Prevalence and Characteristics of Extra-intestinal Manifestations in a Large Cohort of Greek Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Extraintestinal manifestations [EIMs] are common in inflammatory bowel disease [IBD]. Data on epidemiology and risk factors of EIMs in IBD patients are limited. The aim of this study was to investigate the prevalence of EIMs in a large cohort of Greek IBD patients and identify risk factors for their development. METHODS: The study population consisted of IBD patients, who were followed in eight tertiary Greek hospitals. Demographic and clinical characteristics of patients were analysed. The diagnosis of EIMs was based on standard criteria and on specialist consultation. RESULTS: In total, 1860 IBD patients (1001 with Crohn's disease [CD], 859 with ulcerative colitis [UC]) were registered. Among them 615 [33.1%] exhibited at least one EIM; 238 patients [38.6%] developed an EIM before IBD diagnosis. An association between active IBD and presence of an EIM was established in 61.1% of the patients. Arthritic [peripheral arthritis], mucocutaneous [erythema nodosum], and ocular [episcleritis] were the most common manifestations. EIMs were more prevalent in females, patients with CD, smokers [for all p <0.0001], patients with extensive UC [p = 0.007], and patients with a previous appendectomy [p < 0.0001] or a major IBD-related surgery [p = 0.012]. CONCLUSIONS: About one-third of Greek IBD patients developed at least one EIM. Of those, more than one-third had their EIM diagnosed before IBD, and in about two-thirds it was related to disease activity. EIMs were more frequently present in females and patients with extensive UC in multivariate analysis.

Lower fibroblast growth factor 23 levels in young adults with Crohn disease as a possible secondary compensatory effect on the disturbance of bone and mineral metabolism.

Fibroblast growth factor 23 (FGF-23) is a bone-derived circulating phosphaturic factor that decreases serum concentration of phosphate and vitamin D, suggested to actively participate in a complex renal-gastrointestinal-skeletal axis. Serum FGF-23 concentrations, as well as various other laboratory parameters involved in bone homeostasis, were measured and analyzed with regard to various diseases and patients' characteristics in 44 patients with Crohn disease (CD) and 20 healthy controls (HCs) included in this cross-sectional study. Serum FGF-23 levels were significantly lower in patients with CD (900.42 ± 815.85pg/mL) compared with HC (1410.94 ± 1000.53pg/mL), p = 0.037. Further analyses suggested FGF-23 as a factor independent from various parameters including age (r = -0.218), body mass index (r = -0.115), 25-hydroxy vitamin D (r = 0.126), parathyroid hormone (r = 0.084), and bone mineral density (BMD) of hip and lumbar (r = 0.205 and r = 0.149, respectively). This observation remained even after multivariate analyses, exhibiting that BMD was not affected by FGF-23, although parameters such as age (p = 0.026), cumulative prednisolone dose (p < 0.0001), and smoking status (p = 0.024) were strong determinants of BMD regarding hip. Lower FGF-23 levels in patients with bowel inflammation are accompanied but not directly correlated with lower vitamin D levels, showing no impact on BMD determination of young adults with CD. The downregulation of serum FGF-23 levels in CD appears as a secondary compensatory effect on the bone and mineral metabolism induced by chronic intestinal inflammation.

Readressing the role of Toll-like receptor-4 alleles in inflammatory bowel disease: colitis, smoking, and seroreactivity.

BACKGROUND: Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. AIMS: To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. METHODS: TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. RESULTS: UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). CONCLUSIONS: The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles.

Drug-induced nephrotoxicity in inflammatory bowel disease.

Conservative management of inflammatory bowel disease (IBD) is based on a combination of drugs, including aminosalicylates (ASAs), steroids, antibiotics, immunosuppressives and biologic agents. Although various side effects have been related to treatment regimens, drug-induced nephrotoxicity is rather uncommon. Furthermore, it is often underestimated since renal function deterioration may be attributed to the underlying disease. The nephrotoxicity of ASAs and cyclosporine A seems well established, but recent data have suggested a possible role of biologic agents such as infliximab and adalimubab in renal impairment. The aim of this review is to summarize the nephrotoxic effects of medical treatment as well as to express possible caveats in the administration of novel agents in IBD.

Angiogenin, angiopoietin-1, angiopoietin-2, and endostatin serum levels in inflammatory bowel disease.

BACKGROUND: Angiogenesis is a complex process, involving a great number of mediators. It is implicated in the pathogenesis of numerous diseases, holding a critical role in inflammatory bowel disease (IBD). The objective of this study was to assess serum levels of angiogenin, angiopoietin-1, angiopoietin-2, and endostatin in IBD patients. METHODS: Measurement of all angiogenesis mediators was performed with a commercially available enzyme-linked immunosorbent assay. Fifty-two patients with ulcerative colitis (UC), 59 with Crohn's disease (CD), and 55 healthy controls (HC) were included in the study. The values were analyzed with regard to disease and patients characteristics. RESULTS: Angiogenin levels were significantly higher in IBD patients compared to HC (P < 0.001) and in UC and CD smoker patients compared to nonsmokers (P = 0.0121 and P = 0.005, respectively). Angiogenin levels were lower in UC patients receiving 5-aminosalicylate (5-ASA) alone, compared to those receiving combined therapy (P = 0.0478). Angiopoietin-1 levels were significantly lower in IBD patients compared to HC (P < 0.0001) and increased in smokers compared to nonsmoker UC patients (P = 0.0085). IBD patients demonstrated increased angiopoietin-2 levels compared to HC (P = 0.0131), while CD patients with disease restricted to the colon had significantly lower levels compared to other disease locations (P < 0.0001). Higher endostatin levels were recorded in UC patients with extensive colitis. CONCLUSIONS: Elevated serum angiogenin and angiopoietin-2 levels and lower serum angiopoietin-1 levels were shown in IBD patients, as well as a different pattern of angiogenic factor alterations related to location, treatment, smoking habits and gender.

Downregulation of serum epidermal growth factor in patients with inflammatory bowel disease. Is there a link with mucosal damage?

BACKGROUND: Epidermal growth factor (EGF) is a multipotent peptide which contributes to epithelial development, inhibition of gastric acid secretion, acceleration of wound healing, and promotion of angiogenesis. The aim of this study is to evaluate serum EGF concentrations in inflammatory bowel disease (IBD) patients, with regard to disease and patients' characteristics. METHODS: EGF determination was performed by a commercially available enzyme-linked immunosorbent assay. Fifty-two patients with ulcerative colitis (UC), 59 with Crohn's disease (CD), and 55 healthy controls (HC) were included in the study. RESULTS: Mean ( ± SEM) serum EGF levels were 217.2 ( ± 30.40) pg/mL in UC patients, 324.6 ( ± 37.29) pg/mL in CD patients, and 453.1 ( ± 39.44) pg/mL in HC. Serum EGF levels were significantly lower in UC and CD patients compared to HC (P < 0.0001 and P = 0.0199, respectively). Lower serum EGF levels were observed in UC compared to CD patients (P = 0.0277). Extent of the disease was found to affect serum EGF levels in UC, demonstrating significant reduction in patients with left-sided colitis and pancolitis in comparison with those with proctitis (P = 0.0190 and P = 0.0024, respectively). EGF concentration was not influenced by other characteristics of patients and disease. CONCLUSIONS: Significantly, lower levels of serum EGF are observed in IBD patients compared to HC, while disease extent plays a key role in regulation of serum EGF in UC. Downregulation of serum EGF may be correlated with different patterns of bowel inflammation, epithelial development, and wound healing in IBD.