Prevalence of Joint Hypermobility and Patterns of Articular Manifestations in Patients with Inflammatory Bowel Disease

Objective. The objective is the investigation of Joint Hypermobility (JH) and the Hypermobility Syndrome (HMS) in patients with inflammatory bowel disease (IBD). Methods. We examined 83 patients with IBD and 67 healthy individuals for the presence of JH. Patients were excluded if they were under 18 or over 50 years of age and if they had other conditions which affect joint mobility. The x2 and the Fisher exact test were used appropriately between study groups. Odds ratios (ORs) for the risk of JH and HMS in IBD groups were calculated. Results. A total of 150 individuals (83 IBD patients and 67 healthy controls) participated in the study. 69 IBD patients, 41 with Crohn's Disease (CD) and 28 with ulcerative colitis (UC), were finally eligible. JH was detected in 29 CD patients (70.7%), in 10 UC patients (35.7%), and in 17 healthy control subjects (25.4%). Significant difference was detected on JH in CD patients as compared to UC patients (P = .0063) and controls (P < .0001). The estimated OR for JH was 7.108 (95% CI: 2.98–16.95) in CD and 1.634 (95% CI: 0.63–4.22) in UC patients. HMS was detected in 5 (12.2%) CD and in 1 (3.57%) UC patients. The OR for HMS in CD was 3.75 (95% CI: 0.41–34.007), while 7 (17.1%) CD patients had overlapping symptoms for both HMS and early spondylarthropathy. Conclusions. JH and the HMS are common in CD patients, thus articular manifestations should be carefully interpreted. This implies an involvement of collagen varieties in the pathogenesis of IBD

Development of primary malignant melanoma during treatment with a TNF-&alpha; antagonist for severe Crohn&rsquo;s disease: a case report and review of the hypothetical association between TNF-&alpha; blockers and cancer

George Kouklakis,1 Eleni I Efremidou,2 Michael Pitiakoudis,3 Nikolaos Liratzopoulos,2 Alexandros Ch Polychronidis2 1Endoscopy Unit, 2First Surgical Department, 3Second Surgical Department, Medical School, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece Abstract: It is recognized that immunosuppression may lead to reduced immune surveillance and tumor formation. Because of the immunosuppressive properties of tumor necrosis factor (TNF)-alpha (TNF-&alpha;) antagonists, it is plausible that these biologics may increase the risk of the occurrence of malignancies or the reactivation of latent malignancies. TNF-&alpha; antagonists have gained momentum in the field of dermatology for treating rheumatoid arthritis and psoriasis, and they have revolutionized the treatment of other inflammatory autoimmune diseases such as refractory Crohn&#39;s disease. However, there is accumulating evidence that TNF-&alpha; inhibitors slightly increase the risk of cancer, including malignant melanoma (MM). The authors herein report the case of a 54-year-old female patient who developed a primary MM during treatment with adalimumab for severe Crohn&rsquo;s disease resistant to successive medical therapies. The patient had been receiving this TNF-&alpha; blocker therapy for 3 years before the occurrence of MM. After wide surgical excision of the lesion and staging (based on Breslow thickness and Clark level), evaluation with a whole-body computed tomography scan was negative for metastatic disease. The long duration of the adalimumab therapy and the patient&#39;s lack of a predisposition to skin cancer suggest an association between anti-TNF-&alpha; drugs and melanocytic proliferation. The authors also review the literature on the potential association between anti-TNF regimens and the occurrence of malignancies such as melanocytic proliferations. There is a substantial hypothetical link between anti-TNF-&alpha; regimens such as adalimumab and the potential for cancers such as melanoma. However, the risk of malignancy with biological therapy remains to be established, and most of the relevant studies have lacked the statistical power and randomization required for large clinical trials. Further long-term controlled clinical trials and registries are required to investigate this potentially serious association. Keywords: adalimumab, tumor necrosis factor alpha, melanocytic proliferation, causal relationshi

Cytokine receptor profiling in human colonic subepithelial myofibroblasts: A differential effect of Th polarization-associated cytokines in intestinal fibrosis

Background: Colonic subepithelial myofibroblasts (cSEMFs) are mesenchymal cells with a pivotal role in the pathophysiology of Crohn&apos;s disease (CD) fibrosis. Here, we demonstrate for the first time a complete expression mapping of cytokine receptors, implicated in inflammatory bowel diseases, in primary human cSEMFs and how pro-inflammatory cytokines regulate this expression. Furthermore, we show the effect of Th1-, Th2-, Th17- and Treg-related cytokines on a fibrosis-related phenotype of cSEMFs. Methods: Colonic subepithelial myofibroblasts were isolated from healthy individuals&apos; colonic biopsies. Interleukin (IL)-1α- and/or tumor necrosis factor (TNF)-α-induced mRNA and protein expression of cytokine receptors was assayed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunofluorescence, respectively. Th-related cytokine effects on mRNA and protein profibrotic factor expression were analyzed by qRT-PCR and/or colorimetric assays and on the wound-healing capacity of cSEMFs by scratch test. Results: In cSEMFs, we observed basal cytokine receptor expression, which was modified by IL-1α and TNF-α. Th1-related cytokines upregulated tissue factor (TF), collagen, fibronectin and matrix metalloproteinase (MMP)-1 and downregulated α-smooth muscle actin (α-SMA), MMP-9, and wound healing rate. Th2-related cytokines upregulated collagen, TF, α-SMA, MMP-1, and wound healing rate and downregulated fibronectin and MMP-9. IL-17 and IL-23 upregulated fibronectin, and IL-22 downregulated TF. IL-17 and IL-22 decreased wound healing rate. Similar to TGF-β, IL-23 upregulated MMP-1, tissue inhibitor of metalloproteinases-1, collagen expression, and wound healing rates. Conclusions: Our results suggest that cSEMFs have a central role in inflammation and fibrosis, as they express a great variety of Th-related cytokine receptors, making them responsive to pro-inflammatory cytokines, abundant in the inflamed mucosa of CD patients. © 2018 Crohn&apos;s &amp; Colitis Foundation. Published by Oxford University Press. All rights reserved

Crohn&apos;s disease-associated mucosal factors regulate the expression of TNF-like cytokine 1A and its receptors in primary subepithelial intestinal myofibroblasts and intestinal epithelial cells

Intestinal subepithelial myofibroblasts (SEMFs) exert a profibrotic role in Crohn&apos;s disease (CD). Tumor necrosis factor-like cytokine 1A (TL1A) and its receptors, death-domain receptor 3 (DR3) and decoy receptor 3 (DcR3), are mucosal factors with significant involvement in experimental inflammation and CD. We aimed to determine the regulation of expression of this system of proteins in SEMFs and intestinal epithelial cells. The relative amount of mRNA transcripts for TL1A, DR3, and DcR3 was measured by real-time reverse transcription polymerase chain reaction in cultured primary SEMFs, colonic myofibroblast cell line 18CO, and epithelial cell line HT29. Protein expression was determined by immunofluorescence. The effect of various proinflammatory stimuli in mRNA and protein expression was studied. TL1A mRNA and protein expression in primary SEMFs (and 18CO cells) was significantly upregulated after stimulation with interleukin 1-alpha and/or tumor necrosis factor alpha (TNF-α) (32- to 44-fold increase, P &lt; 0.05 vs unstimulated). Following stimulation with interleukin 1-alpha + TNF-α + IFN-γ, HT-29 cells highly expressed DR3 (4.1-fold over unstimulated, P = 0.008) and DcR3 (56-fold, P = 0.009) and secreted soluble factors that led to induction of TL1A mRNA in primary SEMFs (28-fold, P = 0.008). Activated epithelial cells significantly upregulated IL-8 expression in response to stimulation with recombinant TL1A. Supernatants from mucosal cultures of patients with CD were able to stimulate the expression of TL1A in cultured primary SEMFs, in comparison to supernatants from healthy controls (3.8-fold increase, P &lt; 0.05) or culture media alone (P &lt; 0.05). In conclusion, we found that proinflammatory cytokines are important regulators of the expression of TL1A in SEMFs and of its receptors in intestinal epithelial cells. Our results raise the possibility for involvement of TL1A/DR3/DR3-mediated mechanisms in epithelial-mesenchymal interactions and the development of inflammation-induced intestinal fibrosis in CD. © 2016 Elsevier Inc

Phase I/II trial of bevacizumab and radiotherapy for locally advanced inoperable colorectal cancer: vasculature-independent radiosensitizing effect of bevacizumab.

PURPOSE: Anti-vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models, and bevacizumab has therapeutic activity in patients with metastatic colorectal cancer. EXPERIMENTAL DESIGN: Twenty-two patients with locally advanced inoperable colorectal carcinomas (LA/I-CRC) were treated with conformal hypofractionated (3.4 Gy/fraction x 15) split-course accelerated radiotherapy (biological equivalent dose, 67.2 Gy) supported with amifostine, capecitabine (600 mg/m2 daily, 5 days/week), and bevacizumab (5 mg/kg every 2 weeks, five cycles). Biopsies from nine patients, performed before and 1 week after bevacizumab administration, were analyzed for changes in mRNA expression with Illumina gene arrays. RESULTS: No serious grade 3 chemotherapy-related side effects were recorded. There was low acute toxicity, with moist perineal desquamation noted in 2 of 22 patients, diarrhea grade 2 to 3 in 5 of 22 patients, and severe proctalgia in 2 of 22 patients. One patient died from Fournier's gangrene before treatment completion. Within a median follow-up of 18 months, two patients with preradiotheraphy direct involvement of adjacent organs expressed recto-vaginal/perineal fistula. Out of 19 evaluable cases, 13 (68.5%) showed complete response and 4 showed (21.1%) partial response. Fourteen patients are alive with no evidence of loco-regional relapse. In the gene array analysis, 30 known genes associated with transcription factors, DNA repair, and proliferation were downregulated by bevacizumab. DUSP1 gene was the most consistently downregulated transcript. CONCLUSIONS: The combination of radiotherapy with bevacizumab is feasible and results in a high rate of durable complete responses in patients with LA/I-CRC. Radiosensitization may occur through a direct effect on tumor cells followed by a wide scale suppression of transcription factors and genes involved in DNA repair and proliferation

Effects of rabeprazole on early symptom relief in gastro-oesophageal reflux disease: the Hellenic Rabeprazole Study Group surveillance study

Background: In controlled clinical trials, rabeprazole effectively improves symptoms and heals oesophageal erosions in patients with gastro-oesophageal reflux disease (GORD). Aim: To examine symptom relief during week 1 of rabeprazole therapy, in addition to GORD healing, in a clinical practice setting. Methods: In this 8-week, prospective, multicentre, postauthorisation surveillance study conducted in Greece, patients with GORD (intent-to-treat: efficacy, 272; safety, 273) were treated with rabeprazole 20 mg once daily. The primary efficacy end point was the change from baseline in GORD symptom severity on day 1, 2, 3 and 7 using a 5-point Likert scale (1 = no symptoms; 5 = severe symptoms). Oesophageal healing was also evaluated by comparing the results of endoscopic findings at baseline and after 4 and 8 weeks of treatment. Results: On day 1 of treatment, rabeprazole relieved GORD symptoms across all grades of oesophagitis, with statistically significant (p = 0.0001) improvement in heartburn, regurgitation, epigastric pain and dysphagia. Oesophageal healing was achieved in 77% of patients at week 4 and in 90% at week 8 and treatment was well tolerated. Conclusions: In a clinical practice setting, rabeprazole provided rapid relief of GORD symptoms, confirming results seen in controlled clinical trials