Distribution of mucosal PD-1 expressing T cells in patients with colitis of different etiologies.

BACKGROUND: Immunotherapy, targeting programmed death-1 (PD-1) enhances antitumor T-cell activity in patients with malignancies. Blocking PD-1 or its ligand may lead to fulminant colitis as serious adverse event in these patients. Since little is known of the presence and role of PD-1+T cells in colitis of different etiologies, we determined PD-1+T cells in mucosal specimens of patients with inflammatory bowel disease, infectious colitis (InfC), immunotherapy-related colitis (ImC) and healthy controls (HC). METHODS: Newly diagnosed patients with ulcerative colitis (UC, n = 73), Crohn's disease (CD, n = 50), InfC (n = 5), ImC (n = 8) and HC (n = 8) were included. Baseline inflamed colonic biopsies were studied with immunohistochemistry and flowcytometry. RESULTS: Using immunohistochemistry, PD-1 was not present on lymphocytes in the epithelium of all patients, nor in HC. The percentage PD-1+ of all lymphocytes in the lamina propria was 40% in UC, 5% in InfC, 3% in ImC and 0% in HC. Flowcytometry showed significant higher percentages of PD-1+T cells in inflamed biopsy specimens of UC patients (22%) compared to all other groups: CD patients (13%), InfC (12%), ImC (5%) and HC (6%). CONCLUSION: There are relevant differences in distribution and frequencies of mucosal PD-1+ T-cell subsets in patients with UC, CD, InfC and ImC, supporting the hypothesis that these types of colitis are driven by different immunological pathways. The increased numbers of PD-1+ and PD-L1+ lymphocytes in the colonic mucosa of UC patients suggest that the PD-1/PD-L1 pathway might be more activated in UC than in CD.

A comparison of the diagnostic value of MRI and 18F-FDG-PET/CT in suspected spondylodiscitis.

PURPOSE: The purpose of this study was to evaluate the diagnostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT scan) and magnetic resonance imaging (MRI) in diagnosing spondylodiscitis and its complications, such as epidural and paraspinal abscesses. METHODS: From January 2006 to August 2013 patients with a clinical suspicion of spondylodiscitis, with an infection, or with fever of unknown origin were retrospectively included if 18F-FDG-PET/CT and MRI of the spine were performed within a 2-week time span. Imaging results were compared to the final clinical diagnosis and follow-up data were collected. RESULTS: Sixty-eight patients were included of whom 49 patients were diagnosed with spondylodiscitis. MRI showed an overall sensitivity of 67 % and specificity of 84 %. Diagnostic accuracy was 58 %, when MRI was performed within 2 weeks after the start of symptoms and improved to 82 %, when performed more than 2 weeks after onset of symptoms. 18F-FDG-PET/CT showed a sensitivity of 96 % and a specificity of 95 %, with no relation to the interval between the scan and the start of symptoms. CONCLUSIONS: As compared to MRI, 18F-FDG-PET/CT has superior diagnostic value for detecting early spondylodiscitis. After 2 weeks both techniques perform similarly.

The value of serum antibodies in differentiating inflammatory bowel disease, predicting disease activity and disease course in the newly diagnosed patient.

BACKGROUND: Data on serum antibodies in untreated adult inflammatory bowel disease (IBD) patients at diagnosis are scarcely available, and results on the stability of antibody presence over time are inconsistent. Our aim was to investigate antibodies in newly diagnosed, untreated IBD patients in relation to disease phenotype and course. Furthermore, we analyzed antibody presence over time. METHODS: Baseline anti-Saccharomyces cerevisiae antibodies (ASCA), anti-chitobioside carbohydrate antibodies (ACCA), anti-laminaribioside carbohydrate antibodies (ALCA) and anti-mannobioside carbohydrate antibodies (AMCA) were measured with enzyme-linked immunosorbent assays and perinuclear anti-neutrophilic cytoplasmic antibodies (pANCA) was measured by indirect immunofluorescence in serum of 120 untreated IBD patients at diagnosis and 19 healthy controls. Antibodies were related to disease outcomes. Serial measurements were available in 71 patients. RESULTS: The combination of pANCA and ASCA enabled good discrimination between UC and CD (p = .004). Antibody presence was relatively stable over time, even though there were significant changes in concentrations. There was a trend towards larger fluctuations in concentration with immunosuppressive medication. Baseline pANCA in UC patients correlated with calprotectin values (rho = .545, p = .019) and change in pANCA status over time was associated with disease activity at that moment. No associations were found with antibodies at diagnosis and disease outcomes. CONCLUSION: Antibody profiles at diagnosis support the distinction between CD and UC. Anti-glycan antibodies are reasonably stable over time, but may fluctuate under the influence of immunosuppressive treatment which may explain the inconsistency in findings hitherto. The appearance or disappearance of pANCA antibodies during follow-up correlated with disease activity in UC and may be used in disease monitoring.

Mucosal α4ß7+ Lymphocytes and MAdCAM+ Venules Predict Response to Vedolizumab in Ulcerative Colitis.

BACKGROUND: Therapeutic strategies for patients with ulcerative colitis (UC) are based on patient- and disease-related factors in combination with drug characteristics but fail to predict success in individual patients. A considerable proportion of UC patients do not respond to the biological vedolizumab. Therefore, pretreatment biomarkers for therapeutic efficacy are urgently needed. Mucosal markers related to the integrin-dependent T lymphocyte homing could be potent predictors. METHODS: We prospectively included 21 biological- and steroid-naive UC patients with moderate-to-severe disease activity planned to escalate therapy to vedolizumab. At week 0, before initiating treatment, colonic biopsy specimens were obtained for immunophenotyping and immunohistochemistry. Clinical and endoscopic disease activity were determined at week 16 after 4 infusions of vedolizumab. In addition, we retrospectively included 5 UC patients who were first treated with anti-tumor necrosis factor α before receiving vedolizumab to compare with biological-naive patients. RESULTS: Abundance of α4ß7 on more than 8% of all CD3+ T lymphocytes in colonic biopsies at baseline was predictive for responsiveness to vedolizumab (sensitivity 100%, specificity 100%). The threshold for the proportion of MAdCAM-1+ and PNAd+ of all venules in the biopsies predictive for responsiveness to vedolizumab was ≥2.59% (sensitivity 89%, specificity 100%) and ≥2.41% (sensitivity 61%, specificity 50%), respectively. At week 16, a significant decrease of α4ß7+CD3+T lymphocytes was demonstrated in responders (18% [12%-24%] to 8% [3%-9%]; P = .002), while no difference was seen in nonresponders (4% [3%-6%] to 3%; P = .59). CONCLUSIONS: UC responders to vedolizumab have a higher percentage of α4ß7+CD3+ T lymphocytes and a higher proportion of MAdCAM-1+ venules in colonic biopsies than nonresponders before initiating therapy. Both analyses could be promising predictive biomarkers for therapeutic response and may lead to more patient tailored treatment in the future.

Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis.

PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%-8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6-10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4-10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.

Intestinal CD103+CD4+ and CD103+CD8+ T-Cell Subsets in the Gut of Inflammatory Bowel Disease Patients at Diagnosis and During Follow-up.

BACKGROUND: The integrin CD103 is proposed to be a potential therapeutical target in inflammatory bowel disease (IBD), as it can form a heterodimeric integrin with ß7 (Etrolizumab, anti-ß7 integrin) on epithelial T cells. Therefore, we aimed to study the frequencies of different intestinal CD103+T-cell subsets, both CD4+ and CD8+, in newly diagnosed, untreated IBD patients at baseline and during follow-up, compared with healthy controls. METHODS: Intestinal biopsies from inflamed segments during colonoscopy and peripheral blood samples were prospectively taken from IBD patients at diagnosis and during follow-up. Blood and single cell suspensions from biopsies were analyzed for CD103+ T-cell subpopulations by flow cytometry and expressed as median percentages of the total T-cell population. RESULTS: In total, 75 Crohn's disease (CD) patients, 49 ulcerative colitis (UC) patients, and 16 healthy controls were included. At presentation, IBD patients displayed lower percentages of CD103+T-cell subsets in inflamed biopsies: 3% (1 to 5) CD103+CD4+ in IBD vs 5% (5 to 7) in healthy controls (P = 0.007) and 9% (4 to 15) CD103+CD8+ compared with 42% (23 to 57) in healthy controls (P = 0.001). The majority of intestinal T cells was composed of CD103-CD4+ T cells (65% [52 to 74]) in IBD compared with 30% (21 to 50) in healthy controls (P = 0.001). In patients with endoscopic remission during follow-up (n = 27), frequencies of CD103+ and CD103-T-cell subsets were comparable with healthy controls. CONCLUSION: At diagnosis, active inflammation in IBD was associated with decreased percentages of both CD103+CD4+ and CD103+CD8+T-cell subsets in colon and ileum biopsies. In active disease during follow-up, these T-cell populations remained low but increased in remission to values comparable with healthy controls. A shift toward more CD103-T cells was observed during active inflammation.

Inflammatory Bowel Disease Is Not a Contraindication for Bariatric Surgery.

BACKGROUND: Inflammatory bowel diseases (IBD) are listed as a contraindication for bariatric surgery in various guidelines due to a theoretical higher complication risk. Therefore, little is known about safety and efficacy of bariatric surgery in IBD patients. AIM: We assessed the safety and efficacy of bariatric surgery and postoperative quality of life (QoL) in IBD patients. SETTING: The study was conducted in a large peripheral hospital in the Netherlands. METHODS: All IBD patients who underwent bariatric surgery in our facility were included. Complications, mortality, reoperations, and micronutrient deficiencies were analyzed. Weight loss was assessed 6, 12, and 24 months after surgery. Postoperative QoL was assessed using a disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: Forty-five patients were included in this study, all diagnosed with IBD (16 ulcerative colitis (UC) and 29 Crohn's disease (CD)) prior to bariatric surgery. Bariatric procedures included Roux-en-Y gastric bypass, sleeve gastrectomy, gastric banding, and revisional surgery. There was no mortality in the entire follow-up period and there were no major perioperative complications. Two major complications in two CD patients occurred during follow-up, gastro-enterostomy bleeding and pyelonephritis with secondary pancreatitis. Mean percentage (± SD) of overall excess weight loss (%EWL) and total body weight loss (%TBWL), 12 months after surgery, were 62.9 ± 27.1 and 26.2 ± 10.6%, respectively. Twenty-four months postoperatively, mean overall %EWL and %TBWL were similar for both UC and CD patients and were 62.9 ± 31.0 and 26.6 ± 12.2, respectively. Mean Bariatric Analysis and Reporting Outcome System (BAROS) score was 3.34 ± 2.42. Median total IBDQ score was 170.8 (min. 77; max. 218). Both scores did not differ significantly between UC and CD patients. CONCLUSION: As bariatric procedures appear safe and effective in this CU and CD population, one could question why bariatric surgery is contraindicated in the patients. Nevertheless, close lifelong monitoring to assure safety and a favorable outcome remains essential.

Intestinal T Cell Profiling in Inflammatory Bowel Disease: Linking T Cell Subsets to Disease Activity and Disease Course.

INTRODUCTION: A dysregulated intestinal T cell response is presumed in patients with inflammatory bowel disease [IBD]. In this longitudinal study, we investigated the changes in intestinal T lymphocyte subsets in IBD at first presentation and over time during endoscopic active or inactive disease, and relate them to disease activity and outcome. METHODS: We included 129 newly diagnosed patients (87 Crohn's disease [CD], 42 ulcerative colitis [UC]) and 19 healthy controls [HC]. Follow-up biopsy specimens were analysed from 70 IBD patients. Immunophenotyping of specimens was performed by flow cytometry identifying lymphocyte subpopulations. RESULTS: IBD patients at diagnosis displayed higher percentages of CD4 T+ cells, Tregs, and central memory T cells [TCM] and with lower percentages of CD8 and CD103 T lymphocytes than HC. Follow-up specimens of patients with endoscopic inactive disease showed T cell subset recovery comparable to HC. Endoscopic active disease at follow-up coincided with T cell subsets similar to those at diagnosis. In UC, lower baseline percentages of CD3 cells was associated with milder disease course without the need of an immunomodulator, whereas in CD, higher baseline percentages of CD4 and Tregs were associated with complicated disease course. CONCLUSIONS: The intestinal T cell infiltrate in IBD patients with active endoscopic disease is composed of increased percentages of CD4+ T cells, Tregs, and TCM, with lower percentages of CD8+ T cells and CD103+ T cells, compared with HC and endoscopic inactive IBD. Baseline percentages of CD3, CD4, and Tregs were associated with disease outcome. Further research is needed to demonstrate the predictive value of these lymphocyte subsets.

The Complexity of alpha E beta 7 Blockade in Inflammatory Bowel Diseases.

Monoclonal antibodies targeting integrins are emerging as new treatment option in inflammatory bowel diseases. Integrins are molecules involved in cell adhesion and signalling. After the successful introduction of anti-α4ß7, currently anti-ß7 is under evaluation in a phase three trial. Anti-ß7 blocks both α4ß7/MAdCAM-1 and αEß7/E-cadherin interaction, targeting both the homing to and the retention in the gut of potential pathological T cells. Since the physiological and potential pathological roles of immune cells expressing αEß7 are less distinct than of those expressing α4ß7, an overview of the current state of knowledge on αEß7 in mice and humans in both health and inflammatory bowel diseases is presented here, also addressing the potential consequences of anti-ß7 treatment.

Candidate Serum Markers in Early Crohn's Disease: Predictors of Disease Course.

BACKGROUND AND AIMS: More than half of patients with Crohn's disease [CD] develop disease complications requiring aggressive medical therapy or surgery over time. However, predicting disease course and treatment response remains difficult. We therefore identified distinctive serum analytes associated with disease activity and course in newly diagnosed, untreated patients at presentation and during their follow-up. METHODS: In a pilot study, a multiplex immunoassay analysis on 36 markers was performed on serum from 20 CD patients at the time of primary diagnosis following endoscopic evaluation. The 12 most potent markers associated with disease activity, phenotype and course were analysed in a consecutive cohort of 66 CD patients at diagnosis and follow-up [n = 39]. A healthy control group [n = 20] was included as a reference. RESULTS: CD patients had higher baseline levels of sTNF-R2 [p = 0.001], sIL-2R [p = 0.0001], and MMP-1 [p = 0.001] compared with healthy controls. Serial measurements revealed that these three analytes dropped statistically significantly from baseline level during remission and were high during exacerbation. Great decline of sTNF-R1 levels was found during remission, with 6.7-fold lower levels than in healthy controls [p = 0.015]. Patients who did not respond to initial prednisone treatment had higher baseline levels of sTNF-R2 [p = 0.001]. Patients experiencing relapses during follow-up had lower baseline sTNF-R2 and VCAM levels compared with patients with long-lasting remission. CONCLUSIONS: In a large cohort of newly diagnosed untreated CD patients, we identified candidate serum markers [sTNF-R1, sTNF-R2, sIL-2R, and MMP-1] associated with disease activity. Furthermore, sTNF-R2 was associated with prednisone response and, together with VCAM, with long-lasting remission.

On naivety of T cells in inflammatory bowel disease: a review.

: Little is known about different phases of T-cell maturation in gut mucosa. Based on current knowledge about the migratory pathways of naive and memory T cells, it is believed that access to peripheral, nonlymphoid tissues is restricted to memory T cells. Surprisingly, there is increasing evidence of high numbers of naive T cells in the chronically inflamed gut tissue of patients with inflammatory bowel disease. This could partially be explained by new formation of ectopic lymphoid organs. Ongoing recruitment of naive T cells at inflammatory sites might play a role in the immunopathogenesis of inflammatory bowel disease.