Serum levels of soluble HLA-G correlate with disease activity in pediatric patients with Crohn's disease

Abstract Background In patients with inflammatory bowel disease (IBD), up to 30% do not achieve response, 66% do not achieve remission, and 40% experience loss of response to anti-TNFα treatment. In Crohn’s disease (CD), fecal calprotectin is the most widely used fecal biomarker for diagnosis and monitoring of disease activity. Fecal sampling and processing are tedious compared to serum sampling, and biomarker quantification in serum is more efficient, convenient, and also more acceptable for patients. Therefore, there is a need for a robust and reliable serum calprotectin biomarker that performs better than conventional serum biomarkers. The aim of this study was to investigate the performance of a novel serum calprotectin assay, which quantifies a specific human neutrophil elastase (HNE) generated calprotectin (S100a9) fragment (CPa9-HNE), as a measure of true neutrophil granulocyte activity, for monitoring treatment responses in patients with CD. Methods We included 30 CD patients with clinically active (Harvey-Bradshaw Index (HBI)≥5) luminal inflammation scheduled for anti-TNF treatment (adalimumab or infliximab). Serum samples where obtained at baseline (n=30), week 1 (n=29), week 8 (n=28), week 26 (n=15), and week 56 (n=7). CPa9-HNE (Calprotectin, S100a9, specific fragment generated by human neutrophil elastase), CRP and fecal calprotectin were quantified. Remitters (n=11) were defined as patients in clinical remission (HBI<5) at week 8 with no flares at week 26 or week 56. Non-remitters (n=19) were defined by having clinical active disease (HBI≥5) at week 8 or having a flare at week 26 or week 56. Results Patients with severe disease activity (HBI>16) had significantly elevated serum levels of CPa9-HNE compared with patients in remission (p<0.05), with mild (p<0.05) or moderate (p<0.01) disease activity. CPa9-HNE serum levels were significantly suppressed in remitters compared with non-remitters at week 8 (p<0.001), week 26 (p<0.01) and week 56 (p<0.05) (Figure 1). Fecal calprotectin and CRP were significantly suppressed at week 8, week 26 and week 56 compared with baseline levels for remitters and non-remitters, but there was no significant difference between remitters and non-remitters (Figure 1). Non-remitters were more likely to have high levels of CPa9-HNE at baseline (tertile 1,2 vs tertile 3; OR: 6.8 (CI:1.22-36.5), p=0.027) and week 8 (tertile 1,2 vs tertile 3; OR: 24 (CI:2.56-279), p=0.0014). Conclusion CPa9-HNE is a novel non-invasive biomarker for monitoring treatment response to anti-TNFα for CD patients and may be used as a surrogate marker for assessing disease activity and to predict outcome of anti-TNFα treatment.

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Elevated Levels of IL-27 Are Associated with Disease Activity in Patients with Crohn’s Disease

Mediators of Inflammation ◽

10.1155/2021/5527627 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Xiufang Cui ◽

Chunhua Jiao ◽

Di Wang ◽

Ziping Ye ◽

Jingjing Ma ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Clinical Significance ◽

Activity Index ◽

Biological Marker ◽

Disease Activity Index ◽

Serum Levels ◽

Th1 Cells ◽

Control Subjects

Immune disorders play an important role in the pathogenesis of Crohn’s disease (CD). Notably, the increased immune response of Th1 cells and related cytokines is associated with the onset of CD. IL-27 is a newly discovered IL-12-related cytokine, but its expression and clinical significance in CD patients are still controversial. This study is aimed at evaluating the serum levels of IL-27 in CD patients and analyzing their clinical significance. The results indicated that serum levels of IL-27 in CD patients were significantly higher than those in control subjects (median (interquartile range (IQR)): 110.0 (95.0, 145.0) vs. 85.0 (80.0, 95.0) pg/ml, P < 0.001 ). Furthermore, the IL-27 levels significantly increased in CD patients at the active stage compared with CD patients in remission (CDR) (127.5 (100.0, 150.0) vs. 90 (80.0, 110.0) pg/ml, P < 0.001 ). However, there was no difference in IL-27 levels between CDR and control subjects. The levels of IL-27 were positively correlated with Crohn’s disease activity index (CDAI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC), and Simple Endoscopic Score for Crohn’s Disease (SES-CD) and negatively correlated with hemoglobin (Hb) and serum albumin (ALB). IL-27 combined with CRP favored the prediction of CD activity (area under the curve (AUC): 0.88). Additionally, the proportions of Th17 and Th1 cells in peripheral blood were higher in CD patients than in control subjects. Active CD patients exhibited significantly higher proportions of Th17 and Th1 cells than those in remission. Moreover, correlation analysis indicated that the serum levels of IL-27 were positively associated with the frequency of Th17 cells in CD patients ( r = 0.519 , P = 0.013 ) but not associated with the frequency of Th1 cells in CD patients. IL-27 is positively associated with multiple inflammation indicators and may exert a proinflammatory profile by regulating Th17 cell differentiation in the development of Crohn’s disease. In the future, IL-27 combined with CRP is expected to become an important biological marker of CD activity.

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Serum Syndecan-1 Levels and Its Relationship to Disease Activity in Patients with Crohn’s Disease

Gastroenterology Research and Practice ◽

10.1155/2015/850351 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Cem Çekiç ◽

Adnan Kırcı ◽

Sezgin Vatansever ◽

Fatih Aslan ◽

Huriye Erbak Yılmaz ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Activity Index ◽

Normal Population ◽

Disease Activity Index ◽

Serum Levels ◽

Control Group ◽

Serum Samples ◽

Reactive Protein

Background. Syndecan-1 (SDC-1), a member of the family of heparan sulfate proteoglycans, plays an important role in the resolution of inflammation. This study aimed to investigate the relationship between SDC-1 and disease activity in Crohn’s disease (CD).Methods. Serum samples of 54 patients with CD and 30 healthy controls were obtained. First, SDC-1 levels of the CD patients were compared to the control group. Subsequently, SDC-1 levels were analyzed in patients with CD in active and remission periods. Finally, SDC-1 efficacy in predicting disease activity was evaluated by performing correlation analysis between SDC-1 and C-reactive protein (CRP) and Crohn’s disease activity index (CDAI).Results. SDC-1 level was higher in the CD group (61.9 ± 42.6 ng/mL) compared with the control group (34.1 ± 8.0 ng/mL)p=0.03. SDC-1 levels were higher in active CD patients (97.1 ± 40.3 ng/mL) compared with those in remission (33.7 ± 13.5 ng/mL)p<0.001. A significant positive correlation was found between SDC-1 and CRP (r=0.687,p<0.001) and between SDC-1 and CDAI (r=0.747,p<0.001).Conclusion. Serum levels of SDC-1 are higher in CD compared to the normal population and can be an effective marker of disease severity.

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A New Model Based on 25-Hydroxyvitamin D3 for Predicting Active Crohn’s Disease in Chinese Patients

Mediators of Inflammation ◽

10.1155/2018/3275025 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8

Author(s):

Sinan Lin ◽

Ying Wang ◽

Li Li ◽

Peng Chen ◽

Ren Mao ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Activity Index ◽

Disease Activity Index ◽

Serum Levels ◽

Chinese Patients ◽

Care Needs ◽

Roc Curve Analysis ◽

New Model

Background. The association between vitamin D3 and activity of Crohn’s disease (CD) is unclear in Chinese patients. In this study, we aimed to evaluate the correlations between serum levels of 25-hydroxyvitamin D3 (25(OH)D3) and disease activity and predict active disease based on vitamin D status. Methods. Between January 2014 and December 2017, 346 CD patients from the First Affiliated Hospital of Sun Yat-sen University were recruited and categorized into a group with 25(OH)D3 ≤ 20 ng/ml and a group with 25(OH)D3 > 20 ng/ml. The clinical characteristics, medication, and health-care needs were compared between the groups. The correlations among 25(OH)D3 and routine serum biomarkers and disease activity were examined. The predictive efficiency of 25(OH)D3 and other biomarkers for active diseases was also explored using receiver-operating characteristic (ROC) curve analysis. A new predictive model, −5∗25OHD3+2∗Hb+ESR, and a nomogram were established using Logistic Regression. Results. Patients with 25(OH)D3 ≤ 20 ng/ml had higher serum levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and platelets (PLT) and lower levels of hemoglobin (Hb) and albumin (ALB). Serum levels of 25(OH)D3 were inversely correlated with the score of Crohn’s Disease Activity Index (CDAI) (rs=−0.608). ROC analysis showed a better predictive value of −25(OH)D3 and the new model with areas under curve (AUC) of 0.804 and 0.879, respectively, than those of CRP (0.693) and ESR (0.713) in disease activity. A nomogram for prediction was established with a c-index of 0.882. Conclusions. Serum levels of 25(OH)D3 negatively correlated with CD activity in Chinese patients. The new model and a nomogram based on 25(OH)D3 showed a better efficiency in predicting disease activity in CD patients but warrants further study.

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Association between vitamin D serum levels and disease activity markers in patients with Crohn’s Disease

International Journal of Colorectal Disease ◽

10.1007/s00384-016-2555-0 ◽

2016 ◽

Vol 31 (8) ◽

pp. 1495-1496 ◽

Cited By ~ 3

Author(s):

Priscilla Clímaco Rebouças ◽

Joao Gomes Netinho ◽

Geni Satomi Cunrath ◽

Luiz Sergio Ronchi ◽

Marcelo Maia Caixeta de Melo ◽

...

Keyword(s):

Vitamin D ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Serum Levels

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ROLE OF MAGNETIC RESONANCE ENTEROGRAPHY IN THE DIAGNOSTICS OF ACTIVE CROHN’S DISEASE IN CHILDREN

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa347.024 ◽

2021 ◽

Vol 27 (Supplement_1) ◽

pp. S11-S11

Author(s):

Karolina Siejka ◽

Maryla Kuczynska ◽

Magdalena Grzegorczyk ◽

Malgorzata Nowakowska ◽

Monika Piekarska ◽

...

Keyword(s):

Crohn’S Disease ◽

Gastrointestinal Tract ◽

Magnetic Resonance ◽

Crohn's Disease ◽

Disease Activity ◽

Pediatric Patients ◽

Ileocecal Valve ◽

Magnetic Resonance Enterography ◽

Mr Enterography ◽

Local Study

Abstract Background Crohn’s disease (CD) is an idiopathic inflammatory bowel disease of the gastrointestinal tract. It is more common in the developed and industrialized countries, particularly in the Western Europe and North America. Up to 20–30% of patients present first symptoms during childhood or adolescence. Traditionally it is diagnosed by clinical indicates, endoscopy and histological findings. Assessment of the disease activity and location along the gastrointestinal tract are of crucial importance for diagnosis and implementation of the proper treatment. Active inflammation can manifest as mural thickening, edema, ulcerations, abscesses or fistulas. Magnetic resonance enterography (MRE) is the most modern radiological method in depicting all of these manifestations of CD. Objective The aim of the study was to assess the value of MRE in evaluation of Crohn’s disease in pediatric patients. Materials and Methods 18 children (8 boys, 10 girls) with confirmed diagnosis of Crohn’s disease, were included in the study. Each patient underwent MR enterography with intravenous administration of a contrast agent. All studies were performed using a 1.5T scanner according to a local study protocol. Results All MRE findings were associated with small bowel inflammation. All patients showed asymmetric ileal wall thickening and edema. Edematous ileocecal valve was visible in 8 patients. In 7 cases reactive lymphadenopathy was detected (lymph nodes ≥ 10 mm in short axis). In 4 patients small intestine fistulas were found, whereas abscess was observed in another 4 patients. In contrast-enhanced images, a vivid enhancement of the affected bowel section was revealed in all patients and in 10 children inflammatory infiltration of periintestinal fat was depicted. Conclusion MRE is a reliable tool in diagnosis, evaluation of the disease activity and assessment of potential complications of Crohn’s disease. Due to the lack of ionizing radiation MRE exhibits beneficial safety profile and can be offered to patients who repeatedly require follow-up examinations, especially in pediatric patients.

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Autoregressive cross-lagged models of IMPACT-III and Pediatric Crohn's Disease Activity indexes during one year infliximab therapy in pediatric patients with Crohn's disease

Journal of Crohn s and Colitis ◽

10.1016/j.crohns.2013.12.020 ◽

2014 ◽

Vol 8 (8) ◽

pp. 747-755 ◽

Cited By ~ 7

Author(s):

Dolóresz Szabó ◽

Gyöngyi Kökönyei ◽

András Arató ◽

Antal Dezsőfi ◽

Kriszta Molnár ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Pediatric Patients ◽

Infliximab Therapy ◽

Crohn’S Disease Activity ◽

One Year

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P516 Serological biomarkers of tissue remodeling are associated with endoscopic remission in Crohn’s disease patients treated with GED-0301 (mongersen)

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.638 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S494-S495

Author(s):

J Mortensen ◽

B Feagan ◽

A C Bay-Jensen ◽

M A Karsdal ◽

G Horan ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Tissue Remodeling ◽

Serum Levels ◽

Induction Phase ◽

Collagen Formation ◽

Endoscopic Remission ◽

Endoscopic Score ◽

Serological Biomarkers

Abstract Background In Crohn’s disease (CD) Smad7 is overexpressed in the intestinal mucosa, where it contributes to a sustained production of inflammatory cytokines, increased matrix metalloproteinase (MMP) activity and chronic inflammation through inhibition of the anti-inflammatory actions of TGF-beta. GED-0301, an anti-sense oligodeoxynucleaotide complementary to the mRNA of Smad7, inhibits the translation and synthesis of the Smad7 protein. We investigated exploratory biomarkers of collagen degradation by MMPs (C1M, C3M, C4M) and collagen formation (PRO-C3, PRO-C4 and PRO-C5) and their association with endoscopic remission in CD patients treated with GED-0301. Methods 63 CD patients were randomized (1:1:1) to 4, 8 or 12 weeks oral, blinded GED-0301 160 mg daily (ClinicalTrials.gov no: NCT02367183). Simple endoscopic score for CD (SES-CD) (centrally read) was used to evaluate disease activity. Remission was defined as a SES-CD≤4 score at week 12. 54 CD patients completed the 12-week induction phase. Serum biomarkers measured by competitive ELISA se included C1M, C3M, C4M, PRO-C3, PRO-C4, PRO-C5 at baseline, week 4, week 8 and week 12. Spearman rho correlation was applied to evaluate the association with biomarkers and SES-CD score. Results Seven patients (11%) achieved a SES-CD≤4 at week 12. At baseline and at week 12 the biomarkers, C1M (baseline: r=0.36, P=0.005; wk12: r=0.47, P=0.0007), C3M (baseline: r=0.46, P=0.0002; wk12: r=0.28, P=0.047), C4M (baseline: r=0.40, P=0.002; wk12: r=0.36, P=0.011) PRO-C4 (baseline: r=0.36, P=0.004; wk12: r=0.35, P=0.013), and PRO-C5 (baseline: r=0.30, P=0.022) correlated with SES-CD (table 1). Remitters at baseline showed a numerically lower serum levels of C1M (54ng/mL vs. 65ng/mL), C3M (14.7ng/mL vs. 16.5ng/mL), PRO-C4 (241ng/mL vs. 299ng/mL) and PRO-C5 (442ng/mL vs. 660ng/mL) compared to non-remitters. The biomarkers C1M (P<0.05), C4M (P<0.05) and PRO-C5 (P<0.05) were significantly suppressed in remitters at week 12 compared to non-remitters (figure 1). The same biomarkers also demonstrated sustained suppression of serum concentrations at week 4, 8 and 12 (C1M: 21.6% decrease from baseline at week 12; C4M: 15% decrease from baseline at week 12; PRO-C5: 26.6% decrease from baseline at week 12) in remitters compared to non-remitters. Conclusion Biomarkers of tissue remodeling correlated with the SES-CD scores of CD patients treated with mongersen. Patients s who achieved remission based on endoscopic criteria showing greater suppression of these biomarkers relative to non-remitters. Collectively, these data suggest that biomarkers of tissue remodeling may be useful to monitoring disease activity and mucosal changes in CD patients.

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P011 Serum adhesion G protein coupled receptor levels are associated with disease activity in pediatric patients with Crohn’s disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.140 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S131-S134

Author(s):

L Werner ◽

B Weiss ◽

R Shamir ◽

D Shouval

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Activity ◽

Pediatric Patients ◽

Principal Component ◽

Serum Samples ◽

Control Subjects ◽

Treatment Naïve ◽

G Protein Coupled ◽

Active Disease

Abstract Background Despite increasing number of therapies available for patients with Crohn’s disease (CD), response rates are generally not high. Therefore, there is a great need to identify novel targets in patients with active disease. Methods Serum samples were obtained from pediatric patients with CD at the time of diagnosis and following induction therapy with exclusive enteral nutrition (EEN) or anti-TNFa therapy, and from control subjects, defined as having normal colonoscopy without past or present history of inflammatory bowel diseases or other immune-mediated disorder. Associated clinical and laboratory data from these subjects was also collected. Serums were subjected to Olink technology (metabolism panel), based on proximity extension assay, enabling analysis of 92 proteins in each sample. Analysis was performed on a Normalized Protein eXpression (NPX) file comparing effect of different factors on the overall biomarker expression by supervised, multivariate, principal component analysis and verification by univariate ANOVA with Benjamini-Hochberg and post-hoc Tukey analysis. Results Eighty-eight serum samples were collected: 30 from control subjects and 58 from 32 patients with CD. The median age of patients in the control and CD groups was 13.9 years (IQR 11.1–16.6) and 14.6 years (IQR 12.2–16.9), respectively (P=0.32). Twenty-four patients were treated with anti-TNFa agents and 8 with EEN. The median pediatric Crohn’s Disease Activity Index decreased from 35 (22.5–42.5) to 5 (0–12.5, P<0.001) following induction therapy. We identified 34 proteins that significantly differed between patients and controls. Moreover, within patients with CD, 8/34 of these proteins were differentially expressed in patients with active or non-active disease. Among these, adhesion G-protein coupled receptors E2 (ADGRE2) and G2 (ADGRG2), important for macrophage differentiation, were significantly lower among CD patients vs. controls. When stratifying according to disease activity, low levels of both markers were identified in CD patients with active disease (either patients that were treatment-naïve or those with primary non-response to anti-TNFa therapy) or with increased CRP levels. Principal component analysis showed that a combination of ADGRE2 and ADGRG2 showed good separation between control subjects and treatment naïve patients with active CD. Conclusion Serum levels of ADGRE2 and ADGRG2 are differentially regulated in patients with active CD, and should further be validated in additional Cohorts. The expression patterns and function of these receptors on different immune cells should be defined in future studies.

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