynamics of renal immunity, a better understanding may facilitate the discovery of novel therapeutic strategies against CKD.
ABSTRACT
BACKGROUND: Trough levels of the post-induction serum infliximab (IFX) are associated with short-term and long-term responses of Crohn's disease patients to IFX, but the inter-individual differences are large. We aimed to elucidate whether single gene polymorphisms (SNPs) within FCGR3A, ATG16L1, C1orf106, OSM, OSMR, NF-κB1, IL1RN, and IL10 partially account for these differences and employed a multivariate regression model to predict patients' post-induction IFX levels. METHODS: The retrospective study included 189 Crohn's disease patients undergoing IFX therapy. Post-induction IFX levels were measured and 41 tag SNPs within eight genes were genotyped. Associations between SNPs and IFX levels were analysed. Then, a multivariate logistic-regression model was developed to predict whether the patients' IFX levels achieved the threshold of therapy (3 µg/mL). RESULTS: Six SNPs (rs7587051, rs143063741, rs442905, rs59457695, rs3213448, and rs3021094) were significantly associated with the post-induction IFX trough level (P = 0.015, P < 0.001, P = 0.046, P = 0.022, P = 0.011, P = 0.013, respectively). A multivariate prediction model of the IFX level was established by baseline albumin (P = 0.002), rs442905 (P = 0.025), rs59457695 (P = 0.049), rs3213448 (P = 0.056), and rs3021094 (P = 0.047). The area under the receiver operating characteristic curve (AUROC) of this prediction model in a representative training dataset was 0.758. This result was verified in a representative testing dataset, with an AUROC of 0.733. CONCLUSIONS: Polymorphisms in C1orf106, IL1RN, and IL10 play an important role in the variability of IFX post-induction levels, as indicated in this multivariate prediction model of IFX levels with fair performance.
