Correlation of ex vivo cytokine secretion profiles with scoring indices in ulcerative colitis.

BACKGROUND: In ulcerative colitis, the complexity of mucosal cytokine secretion profiles and how they correlate with endoscopic and clinical scores is still unclear. METHODS: In this study, we collected fresh biopsies from UC patients to investigate which cytokines are produced in ex vivo culture conditions, a platform increasingly used for testing of novel drugs. Then, we correlated cytokine production with several scoring indices commonly used to assess the severity of the disease. RESULTS: Increased levels of IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNFα and IFNÉ£ were produced by biopsies of UC patients compared to non-IBD controls. Our results show a better correlation of cytokine levels with Mayo Endoscopic Subscore (MES) and Mayo score, than the more complex Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Out of 10 measured cytokines, eight correlated with MES, six with Mayo score and only three with UCEIS, due to the partial increase in cytokine secretion observed in donors with UCEIS = 7-8. When we analysed individual subscores within the UCEIS, Vascular Network subscore showed a correlation similar to MES (7/10 cytokines), while Bleeding as well as Erosions and Ulcers subscores correlated with only 3/10 cytokines, similarly to the total UCEIS. CONCLUSIONS: Our findings suggest that choosing biopsies from donors with MES = 2-3 and UCEIS = 2-6 from areas with no bleeding and no superficial and/or deep ulcers could enable a deeper insight into the cytokine profile of the inflamed tissue and represent a better tool for studying potential therapeutic targets and evaluation of novel therapies.

Sex-Based Differences in Incidence of Inflammatory Bowel Diseases-Pooled Analysis of Population-Based Studies From Western Countries.

BACKGROUND & AIMS: Although the incidence of inflammatory bowel diseases (IBDs) varies with age, few studies have examined variations between the sexes. We therefore used population data from established cohorts to analyze sex differences in IBD incidence according to age at diagnosis. METHODS: We identified population-based cohorts of patients with IBD for which incidence and age data were available (17 distinct cohorts from 16 regions of Europe, North America, Australia, and New Zealand). We collected data through December 2016 on 95,605 incident cases of Crohn's disease (CD) (42,831 male and 52,774 female) and 112,004 incident cases of ulcerative colitis (UC) (61,672 male and 50,332 female). We pooled incidence rate ratios of CD and UC for the combined cohort and compared differences according to sex using random effects meta-analysis. RESULTS: Female patients had a lower risk of CD during childhood, until the age range of 10-14 years (incidence rate ratio, 0.70; 95% CI, 0.53-0.93), but they had a higher risk of CD thereafter, which was statistically significant for the age groups of 25-29 years and older than 35 years. The incidence of UC did not differ significantly for female vs male patients (except for the age group of 5-9 years) until age 45 years; thereafter, men had a significantly higher incidence of ulcerative colitis than women. CONCLUSIONS: In a pooled analysis of population-based studies, we found age at IBD onset to vary with sex. Further studies are needed to investigate mechanisms of sex differences in IBD incidence.

[Screening for opportunistic infections and vaccination before introduction of biologic therapy]. / Probir na oportunisticke infekcije i cijepljenje prije pocetka bioloske terapije.

Patients on anti-TNFalpha medications carry a higher risk for developing opportunistic infections. In order to introduce anti-TNFalpha therapy, screening for hepatitis viruses B and C, HIV, EBV, HPV, TBC, bacterial, fungal and parasitic infections should be performed. Screening involves patient's history of earlier infectious diseases, vaccinations and traveling to parts of the world with endemic diseases. Clinical examination should be supplemented with stomatologic and gynecologic exams. Laboratory results include leukogram, transaminases, C-reactive protein, urine analysis, hepatitis B, C, HIV and EBV serology. Varicella zoster virus serology depends on past medical history. If the patient has traveled to tropical areas, both stool analysis and strongiloidiasis serology should be performed. Other mandatory examinations include chest radiography, PPD and TBC serology using interferon gamma release test (IGRA). If suspecting intra-abdominal abscess, magnetic resonance of the abdomen is recommended. In case of abscess, CMV or Clostridium difficile colitis anti-TNF-alpha therapy is contraindicated. Live vaccine application is contraindicated in patients receiving anti-TNFalpha therapy. All seronegative patients should be vaccinated against hepatitis B virus. Seasonal flu vaccination is recommended to be applicated yearly and pneumococcal polysaccharide vaccine once in every five years. Based on the past medical history and serologic results, patients are vaccinated against VZV with extra precaution. Human papilloma virus vaccination is performed in a group of women under 23 years of age, after gathering cervical smear sample analysis.

Absence of Oral Opportunistic Infections in Patients with Inflammatory Bowel Disease Receiving Anti-TNF-α and Anti-Integrin-α4ß7 Therapy.

Biological therapy of inflammatory bowel disease (IBD) carries an increased risk for the development of opportunistic infections due to immunomodulation. The aim of this study was to determine the prevalence and types of oral infections in IBD patients treated with biological (anti-TNF-α and anti-integrin-α4ß7) and conventional medication protocols. The study included 20 IBD patients receiving anti-TNF-α therapy, 20 IBD patients receiving anti-integrin-α4ß7 therapy and 20 IBD patients without immunomodulatory therapy. Participants completed questionnaires on medical information, oral lesions and symptoms. For each patient, clinical examination and a salivary flow rate test were performed, followed by a swab of the oral mucosa. The swab samples were cultured to identify Candida spp. and oral bacteria. No bacterial opportunistic infections were detected. Candidiasis was detected in four participants, with no significant difference between groups (p = 0.765). Hyposalivation was most common in the anti-TNF-α group, with a significant difference between groups (p = 0.036). There were no significant differences between groups in self-reported oral mucosal lesions and symptoms (p > 0.05), or in the distribution of oral mucosal lesions (p > 0.05). This study suggests that IBD patients receiving biological therapy are at no greater risk of developing oral opportunistic infections than IBD patients not receiving immunomodulatory therapy.

Gender related differences in quality of life and affective status in patients with inflammatory bowel disease.

According to the literature, quality of life has been shown to be reduced in females compared with males with Inflammatory Bowel Disease (IBD). Psychosocial factors are also playing an important role in IBD, especially emotional lability. The aims of study was to investigate the sex differences in general and specific health-related quality of life (HRQoL), anxiety and depression in IBD patients. Hundred and twelve outpatients of the Gastroenterology Division, Clinical Hospital Centre Rijeka, were enrolled in our study and divided in two groups: 50 females (31 with ulcerative colitis, UC and 19 with Crohn disease, CD) and 62 males (30 with UC and 32 with CD), age range 19 to 74 (M = 41.46; SD = 13.06). Most patients have been in long clinical remission or with mild disease according to Clinical Disease Activity Index (CDAI) score for CD and Clinical Activity Index (CAI) score for UC. There were significant differences in physical (F = 13.96, p < .0001) and mental (F = 9.44, p < .001) component of the general HRQoL, emotional domain ((F = 9.26, p < .001) and bowel symptoms (F = 7.04, p < .001) of the Inflammatory Bowel Disease Quality of life (IBDQoL), as well as, in anxiety (F = 7.03, p < .001) and depression (F = 12.09, p < .0001) between men and women with IBD. Women have expressed significantly lower level of the general HRQoL and more emotional disturbances connected with their disease as well as more frequent bowel symptoms compared with men. Effect sizes of those differences were large. Results of this study confirm that women with IBD are more prone to the negative impact of the disease on their HRQoL than men. Women with higher level of depression and anxiety experienced more emotional disturbances, bowel and systemic symptoms and lower general HRQoL. These results should deserve more considerations in the clinical treatment of IBD patients.

Claudins: Beyond Tight Junctions in Human IBD and Murine Models.

Claudins are transmembrane proteins constituting one of three tight junction protein families. In patients with inflammatory bowel disease (IBD), disease activity-dependent changes in expression of certain claudins have been noted, thus making certain claudin family members potential therapy targets. A study was undertaken with the aim of exploring expression of claudins in human disease and two different animal models of IBD: dextrane sulfate sodium-induced colitis and adoptive transfer model of colitis. The expression of sealing claudin-1, claudin-3, claudin-4, and claudin-8, and pore-forming claudin-2 in humans and rodents has been evaluated by immunohistochemistry and quantitative polymerase chain reaction. Claudins were expressed by epithelial and cells of mesodermal origin and were found to be situated at the membrane, within the cytoplasm, or within the nuclei. Claudin expression by human mononuclear cells isolated from lamina propria has been confirmed by Western blot and flow cytometry. The claudin expression pattern in uninflamed and inflamed colon varied between species and murine strains. In IBD and both animal models, diverse alterations in claudin expression by epithelial and inflammatory cells were recorded. Tissue mRNA levels for each studied claudin reflected changes within cell lineage and, at the same time, mirrored the ratio between various cell types. Based on the results of the study, it can be concluded that 1) claudins are not expressed exclusively by epithelial cells, but by certain types of cells of mesodermal origin as well; 2) changes in the claudin mRNA level should be interpreted in the context of overall tissue alterations; and 3) both IBD animal models that were analyzed can be used for investigating claudins as a therapy target, respecting their similarities and differences highlighted in this study.

How activity of inflammatory bowel disease influences bone loss.

Bone loss is a common problem for individuals with inflammatory bowel disease (IBD). The aim of our study was to assess bone mineral density (BMD) in patients with IBD and to investigate the role of corticosteroid (CS) use and duration and activity of disease on BMD. Ninety-two patients (56 men and 36 women) with IBD, of whom 32 had ulcerative colitis (UC) and 60 had Crohn's disease (CD), underwent clinical assessment. Lumbar and femoral neck BMDs were measured by dual-energy X-ray absorptiometry. Osteopenia was observed in 14 patients (43%) with UC and in 24 patients (40%) with CD (p=0.187). Four patients (12%) with UC and 7 patients (11%) with CD had osteoporosis (p=0.308). Femoral BMD decreased in patients with long duration of CS use and correlated inversely with disease activity. Multiple regression analysis of BMD showed that statistically significant risk factors were duration of active disease and body mass index as well. Based on our results, it is necessary to take into account the risk of decreased BMD in patients with IBD. It is most important to achieve disease remission as soon as possible in addition to nutritional support.

Splenic hematoma as a first manifestation of cytomegalovirus infection.

Splenic rupture is rare but life threatening complication of mononucleosis syndrome. It has been suggested that subcapsular splenic hematoma formation precedes rupture. The case of 44-year-old, previously healthy, male with splenic hematoma occurring after rising of heavy cargo is reported. Mononucleosis syndrome was suggested based on routine laboratory tests (elevated white blood cell count with predominance of lymphocytes and raised serum transaminases) and CMV infection was confirmed by serological test. Nonoperative management was used since the patient was hemodynamically stable with no further signs of splenic rupture. The same approach has been used in growing number of cases of patients with spontaneous splenic rupture in mononucleosis syndrome. Importance of considering splenic hematoma and/or rupture if abdominal pain occurs in the course of mononucleosis syndrome is outlined as well as importance of routine laboratory tests in suspecting mononucleosis syndrome in otherwise clinically silent patient.

Pyostomatitis vegetans associated with inflammatory bowel disease--report of two cases.

Pyostomatitis vegetans (PV) is a rare, chronic mucocutaneous disorder associated with inflammatory bowel disease (IBD). Oral lesions of PV are distinct and present as multiple white or yellow pustules with an erythematous base that coalesce and undergo necrosis to form a typical "snail tracks" appearance. Two cases of PV associated with IBD--one with Crohn's disease (CD) and the other with ulcerative colitis (UC) are reported. In the first case, adalimumab therapy brought the oral and gastrointestinal manifestations to complete remission. In the second case, the remission was achieved with systemic steroid therapy, but the disease relapsed after therapy discontinuation. Azathioprine was added leading to sustained remission of PV. Because of persistent active intestinal manifestation of UC, in spite of immunosuppressive therapy, infliximab was introduced. With the therapy remission of intestinal manifestation of UC was achieved as well. Our cases confirm previously reported good experience with immunomodulators and biologics in the treatment of PV. But, before using them we have to exclude an infectious etiology of oral lesions.

[Croatian guidelines for use of enteral nutrition in Crohn's disease]. / Hrvatske smjernice za primjenu enteralne prehrane u Crohnovoj bolesti.

Nutrition has an important role in the management of inflammatory bowel disease (IBD), especially in patients with Crohn's disease (CD). This role includes the prevention and correction of malnutrition, the prevention of osteoporosis and the promotion of optimal growth and development in children. In active Crohn's disease, nutritional therapy (in the form of enteral feeding) is an effective primary therapy for pediatric patients. Studies have shown that there is no difference in the efficacy of elemental, oligomeric and polymeric enteral formulas. Therefore, the use of polymeric formula is recommended because of higher palatability, better acceptance by patients, lower rate of complications and lower cost when compared with other enteral formulas. Today we have knowledge that some nutrients which are added to modified special enteral formulas have almost pharmacological terapeutic potential in the management of inflammatory bowel disease. Novel nutritional therapeutic strategies for inflammatory bowel disease, such as transforming growth factor-beta-enriched (TGF-beta2) enteral feeding, showed beneficial effects in several clinical studies. Croatian guidelines for enteral nutrition in Crohn's disease have been developed by interdisciplinary expert group of Croatian clinicians involved with inflammatory bowel disease. The guidelines are based on evidence from relevant medical literature and clinical experience of working group.

Inequalities in health related quality of life in Primorsko-goranska County, Croatia. How healthy are people using primary health care?

We present a cross sectional study on health related quality of life and EQ5D questionnaire practical use in Primorsko-goranska County in Croatia and inequalities in health between its sub regions with a potential application in regional policies social and healthcare organisation. Of 1066 participants that were patients at 42 family health physician's waiting room, women stood for 636 (59.7%) and men for 430 (40.3%). The most commonly reported problem was "Pain/discomfort" with 634 (59.5%) of all respondents and "Anxiety/depression" with 496 (46.6%). The worst health was reported within older age group and in a group with the lowest socio-economic status. Sub regional differences were found. The best health was reported in the suburbs of the town Rijeka and on the Islands, while the worst was reported in the Mountains. EQ5D is a simple and cost-effective instrument for measuring health related quality of life and recognising subgroups for identification of inequalities in the population.

Nutritional risk screening in hospitalized and haemodialysis patients.

Malnutrition is an independent risk factor impacting on higher complications and increased length of hospital stay and costs. The aim of this study was to determine the prevalence of nutritional risk among patients on regular haemodialysis (HD) (Group I, N = 105) and among the patients at Gastroenterology, Endocrinology, Hematology and Clinical Immunology (Group II, N = 652). Cross-sectional nutritional evaluation was done using Nottingham Hospital Screening Tool (NS). The prevalence of nutritional risk was 9% in Group I and 21% in Group II (p = 0.0002). We found statistically significant larger quantity of malnourished patients among acute internistic patients than among chronic from the same Group II. Malnutrition among patients on HD didn't differ statistically to chronic internistic patients. We didn't found a significantly higher percentage of nutritional risk among elderly patients (65 years and more). Correlation between body mass index (BMI) and NS was significant, but weak (r = -0.32). We can conclude that the prevalence of nutritional risk among HD patients was lower than we had expected. It seems that the screening tool we used is not sensitive enough for HD patients and needs further investigations.

Oral pathology in inflammatory bowel disease.

The incidence of inflammatory bowel diseases (IBD) - Crohn's disease (CD) and ulcerative colitis (UC) - has been increasing on a global scale, and progressively, more gastroenterologists will be included in the diagnosis and treatment of IBD. Although IBD primarily affects the intestinal tract, extraintestinal manifestations of the disease are often apparent, including in the oral cavity, especially in CD. Specific oral manifestations in patients with CD are as follows: indurate mucosal tags, cobblestoning and mucogingivitis, deep linear ulcerations and lip swelling with vertical fissures. The most common non-specific manifestations, such as aphthous stomatitis and angular cheilitis, occur in both diseases, while pyostomatitis vegetans is more pronounced in patients with UC. Non-specific lesions in the oral cavity can also be the result of malnutrition and drugs. Malnutrition, followed by anemia and mineral and vitamin deficiency, affects the oral cavity and teeth. Furthermore, all of the drug classes that are applied to the treatment of inflammatory bowel diseases can lead to alterations in the oral cavity due to the direct toxic effects of the drugs on oral tissues, as well as indirect immunosuppressive effects with a risk of developing opportunistic infections or bone marrow suppression. There is a higher occurrence of malignant diseases in patients with IBD, which is related to the disease itself and to the IBD-related therapy with a possible oral pathology. Treatment of oral lesions includes treatment of the alterations in the oral cavity according to the etiology together with treatment of the primary intestinal disease, which requires adequate knowledge and a strong cooperation between gastroenterologists and specialists in oral medicine.

Cannabis-induced acute pancreatitis.

Acute pancreatitis is a common disease. Despite the frequent use of cannabis worldwide, only six reports have described cases of acute pancreatitis secondary to the use of tetrahydrocannabinoid (THC). Here we describe two cases of THC-induced pancreatitis. The first case occurred in a 38-year-old man with multiple admissions for THC-induced pancreatitis; the second case involved a 22-year-old man with no previous medical history. In both cases, other possible causes of acute pancreatitis were ruled out.

Celiac disease associated with autoimmune hepatitis and autoimmune hyperthyroidism.

Although celiac disease (CD) may occur in patients with other immune-mediated disorders, its coexistence with multiple autoimmune diseases is not frequently described. We report the case of a 23-year-old woman referred to our centre because of jaundice and diarrhoea, who was diagnosed with CD in childhood. She complied with a gluten-free diet until puberty. Laboratory tests and liver biopsy were performed to establish the diagnosis of autoimmune hepatitis. Her thyroid- specific peroxides levels and thyroid gland function tests were altered as well, indicating the presence of an autoimmune disorder of the thyroid gland. Immunosuppressive treatment led to normalization of transaminases levels and bilirubin. In conclusion, other autoimmune diseases should be ruled out in patients with CD.

Incidence of inflammatory bowel disease in Primorsko-goranska County, Croatia, 2000-2004: A prospective population-based study.

OBJECTIVE: It has been suggested that the incidence of inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is higher in northern than in southern Europe. Recent epidemiological studies showed the loss of the previously described geographical north-south gradient. The aim of this study was to investigate the incidence of UC and CD in Primorsko-goranska County, Croatia. MATERIAL AND METHODS: In the period 1 January 2000 to 31 December 2004 (5 years) all new patients diagnosed with IBD were prospectively identified according to a standard protocol for case ascertainment and definition. A total of 178 residents (81 F, 97 M) were newly diagnosed as having IBD during the study period. Of these, 70 had UC and 100 CD. Eight patients had indeterminate IBD. The data on patients were collected using a data form completed by gastroenterologists. RESULTS: Annual age-standardized incidence rates were 4.3/10(5) (95% CI 2.6-6.0) for UC and 7.0/10(5) (95% CI 3.4-10.6) for CD. The highest incidence rate was observed in the age group 35-44 years for UC and the 25-34 years age group for CD. The incidence of IBD was higher in the urban than in the rural population, with the exception of on the islands. CONCLUSIONS: The incidence of IBD was higher than previously observed in Croatia. Our results suggest that CD incidence rates in the northern coastal part of Croatia are currently comparable with those reported in northern Europe.

3,4-methylenedioxymethamphetamine (MDMA): an important cause of acute hepatitis.

BACKGROUND: MDMA, i.e. 3,4-methylenedioxymethamphetamine ("Ecstasy"), occasionally produces significant hepatotoxicity in humans. It is characterized by a wide range of variability in clinical expression, ranging from asymptomatic liver injury, as observed by altered liver function tests, to acute hepatic failure. Prognostic factors that may predict the outcome of this condition remain unknown. CASE REPORT: We report a case of a 19-year-old male who presented deeplyjaundiced two weeks after ingestion of two tablets of Ecstasy. The clinical picture, laboratory data, and morphological studies were consistent with acute hepatitis. There was no evidence for a viral, alcoholic, metabolic, or autoimmune etiology of the disease. A mild clinical course with complete recovery after two months was observed. The presence of All molecule was confirmed in the patient. CONCLUSIONS: The possible association of specific human leukocyte antigen (HLA) phenotypes and MDMA-induced hepatotoxicity needs future evaluation.