Ellen G. van Lochem

Gout Is a Chronic Inflammatory Disease in Which High Levels of Interleukin-8 (CXCL8), Myeloid-Related Protein 8/Myeloid-Related Protein 14 Complex, and an Altered Proteome Are Associated With Diabetes Mellitus and Cardiovascular Disease.

The frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients.

Gout is a chronic inflammatory disease where high levels of interleukin 8 (CXCL8), MRP8/14 and an altered proteome associate with diabetes and cardiovascular disease

The frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients.

Naive T cells in the gut of newly diagnosed, untreated adult patients with inflammatory bowel disease.

Background:The phenotype of the T-cell subpopulations and their related cytokine networks in the gastrointestinal mucosa of patients with inflammatory bowel disease can potentially be used as a predictive value for clinical course and response to therapy. Here, we analyzed T-cell subpopulations in newly diagnosed, untreated adult patients and correlated them with clinical presentation. Methods:Mucosal biopsies from duodenum, ileum, and colon mucosa of patients with Crohns disease and ulcerative colitis and controls were obtained. The simple endoscopy score in Crohns disease and the full Mayo score in ulcerative colitis were used to score disease activity. Mucosa-infiltrating T cells were characterized by flow cytometric immunophenotyping and were stimulated to assess cytokine secretion. Results:Based on the expression of the maturation and activation markers CD45RA and CD27, we identified 4 different profiles. Profile A contained mainly CD45RA+CD27+ naive T cells; profile B contained mainly CD45RA−CD27+ central memory T cells; profile C contained mainly CD45RA−CD27− effector memory T cells; and profile D consisted of similar percentages of these aforementioned subpopulations. Profile A was only observed in the ileum/colon of patients with inflammatory bowel disease, associated with upper gastrointestinal location and perianal disease in Crohns disease and expressed more tumor necrosis factor &agr; and less interferon &ggr;. In contrast, profile D was restricted to controls. There was no correlation between the different T-cell profiles and endoscopic disease activity. Conclusions:Newly diagnosed patients with inflammatory bowel disease display different T-cell maturation profiles in the gut mucosa, corresponding to distinct cytokine responses. Follow-up studies are needed to determine whether the profiles associate with clinical course and response to therapy.

Prevalence of Upper Gastrointestinal Lesions at Primary Diagnosis in Adults with Inflammatory Bowel Disease.

Background:The prevalence of upper gastrointestinal (GI) involvement in adult inflammatory bowel disease has mostly been studied in patients with long-standing disease. The aim of this study was to prospectively evaluate the prevalence of upper GI involvement in a consecutive series of newly diagnosed, treatment-naive adult patients with inflammatory bowel disease, irrespective of upper GI tract symptoms. Methods:Consecutive patients with suspected inflammatory bowel disease underwent combined ileocolonoscopy and upper endoscopy with biopsies. Patients diagnosed with either Crohns disease (CD) or ulcerative colitis (UC), denying use of nonsteroidal anti-inflammatory drug, were included in the study. Helicobacter pylori infection was diagnosed histologically and positive patients were excluded from the analysis. Endoscopic and histologic lesions in the stomach and duodenum were recorded. Upper GI location (+L4) was defined as a combination of endoscopic and histological lesions. Results:A total of 152 patients (108 CD and 44 UC) were analyzed. Endoscopic lesions were only seen in patients with CD (60 of 108, 55%). Histological lesions were present in both patients with CD and patients with UC: focally enhanced gastritis in 58 CD (54%) and 10 UC (23%), granulomas in 30 CD (28%). Upper GI disease location was diagnosed in 44 patients with CD (41%) and no patients with UC. Upper GI tract symptoms were reported in 14 of 44 patients (32%) with upper GI location. Conclusions:A high prevalence of upper GI involvement was observed in newly diagnosed patients with CD, with a majority of the patients being asymptomatic. Focally enhanced gastritis was common in both patients with CD and patients with UC, whereas granulomatous inflammation was restricted to patients with CD.

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

Abstract: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.

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

Abstract 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.

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

Background and Aims More than half of patients with Crohns 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.

A pilot study of CXCL8 levels in crystal proven gout patients during allopurinol treatment and their association with cardiovascular disease

OBJECTIVES Gout is associated with cardiovascular diseases, and systemic inflammation has a role in this. CXCL8 (interleukin-8) levels were increased in synovial fluid of gout patients, and in serum in gout patients irrespective of their disease activity. We hypothesized that the well-known cardiovascular protective effects of allopurinol could be related to effects of this drug on CXCL8 levels. METHODS Patients with a crystal proven gout diagnosis, who newly started allopurinol treatment, were included in this prospective cohort study. After evaluation at baseline for cardiovascular diseases, tophi, uric acid, CRP and CXCL8 serum levels, patients were followed for changes in uric acid and CXCL8 levels. A subgroup analysis was performed in 10 patients with the longest follow-up period and at least 4 assessments of serum uric acid and CXCL8. RESULTS Sixty patients were included, and patients known with cardiovascular diseases at baseline had significantly higher CXCL8 and uric acid levels (P<0.01). In the whole group, median CXCL8 levels had not decreased after a median (IQR) follow-up of 27 (12-44) weeks (P=0.66). In the subgroup analysis in 9 out of 10 patients, CXCL8 levels showed a slight decrease, sometimes after an initial increase after a median (IQR) follow-up of 51 (45-60) weeks. CONCLUSIONS This pilot study indicates that higher CXCL8 levels were associated cardiovascular diseases in gout patients. Short-term use of allopurinol does not decrease CXCL8 levels in gout patients, but longer use possibly does. Further studies are warranted to establish the potential mechanisms of treatment and effects on CXCL8 levels.

Integrin αEβ7 in Inflammatory Bowel Disease: Friend or Foe?

1 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 Dear Editors: We read with great interest the article by Tew et al on the association between increased gene expression of integrin aE and granzyme A (GZMA) and clinical remission to etrolizumab treatment in patients with ulcerative colitis (UC). This report follows the recent publication of the phase II trial on etrolizumab, describing its moderate potential as induction therapy for UC. Etrolizumab is a humanized monoclonal immunoglobulin (Ig)G1 antibody that targets integrin subunit b7 and, therefore, both aEb7 and a4b7. It does not target GZMA expression. Baseline characteristics of the study by Tew et al showed statistically significant lower endoscopy and histology score in patients with aE gene expression compared with patients with aE gene expression. Moreover, a significant histologic improvement after etrolizumab was only found in the aE gene expression group and not in the aE gene expression group. The clinical relevance of these observations is denoted as unclear, but aE expression might in fact reflect an intrinsic protective immunologic mechanism in these patients. This opposes the emerging pathogenic role attributed to aEb7 in UC by Tew et al, based on, inter alia, an unpublished paper from 2014. The role of aEb7 in physiological conditions as well as in inflammatory bowel disease (IBD) is less distinct than that of the gut homing a4b7. In murine colitis anti-b7 has shown contradictory results. We recently showed that newly diagnosed, untreated IBD patients had significantly lower percentages of aEþ T cells in their actively inflamed intestinal biopsy specimen (Crohn’s disease 15% vs UC 11%) compared with healthy controls (30%; P 1⁄4 .02), challenging the pathogenic role in IBD. Furthermore, in contrast with the present study from Tew et al, which showed a higher gene expression of aE in anti-tumor necrosis factor–naïve clinical remitters, Arijs et al found no increased gene expression of aE or b7 in IBD patients when compared with healthy controls or infliximab responders. The gene expression of the principal ligand of aEb7, E-cadherin, was decreased in active colonic IBD when compared with healthy controls, and the use of this pathway as treatment target was seriously challenged in this paper. E-cadherin was also down-regulated in active UC in the phase II