Introduction

Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common gastroenterological emergency associated with significant morbidity and mortality [1-3]. Upper gastrointestinal endoscopy is currently recommended as the gold standard modality for both diagnosis and treatment [4]. As historically played a limited role in the diagnosis of acute NVUGIB, multidetector-row computed tomography angiography (MDCTA) is emerging as a promising tool in the diagnosis of NVUGIB, especially for severe cases [5-6]. However, to date, evidence concerning the role of MDCTA in the NVUGIB diagnosis is still lacking.

Aims & Methods

The purpose of this study was to retrospectively investigate the diagnostic performance of emergent MDCTA performed prior to any diagnostic modality or following urgent upper endoscopy to identify the status, the site and the underlying etiology of severe NVUGIB. Institutional databases were reviewed in order to identify severe acute NVUGIB patients who were admitted to our bleeding unit and were referred for emergent MDCTA prior to any hemostatic treatment (<3 hours) or following (<3 hours) endoscopy, between December 2019 and October 2022. The study aim was to evaluate the diagnostic performance of MDCTA to detect the status, the site and the etiology of severe NVUGIB with endoscopy, digital subtraction angiography, surgery, pathology or a combination of them as reference standards.

Results

A total of 68 patients (38 men, median age 69 years [range 25–96]) were enrolled. The overall MDCTA sensitivity, specificity, and accuracy to diagnose bleeding status were 77.8% (95% CI: 65.5-87.3), 40% (95% CI: 5.3-85.3), and 75% (95% CI: 63.0-84.7), respectively (Table 1). Finally, the overall MDCTA sensitivity to identify the bleeding site and the bleeding etiology were 92.4% (95% CI: 83.2-97.5) and 79% (95% CI: 66.8-88.3), respectively.

Table 1. The diagnostic performance of MDCTA in detecting bleeding status.

	Active (n = 40)	Recent (n = 26)	Non-active and non-recent (n = 2)	Total (n = 68)
TP	29	20	-	49
TN	-	-	2	2
FP	0	3	-	3
FN	11	3	0	14
Sensitivity (95% CI)	72.5 (56.1-85.4)	87.0 (66.4-97.2)	-	77.8 (65.5-87.3)
Specificity (95% CI)	-	-	100 (15.81-100)	40.0 (5.3-85.3)
PPV (95% CI)	100 (88.1-100)	87.0 (66.4-97.2)	-	94.2 (84.1-98.8)
NPV (95% CI)	-	-	100 (15.81-100)	12.5 (1.55-38.4)
Accuracy (95% CI)	-	-	-	75 (63.0-84.7)

TP, true positive; TN, true negative; FP, false positive; FN, false negative; CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value.

Conclusion

MDCTA seems to be a feasible and effective modality in detecting the site, the status and the etiology of severe acute NVUGIB. It may play a crucial role in the management of selected cases of NVUGIB, especially those clinically severe and/or secondary to rare and extraordinary rare sources, effectively guiding timing and type of treatment. However, further large prospective studies are needed to clarify the role of MDCTA in the diagnostic process of acute NVUGIB.

References

1. Wuerth BA, Rockey DC. Changing Epidemiology of Upper Gastrointestinal Hemorrhage in the Last Decade: A Nationwide Analysis. Dig Dis Sci 2018; 63: 1286–1293.
2. Laine L, Yang H, Chang S-C, et al. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am J Gastroenterol 2012; 107: 1190–1195; quiz 1196.
3. Sanders DS, Perry MJ, Jones SGW, et al. Effectiveness of an upper-gastrointestinal haemorrhage unit: a prospective analysis of 900 consecutive cases using the Rockall score as a method of risk standardisation. Eur J Gastroenterol Hepatol 2004; 16: 487–494.
4. Gralnek IM, Stanley AJ, Morris AJ, et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021. Endoscopy 2021; 53: 300–332.
5. Napoli A, Fleischmann D, Chan FP, et al. Computed tomography angiography: state-of-the-art imaging using multidetector-row technology. J Comput Assist Tomogr 2004; 28 Suppl 1: S32-45.
6. Wu L-M, Xu J-R, Yin Y, et al. Usefulness of CT angiography in diagnosing acute gastrointestinal bleeding: a meta-analysis. World J Gastroenterol 2010; 16: 3957–3963.

Disclosure

No conflict of interest to declare.

Introduction

Acute severe colitis (ASC) is an important cause of morbidity and mortality in Ulcerative Colitis (UC), requiring hospitalisation and, frequently, colectomy. Intravenous corticosteroids (CS) remain the first-line medical treatment. Approximately 40% of episodes of ASC do not respond to this treatment and require rescue therapy with ciclosporin (CIC) or infliximab (IFX)¹. In the past decades, these treatments and protocol-driven management algorithms led to reduced mortality and colectomy rates. A simple clinical scoring system (the Admission Model for the Intensification of Therapy in Acute Severe Colitis (ADMIT-ASC))³, based on CRP, albumin, and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score, was recently developed to predict the steroid response on admission.

Aims & Methods

We aimed to retrospectively assess the steroid non-response during admission with ASC and the usefulness of the new prognostic clinical index ADMIT-ASC at admission to predict steroid response in a Belgian tertiary center. All patients admitted with ASC between 1^st January 2015 and 1^st April 2023 were identified from our inflammatory bowel disease database at Erasme University Hospital. Inclusion criteria were ASC patients admitted at the hospital, standard treatment with at least 3 days of intravenous CS and endoscopy evaluation upon admission. ASC was defined according to modified Truelove and Witts’ criteria as ≥6 bloody stools/day with one or more markers of systemic disturbance (tachycardia >90 beats/min, temperature >37.8°C, haemoglobin <105 g/L or CRP >30 mg/L). Steroid non-response was defined as the need for medical rescue therapy (CIC of IFX) or colectomy during the admission. ADMIT-ASC index consists of four points: CRP ≥100 mg/L (1 point), albumin ≤25 g/L (1 point) and UCEIS score ≥4 (1 point) or ≥7 (2 points).

Results

Table I Admission Demographics data (n= 84)	Steroid response (n=49)	Steroid non-response (n=35)	P value
Median disease duration (years) (IQR)	3.6 (0.3-0.9)	2.1 (0.8-5.5)	0.5
Montreal Classification	E1 : 5/49 (10%) E2 : 20/49 (41%) E3 : 24/49 (49%)	E1 : 0/35 E2 : 12/35 (34%) E3 : 23/35 (66%)	0.084
5-ASA, n (%)	22 (45%)	10 (29%)	0.13
Methotrexate or thiopurine, n (%)	6 (12%)	9 (26%)	0.11
Infliximab, n (%)	4 (8.2%)	8 (23%)	0.058
Vedolizumab, n (%)	7 (14%)	5 (14%)	>0.9
Tofacitinib, n (%)	2 (4.1%)	2 (5.7%)	>0.9
Readmission, n (%)	12 (24%)	10 (29%)	0.7
5-ASA, 5-aminosalicylate P values from Wilcoxon rank-sum test or Fisher’s exact test.

Out of 127 patients admitted with UC and treated with intravenous CS during three days, 84 (45% male, median age of 31 years old) were included in the study. Admission demographics and clinical characteristics are described in Table 1.
For 17 patients (20%), the admission was their index presentation of UC. Response to CS was seen in 49 patients (58%). Thirty-three patients (39%) received medical rescue therapy (17/33 IFX and 16/33 CIC). Colectomy rate during admission was 13% after a median duration of 18 days (IQR: 16-54). Admission C reactive protein (CRP) (p=0.036), albumin (p=0.026) and UCEIS scores (p=0.022) were significantly associated with steroid non-response. Patients scoring 0, 1, 2, 3 and 4 had steroid response rates of 90%,75%, 55%, 19% and 0%, respectively. Scoring of ≥3 was 75% (95% CI, 0.43 to 0.95) predictive of steroid failure (OR 5.08, 95%, CI 1.38 to 24.5).

Conclusion

In this tertiary referral cohort study, we confirmed that the ADMIT-ASC index is a simple clinical tool that can be used on the day of admission to predict steroid non-response in ASC with a threshold of ≥3 to identify patients who are unlikely to respond to intravenous CS and enabling timely treatment escalation or surgery.

References

1. Travis S, Satsangi J, Lémann M. Predicting the need for colectomy in severe ulcerativecolitis: a critical appraisal of clinical parameters and currently available biomarkers. Gut 2011;60:3–9.
2. Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis.Gut 1996;38:905–10.
3. Adams A, Gupta V, Mohsen W, et al. Gut 2023;72:433–442.

Disclosure

VB has not disclosure.
CDT has not disclosure.
CM has not disclosure.
AC has received lecture fees from Galapagos, Abbvie, Janssen, celltrion, Pfizer, Takeda.
DF has received lecture fees from Abbvie, Astrazeneca, Dr.Falk Pharma, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, Amgen, and advisory board fees from Abbvie, Janssen,Takeda, Celltrion, Amgen.
CL has received consultancy fees from Janssen, Abbvie, Takeda and Galapago and speaker fees from Sandoz, Janssen, Abbvie

Introduction

Postoperative ileus, is one of the most common causes of prolonged hospital stays after abdominal surgery which cause from physiologic hypomotility of the gastrointestinal tract occurring immediately after abdominal surgery. Multi-modal approach to the resolution of postoperative ileus includes ERAS protocol such as opioid minimization, early ambulation, intake of prokinetic drug. Mosapride citrate (mosapride) is known to promote gastrointestinal motility. The objective of this study is to evaluate the effects of mosapride on postoperative ileus and postoperative gastrointestinal motility in patients undergoing elective open and laparoscopic colorectal surgery.

Aims & Methods

The study was approved by ethics committee of the Faculty of Medicine Ramathibodi Hospital Mahidol University (Ref. Number COA.MURA2021/328,ClinicalTrials.gov Identifier: NCT04905147). Forty-four colorectal cancer patients, undergoing open and laparoscopic colorectal surgery in Ramathibodi Hospital during July 2021-August 2022, were randomly assigned to a mosapride group or control group. The mosapride group received 15 mg of mosapride by enteric route with 50 ml of water three times a day, starting on postoperative day 1. The control group received 15 mg of placebo drug with 50 ml of water at the same time. Postoperative time to the first passage of flatus and the first bowel movement were evaluated by one investigator with triple blind study. Time to step diet, length of postoperative hospital stays, and adverse effects were also evaluated in secondary outcomes.

Results

All forty four patients were include, twenty-three in control group and twenty-one in mosapride group. There were no statistically significance differences between mean age and type of surgery (laparoscopic or open) in two group (P>0.05). Time to first bowel movement and time to passage of flatus after operation were significantly shorter in the mosapride group than the control group (26 vs 50 hours, P=0.004 and 40 vs 70 hours, P=0.003, respectively). Time to step diet (soft diet) was also shorter in the mosapride group (90 vs 132 hours, P=0.004). Time to defecate was less in mosapride group than control group (80 vs 120 hours, P <0.001). Length of hospital stay was significantly shorter in patients receiving mosapride (7 vs 10 days, P=0.004).

Conclusion

This study demonstrated the efficacy of mosapride when administered to patients who underwent elective colorectal surgery. Mosapride significantly enhance recovery of gastrointestinal motility and shorter length of hospital stay with no significant adverse effects.

References

1. Collins TC, Daley J, Henderson WH, Khuri SF. Risk factors for prolonged length of stay after major elective surgery. Ann Surg 1999;230:251–9
2. Vather R, O'Grady G, Bissett IP, Dinning PG. Postoperative ileus: mechanisms and future directions for research. Clin Exp Pharmacol Physiol. 2014;41(5):358-370.
3. Goldstein JL, Matuszewski KA, Delaney C, Senagore A, Chiao E, Shah M, et al. Inpatient economic burden of postoperative ileus associated with abdominal surgery in the United States. P AND T.2007;32(2):82.
4. Venara A, Neunlist M, Slim K, Barbieux J, Colas PA, Hamy A, et al. Postoperative ileus: Pathophysiology, incidence, and prevention. J Visc Surg 2016;153:439-46.
5. Luckey A, Livingston E, Taché Y. Mechanisms and Treatment of Postoperative Ileus. Arch Surg. 2003;138(2):206–214.
6. Georgiadis, G & Markantonis, Sophia & Triantafillidis, John. (2000). Prokinetic agents: Current aspects with focus on cisapride. Annals of Gastroenterology. 13.
7. Reynolds, J.C. & Putman, P.E. (1992) Prokinetic Agents, Gastroenterol Clin of North Am, Vol.21, pp.567-596.
8. Taniyama, K., Makimoto, N., Furuichi, A. et al. Functions of peripheral 5-hydroxytryptamine receptors, especially 5-hydroxytryptamine₄ receptor, in gastrointestinal motility. J Gastroenterol 35, 575–582 (2000).

Introduction

Thiopurines are one of the major drugs for inflammatory bowel disease. In Asian individuals, the SNP p.Arg139Cys in exon 3 of NUDT15 is associated with leucopenia and hair loss.

Aims & Methods

The aims of this study are to evaluate the long-term effects of NUDT15 on clinical outcomes.
The patients (ulcerative colitis130, Crohn’s disease 55 cases) were divided into the mutant and the wild group of NUDT15, and the daily dosage of thiopurines and the effect of the mutation on hospitalization and surgery were investigated.

Results

Compared to the mutant group (n = 48), the daily thiopurine dosage increased in the wild group (n = 137)(p = 0.024). The time to dose reduction and discontinuation of thiopurine was significantly shorter in the mutant group, respectively (p < 0.001, p = 0.039). The mutant group tended to have more hospitalizations (p = 0.067), and surgeries were significantly more frequent (p = 0.028). In ulcerative colitis, thiopurine discontinuation was associated with hospitalization and surgery, respectively (p = 0.003, HR 2.87, 95% CI 1.44 - 5.71, p = 0.036, HR 5.45, 95% CI 1.12 - 26.5). In Crohn's disease, the presence of SNPs was associated with hospitalization (p = 0.019, HR 3.68, 95% CI 1.24-10.97) and surgery (p = 0.036, HR 6.81, 95% CI 1.14 - 40.86).

Conclusion

In ulcerative colitis, it is important to continue thiopurine with fine-tuning of the dosage to avoid hospitalization and surgery. In Crohn's disease, a direct association between the NUDT15 SNP and hospitalization and surgery was demonstrated.

References

1. Yang, S. K. et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 46, 1017-1020, doi:10.1038/ng.3060 (2014).
2. Kojima, Y. et al. Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines. World J Gastroenterol 24, 511-518, doi:10.3748/wjg.v24.i4.511 (2018).
3. Coenen, M. J. H. et al. Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology 149, 907-917.e907, doi:10.1053/j.gastro.2015.06.002 (2015).
4. Hirotsu, Y. et al. Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next-generation sequencing. Mol Genet Genomic Med 3, 121-129, doi:10.1002/mgg3.120 (2015).
5. Sakamoto, I. et al. BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer. Cancer 122, 84-90, doi:10.1002/cncr.29707 (2016).
6. Hirotsu, Y. et al. Intrinsic HER2 V777L mutation mediates resistance to trastuzumab in a breast cancer patient. Med Oncol 34, 3 (2017).
7. Hirotsu, Y. et al. Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer. Mol Genet Genomic Med 3, 459-466 (2015).

Disclosure

The authors have no conflict of interest to declare. All co-authors have seen and agree with the contents of the manuscript, and there is no financial interest to declare.

Introduction

Therapeutic progress in inflammatory bowel disease (IBD) is limited by the lack of understanding of the pathophysiology and the mechanisms involved in response or lack/loss of response to treatments. IBD patients are treated with anti-inflammatory drugs, including biologics such as anti-tumor necrosis factor (TNF) agents, which have been crucial in achieving steroid-free remission and prevention of long-term complications. However, a significant subgroup of patients becomes refractory to these biologicals due to the development of immunogenicity, characterized by the presence of anti-drug antibodies (ADAs). The antibody production and peripheral tolerance are initiated and maintained within lymphoid organs, such as the peripheral lymph nodes, but the exact role of immune cells in these lymphoid structures and whether they are involved in anti-drug antibody (ADA) formation is unknown.

Aims & Methods

We aimed to unravel the pathophysiology behind the development of anti-drug antibodies. Therefore, we performed ultrasound-guided inguinal lymph node needle biopsies from which we isolated leukocytes along with PBMCs from the same patients. Leukocyte populations were analyzed at single cell level via high dimensional phenotyping through mass cytometry (CyTOF).

Results

Using this unique approach, we have so far results from 4 Crohn’s Disease (CD) patients with ADAs (75% females, 50% active disease) and 4 without ADAs (50% females, 75% active disease). Active disease was defined, as an observation of an elevated CRP (c-reactive protein) (>5 mg/L) and/or calprotectin >250 (mg/kg), including symptoms (Harvey-Bradshaw index score > 4 or disease activity index score-CDAI >150).
The proportion of CD4⁺ TEMRA (terminally differentiated effector memory T-cells), CD4⁺ effector and central memory T-cells were increased in the peripheral lymph nodes of patients that developed immunogenicity. Mature NK cells, classical and non-classical monocytes were also increased. Furthermore, the levels of the alpha-4 integrin expression were higher in the lymph node T-lymphocytes, as well as, in the lymph node naïve and memory B-cell subsets in the patient group with ADAs.

Table: Cytometry and Biochemical Characteristics.

Parameters	ADAs (n=4)	no ADAs (n=4)	p-value
Proportion of Lymph Node CD4+ TEMRA T-Cells; median (Range)	5.3 (1.05-16.5)	0.16 (0.1-0.39)	0.02
Proportion of Lymph Node CD4+ Effector Memory T-Cells; median (Range)	3.2 (0.64-7.2)	0.5 (0.14-1.37)	0.049
Proportion of Lymph Node Mature NK-Cells; median (Range)	4.04 (0.49-5.17)	0.08 (0.05-0.2)	0.029
Proportion of Lymph Node Classical Monocytes; median (Range)	4.8 (1.47-16.9)	0.8 (0.91-1.1)	0.027
Proportion of Lymph Node Non Classical Monocytes; median (Range)	6.9 (0.99-9.4)	0.9 (0.68- 0.99)	0.026
Mean alpha-4 Integrin Expression Levels (Effector T-cells)	1.61	0.87	0.03
Mean alpha-4 Integrin Expression Levels (Memory B-cells)	1.58	0.94	0.03
CRP (c-reactive protein) (mg/l); median (Range)	2.85 (0.5-8.5)	3.90 (0.7-14.75)	0.396
Calprotectin (mg/kg); median (Range)	650 (228-1130)	1007 (476-2037)	0.17

Conclusion

Lymph node T-helper cells, monocytes and NK cells potentially play a role in the development ADAs in IBD patients treated with biologics. Although, there was no significant difference in the proportion of naïve and memory B-cells, our findings concerning the alpha-4 integrin expression levels also indicate that both lymph node T and B-lymphocytes, are possibly characterized by a higher migratory potential during immunogenicity conditions.

References

1. Stein RE, Lee DY, Leonard MB, et al. The association between drug levels, anti-drug antibodies, and therapeutic response during infliximab therapy in pediatric Crohn’s disease. J Crohns Colitis 2014; 8: S434.
2. Bodini G, Savarino V, Dulbecco P, et al. The influence of anti-adalimumab antibodies on adalimumab trough levels, TNF-alpha levels and clinical outcome. J Crohns Colitis 2014; 8: S42
3. Stefan S, Sandborn WJ, Choi J, et al. Anti-drug antibodies separate responses of markers of inflammation (c-reactive protein, fecal calprotectin) in Crohn’s disease patients treated with certolizumab pegol. Inflamm Bowel Dis 2014; 20: S68.
4. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017;31(4):299-316. doi:10.1007/s40259-017-0231-8.
5. Brun MK, Goll GL, Jørgensen KK, et al. Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial. J Intern Med. 2022;292(3):477-491. doi:10.1111/joim.13495.

Disclosure

The authors state no conflict of interest.

Introduction

Inflammatory bowel disease (IBD) is characterized by chronic inflammation due to an uncontrolled immune response orchestrated through, i.e. neutrophils. The basement membrane acts as a front-line defense promoting tissue integrity, where the α-3 chain of type IV collagen is solely expressed on the outermost layer of the mucosa. Detection of subclinical ulceration is crucial since early-stage IBD presents a unique window of opportunity for intervention, as the disease might become a self-sustaining process once deep inflammation becomes established. We therefore, wanted to develop a biomarker reflecting early tissue injury, aiding in the implementation of prompt treatment.

Aims & Methods

A competitive enzyme-linked immunosorbent assay quantifying a human neutrophil elastase (HNE) degraded fragment of type IV collagen α-3 chain was developed (C4A3-HNE). Dilution- and spiking recovery, inter- and intra-variability, and interference were evaluated. Acceptance criteria for technical validation were a recovery of 100% ±25 and an inter-intra variability of <15%. Commercial serum samples were purchased from ProteoGenex. Biological relevance was validated in an observational study from Odense University Hospital (OUH) and healthy controls. Groups were compared using Kruskal Wallis (Dunn‘s corrected).

Results

The technical validation of the C4A3-HNE assay demonstrated acceptable results for recovery, variation, and interference. Biological relevance was assessed in commercial IBD samples and healthy donors. C4A3-HNE was elevated in both CD and UC compared to healthy (p=0.001 and <0.0001)(AUC [95% CI]: 0.820 [0.669-0.971]; 0.875 [0.775-1.000]). The results were validated in an independent cohort of IBD patients (both p<0.0001). For UC, analysis showed that compared to patients in endoscopic remission, C4A3-HNE is elevated in patients with mild endoscopic activity, decreasing dose-dependently for moderate and severe disease (T1). Fecal calprotectin and CRP levels were also lower in IBD patients with high levels of C4A3-HNE (T1). With a cut-off value of 54.1 ng/ml, C4A3-HNE could significantly discriminate between mild and severe endoscopic disease (T1).

	Median conc. (ng/ml)	[IQR]	Patients (n)
Remission Mild Moderate Severe	61.16 71.77 56.07 40.52	49.74, 65.52 53.96, 79.17 39.21, 68.71 25.65, 69.01	10 18 19 10
	Low C4A3-HNE	High C4A3-HNE	Δ %
CD: Fecal Calprotectin (µg/g) UC: Fecal Calprotectin (µg/g) CD: CRP (mg/L) UC: CRP (mg/L)	721.8 840.0 8.4 7.4	365.7 491.6 6.5 5.0	67.7 52.3 26.5 38.5
	AUC [95% CI]	Cut-off value	Sens./Spec. (%)	OR
Remission vs. mild Mild vs. moderate Mild vs. severe	0.68 [0.48–0.85] 0.68 [0.51–0.83] 0.74 (*) [0.54–0.89]	68.8 59.9 54.1	61.1/90.0 72.2/73.3 77.8/70.0	14.1 (*) [1.7–166.6] 6.9 (*) [1.8–31.1] 6.4 (*) [1.2–33.5]

Conclusion

Our study demonstrates the biological and possible clinical relevance of the novel C4A3-HNE biomarker. The biomarker is elevated in patients with IBD compared with healthy, and high levels may reflect early mucosal damage in patients with UC. Furthermore, inflammatory markers were lower in IBD patients with high levels of C4A3-HNE, pointing towards high levels being indicative of early disease. C4A3-HNE may provide early detection of mucosal damage or prediction of relapse; however, further studies are required to assess the clinical validity of this biomarker.

Disclosure

MA, MP, MK, and JM are employees of Nordic Bioscience A/S. MK owns stocks in Nordic Bioscience A/S.

Introduction

Ulcerative colitis (UC) is a refractory inflammatory bowel disease of the colon with repeated relapses and remissions that requires lifelong treatment. Previous studies indicated that proinflammatory cytokines involved the onsets and developments of UC. New treatments for targeting these cytokines, such as TNF-α, IL-12 and IL-23 have been developed in a recent decade, underlying that immune abnormalities are the core for the etiology of UC.
Platelets play a role not only in hemostatic coagulation but in inflammatory mediator by interacting with various cells in the innate and adaptive immunity. Chronic inflammatory response confers platelets activation leading to elevated platelet count and hypercoagulability. Moreover, platelets aggregates with leukocyte in active inflammatory milieu. In fact, thrombocytosis, thromboembolism and upregulation of platelet-monocyte complex (PMC) in UC patients have been reported, implying that platelets could be novel biomarker, therapeutic target and clues for elucidating the pathology of UC. However, the clinical significance of platelet activation and PMC formation in UC is not fully elucidated and few studies were conducted to assess how platelet activation contributes to disease aggravations of UC. Therefore, we comprehensively analyzed platelet activation and platelet-monocyte complex by focusing on a correlation with clinical severity of UC.

Aims & Methods

Patients with UC (n=70) including MES0-2 group (n=34) and MES3 group (n=27), diagnosed according to a combination of symptoms, endoscopic findings, histologic findings, and the absence of alternative diagnoses, and age and sex-matched healthy controls (HCs) (n =19) were enrolled for this study. We analyzed the surface markers such as CD62P, CD40L, CD63, PAC-1 and Annexin V on CD61+ platelets by flowcytometry (FCM) in patients with UC in comparison with those in healthy adults. We also analyzed the proportion of CD61+CD14+ platelet-monocyte complexes and quantified the activation of PMCs by FCM. Moreover, we also investigated the correlation among surface markers, proportion of platelet-monocyte aggregates and Mayo endoscopic score (MES) in UC patients.

Results

The expression of CD62P but not other surface markers on platelets was significantly upregulated in UC when compared to HCs (p<0.01), and was significantly upregulated in in MES3 group when compared to the MES0-2 group (P<0.001). The proportion of PMC was also higher in MES3 groups when compared to MES0-2 group (P<0.05), and was markedly reduced by treatment (P<0.05). In addition, CD16+ monocytes, phenotypically mature and pro-inflammatory cell population, were increased in patients with UC when compared to HCs (P<0.01). The expression of CD16 on monocytes aggregated with platelets was significantly higher when compered to that without platelet (P<0.001).

Conclusion

Our study suggests that platelet activation accelerates mucosal inflammation via adhesion with monocytes in UC and contributes to the aggravation of disease.

References

Semple JW, et al. Platelets and the immune continuum.
Nat Rev Immunol. 2011 Apr;11(4):264-74.
Collins CE, et al. Platelets circulate in an activated state in inflammatory bowel disease.
Gastroenterology. 1994 Apr;106(4):840-5.