Background Crohn‘s disease (CD) is a form of inflammatory bowel disease characterized by high infiltration of immune cells into the intestinal tissue, resulting in increased proteolytic mediated extracellular matrix (ECM) remodeling. Disease management has improved with the use of biologics such as vedolizumab (VEDO). However, considering the high rate of primary non-response to VEDO, there is an unmet need for predictive serum biomarkers capable of determining response to treatment prior to its initiation. This study investigated whether biomarkers of neutrophil activity, mucosal damage, and ECM remodeling could serve as non-invasive tools for predicting long-term response to VEDO in patients with CD. Methods Serum biomarkers of human neutrophil elastase (HNE)-derived fragment of calprotectin (CPa9-HNE [serum calprotectin]) and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n=32) before VEDO therapy initiation. The ratio C4M/C4G (myeloid/lymphoid mediated degradation) was computed. Long-term response was defined as the continuation of treatment beyond one year after the start of therapy. Baseline biomarker levels were compared between responders and non-responders using Mann-Whitney U-tests, and area under the curve (AUC) values were generated using receiver operating characteristics (ROC) statistics. Biomarker levels were divided into tertiles and chi-square tests were used to investigate the relationship between tertiles and response proportions. Results Biomarkers CPa9-HNE, C1M, C3M, C4M, PRO-C3, C3M/PRO-C3, and C4M/C4G were significantly increased at baseline in non-responders compared with responders (all P<0.05). All markers were able to predict response to VEDO at baseline (AUC [95% CI]: CPa9-HNE 0.81 [0.66–0.96]; C1M 0.85 [0.75–0.98]; C3M 0.79 [0.62–0.95]; C4M 0.77 [0.6–0.93]; C3M/PRO-C3 0.78 [0.6–0.95]; C4M/C4G 0.74 [0.56–0.92] all P<0.05). Proportions of long-term VEDO users were highest in the first tertiles for all the markers (73–91%) and decreased in a concentration-dependent manner across the second and third tertiles, indicating that patients with the lowest concentrations of these markers less frequently discontinued treatment at one year after initiation (Figure 1). Conclusion Baseline levels of serum biomarkers for neutrophil activity (CPa9-HNE [serum calprotectin]) and mucosal damage (C1M, C3M, C4M, C4G, PRO-C4, and PRO-C3) could predict long-term response to VEDO in patients with CD. Therefore, these biomarkers could aid in early decision making concerning treatment with vedolizumab in patients with CD.
BackgroundTreatment of rheumatoid arthritis (RA) patients by anti-tumour necrosis factors (anti-TNFs), such as golimumab, has substantially improved patient outcomes. However, unmet therapeutic needs exist for the significant proportion of patients who do not respond to current biologics treatment. Mavrilimumab is a fully human monoclonal antibody which inhibits the granulocyte-macrophage colony-stimulating factor receptor α (GM–CSFR-α). Recently, a Phase IIb study has been completed to evaluate the efficacy and safety of mavrilimumab and golimumab in both disease-modifying antirheumatic drug (DMARD)-inadequate responder (IR) and anti-tumor necrosis factor-inadequate responders (anti-TNF-IR) patients (EARTH EXPLORER 2, NCT01715896).ObjectivesTo assess peripheral biomarkers and pathophysiological pathways modulated by mavrilimumab in comparison with golimumab in both DMARD-IR and anti-TNF-IR RA patients.MethodsIn total, 75 DMARD-IR and 63 anti-TNF-IR patients were randomized in a 1:1 ratio to receive subcutaneous 100 mg mavrilimumab (n=70) every other week (Q2W) or 50 mg golimumab (n=68) Q2W alternating with placebo, in combination with methotrexate (7.5–25.0 mg/week) for 24 weeks. Serum levels of 18 RA-associated proteins as well as 3 protease-derived protein fragments were measured in 71 DMARD-IR and 61 anti-TNF-IR RA patients at baseline and 4 time points post-administration. Transcriptome sequencing was used to measure gene expression changes in whole blood of RA patients at baseline and day 169 post-administration.ResultsSerum levels of CCL22 and CCL17 were suppressed by mavrilimumab but not golimumab, while CXCL13 and ICAM1 levels were suppressed by golimumab but not mavrilimumab. Those four proteins may be specific pharmacodynamic markers for the two biologics respectively. More interestingly, both mavrilimumab and golimumab demonstrated early and sustained suppression of multiple inflammatory markers in DMARD-IR patients, including CRP, SAA, MMP1, MMP3, IL6, VEGF, IL2R, and CD163. However, golimumab-induced early changes rapidly returned towards baseline levels in anti-TNF-IR patients, while serum protein suppression by mavrilimumab was maintained through day 169 in anti-TNF-IR patients. Similarly, mavrilimumab administration was associated with durable suppression of extracellular matrix markers, C1M, C3M, and P4NP7S, while golimumab only induced a transient change of the three markers in anti-TNF-IR patients. Furthermore, RNA sequencing results demonstrated significant regulation of 1547 transcripts at day 169 after mavrilimumab administration while golimumab had no impact on whole blood gene expression in anti-TNF-IR patients. In contrast, significant changes of 1042 and 2058 transcripts were observed in DMARD-IR patients at day 169 after mavrilimumab and golimumab administration respectively.ConclusionsOur study demonstrated sustained suppression of RA disease markers by mavrilimumab but not golimumab in anti-TNF-IR patients, suggesting the potential of greater long-term disease control by mavrilimumab ...
Background Inflammatory bowel disease (IBD) is characterized by chronic inflammation leading to extracellular matrix remodeling, reactive stroma and activated inflammatory cells. In the pursuit of non-invasive biomarkers of disease severity and treatment response for IBD, we evaluated Protein FingerPrint Assay (PFA) of collagen formation and degradation (PRO-C3, C3M, PRO-C4, C4M), neutrophil elastase cleaved calprotectin (CPa9-HNE) and citrullinated vimentin degradation (VICM) in serum collected from 2 clinical trials in Ulcerative Colitis (UC) and Crohns Disease (CD) (NCT01466374 and NCT01294410) and matched healthy volunteers (NHV). Methods PFA were generated from serum of 88 UC, 120 CD at baseline and at Day 78 of treatment and 78 NHV. Clinical remission in UC was defined as Mayo score 2 with no individual subscore >1. Clinical response as reduction from baseline in Mayo score 3 and 30%, and decrease from baseline in rectal bleeding subscore 1 or absolute rectal bleeding subscore 1. Clinical remission in CD was defined by an absolute CD Activity Index [CDAI] score < 150 and clinical response as a reduction in CDAI100 points from baseline or an absolute CDAI score < 150. Endoscopic remission was defined as SES-CD of 0. Statistical analysis was performed on all markers between diseased and NHV, pooled responders/remitters vs non-response independent of treatment arm and longitudinally. Results At baseline, C3M, C4M and PRO-C4 had significantly higher median levels in UC and CD patients than NHVs. CPa9-HNE and VICM were significantly higher in CD compared to NHV, an increase in these markers was observed but did not meet significance in UC patients (Figure 1). Decrease of VICM from baseline at Day 78 were associated with remission (median -55%, p<0.05) in UC, while VICM decrease from baseline (median -56%, p<0.05) at Day 78 was associated with CD patients achieving endoscopic remission. In CD C3M and C4M was present at lower levels at baseline and during study in patients with clinical remission compared with those without remission. SES-CD scores were positively correlated with C4M, C3M, CPa9-HNE and PRO-C4 at both baseline and Day 78. CD patients achieving endoscopic remission had lower levels of C3M, C4M, PRO-C4 and CPa9-HNE at both baseline and Day 78. Conclusion C4M, C3M, PRO-C4, CPa9-HNE and VICM were found at higher levels in serum of IBD patients. VICM demonstrated potential as a biomarker for monitoring disease activity changes. Association of C4M, C3M and PRO-C4 with endoscopic remission in CD patients suggest that these markers may predict disease progress or regression in CD patients. However, further studies are warranted to evaluate these biomarkers in IBD patients.
Purpose: The fragment of C-terminal cross-linked telopeptide of type II collagen (CTX-II) is released into circulation and subsequently secreted into urine as a result of articular cartilage degradation in osteoarthritis (OA) disease. The urinary CTX-II (uCTX-II), a competitive immunoassay, has been studied in numerous studies. It is considered as one of the best-validated biomarker in OA field. However, the CTX-II in blood have shown limited value, although there would be some advantages of blood versus urine measurement. We intended to develop a sensitive serological immunoassay of CTX-II (sCTX-II) and to quantify sCTX-II and uCTX-II in a cross-sectional osteoarthritis (OA) cohort. The correlation between sCTX-II and uCTX-II and clinical parameters was investigated as well. Methods: A serological CTX-II sandwich electrochemiluminescence immunoassay (ECLIA), sCTX-II, was developed on the MesoScale Discovery (MSD) platform by employing the same antibody as in the uCTX-II. The uCTX-II was quantified by Urine CartiLaps ELISA (IDS, UK). The concentration of urinary creatinine was analyzed by using the QuantiChrom Creatinine Assay Kit (BioAssay Systems, US). Firstly, a commercially available correlation panel consisting of 18 matched human sera and plasma was measured in sCTX-II to test its ability for different types of blood. In addition, EDTA-treated plasma and urine samples from 227 individuals with complete data in the C4Pain Study were assayed using sCTX-II and uCTX-II, respectively. To evaluate the correlation of the sCTX-II and uCTX-II, Pearson's correlation was performed. Biomarker levels were correlated with Kellgren-Lawrence grade (KL), as well as WOMAC pain, stiffness and function by multiple linear regression, adjusted for age, gender and body mass index (BMI). Results: A good performing sCTX-II immunoassay was developed (inter CV¼11%; intra CV¼3%) and exhibits more sensitivity in terms of Low Limit of Detection (LLOD) compared to uCTX-II (0.003 vs 0.2 ng/ml). The correlation panel between serum and EDTA-treated plasmas was relatively high (r¼0.99, P < 0.0001), showing that sCTX-II levels are independent of blood preparation method. The sCTX-II levels in plasma were not associated with uCTX-II in urine (Table 1). However, sCTX-II levels in urine were significantly correlated with uCTX-II ( Table 1), indicating that sCTX-II ECLIA measured, to some degree, the same analytes as uCTX-II did when measured in urine.Not surprisingly, uCTX-II levels were significantly associated with the pain and joint stiffness recorded by WOMAC (r¼0.13, P¼0.039; r¼0.18, P¼0.0029, respectively) after adjustment for age, BMI, and gender. In contrast, sCTX-II plasma levels were negatively associated with WOMAC pain and WOMAC stiffness (r¼ -0. 13, P ¼ 0.037; r¼ -0.13, P¼0.042, respectively). The WOMAC pain and stiffness levels were higher in the lowest sCTX-II tertile (T1) compared to the highest tertile (T3) (Fig. 1A, P<0.05, Fig. 1E, P<0.05). In contrast, an entirely reverse trend was observed for uCTX-II (Fig. 1D, P<0.01; Fig....
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.