European experience with methotrexate treatment in Crohn's disease: a multicenter retrospective analysis.

INTRODUCTION: Methotrexate (MTX) has been utilized for the treatment of Crohn's disease (CD) for decades. Nevertheless, current data provide equivocal evidence on the efficacy of MTX in CD.The aims of this study were to describe the efficacy of MTX for maintenance of remission in CD and to identify the factors associated with the probability of steroid-free clinical remission in a multicenter European referral center cohort. PATIENTS AND METHODS: This was a retrospective cohort analysis. Consecutive patients treated with MTX for CD were included from 11 referral centers. Patients receiving concomitant treatment with tumor necrosis factor inhibitors or thiopurines were excluded. The main outcome was steroid-free clinical remission; the secondary outcomes included the rate of complications leading to MTX discontinuation and duration of relapse-free survival in patients achieving the main outcome. RESULTS: Between July 1992 and January 2012, 118 patients were identified for inclusion. MTX administration route was oral for induction in 31.4% and for maintenance in 49.1% of the patients. Steroid-free remission was achieved in 44/118 (37.2%) patients and was maintained relapse free by 28/44 (63.6%) for a median of 12 (3.5-18.5) months. At least one adverse effect was reported by 28.9% of the patients. No clinical or demographic factors were associated with either likelihood of achieving a clinical response or duration of relapse-free survival. CONCLUSION: MTX treatment induced steroid-free clinical remission in over a third of CD patients and maintained it for a year in almost two-thirds of the responders. MTX should be considered a viable therapeutic option in CD patients refractory to other therapies.

Optic Neuritis Associated or Not with TNF Antagonists in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Acute optic neuritis [ON] is an inflammatory condition affecting the optic nerve. Clinicians should suspect optic neuritis in cases of painful and rapidly progressive loss of central visual field. This condition may be associated with a multitude of diseases, and mostly with multiple sclerosis [MS] where it may present as an initial symptom. The literature reports that optic neuritis and MS occur in patients with inflammatory bowel disease [IBD] before and after the era of anti-tumour necrosis factor-α [TNFα] drugs. At the present moment, there is little consensus for managing this complication, currently treated with corticosteroids and discontinuation of the causative agents. METHODS: We collected cases through a retrospective multicentre European Crohn's and Colitis Organisation CONFER [COllaborative Network For Exceptionally Rare case reports] project. We also performed a comprehensive retrospective search of the available literature on this topic. RESULTS: We report herein 12 new cases of ON, including 10 under anti-TNF therapy, collected through the CONFER project. We also compare characteristics of ON associated or not with anti-TNFα agents. CONCLUSIONS: The exceptional and current observation of distant family history of MS in 17% of our patients who developed ON, despite the small number and the lack of a control arm, might be an important signal that should be taken into account in our therapeutic strategies in the future.

The effectiveness and safety of rescue treatments in 108 patients with steroid-refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients.

BACKGROUND: Among patients with steroid-refractory ulcerative colitis (UC) in whom a first rescue therapy has failed, a second line salvage treatment can be considered to avoid colectomy. AIM: To evaluate the efficacy and safety of second or third line rescue therapy over a one-year period. METHODS: Response to single or sequential rescue treatments with infliximab (5mg/kg intravenously (iv) at week 0, 2, 6 and then every 8weeks), ciclosporin (iv 2mg/kg/daily and then oral 5mg/kg/daily) or tacrolimus (0.05mg/kg divided in 2 doses) in steroid-refractory moderate to severe UC patients from 7 Swiss and 1 Serbian tertiary IBD centers was retrospectively studied. The primary endpoint was the one year colectomy rate. RESULTS: 60% of patients responded to the first rescue therapy, 10% went to colectomy and 30% non-responders were switched to a 2(nd) line rescue treatment. 66% of patients responded to the 2(nd) line treatment whereas 34% failed, of which 15% went to colectomy and 19% received a 3(rd) line rescue treatment. Among those, 50% patients went to colectomy. Overall colectomy rate of the whole cohort was 18%. Steroid-free remission rate was 39%. The adverse event rates were 33%, 37.5% and 30% for the first, second and third line treatment respectively. CONCLUSION: Our data show that medical intervention even with 2(nd) and 3(rd) rescue treatments decreased colectomy frequency within one year of follow up. A longer follow-up will be necessary to investigate whether sequential therapy will only postpone colectomy and what percentage of patients will remain in long-term remission.

Autoimmune polyglandular syndrome type 2, alopecia universalis and Crohn's disease.

Autoimmune polyglandular syndromes are defined as a spectrum of association between 2 or more organ specific endocrinopaties and non-endocrine autoimmune diseases. Autoimmune polyglandular syndromes type 2 is characterized by the coexistence of adrenal failure with autoimmune thyroid disease and diabetes mellitus type 1. Inflammatory bowel diseases are rarely associated with these autoimmune disorders. Here, we report about a case of 33 years old male with known history of Crohn's colitis diagnosed in childhood. In 2003 the patient experienced sudden loss of hair, eyebrows, eyelashes, beard and body hair - alopecia universalis was diagnosed. At the age of 28, the patient was hospitalized with severe dehydration and clinical signs of ketoacidosis. Increased blood glucose (40 mmol/L), ketonuria and metabolic acidosis indicated diabetes mellitus type 1. In 2005, he had severe relapse of Crohn's disease and was treated with systemic corticosteroid. Although patient responded well to the induction therapy, fatigue, hypotension, bradycardia called for further investigations: free thyroxine - 6.99 pmol/L, thyroid-stimulating hormone >75 U/ml, anti-thyroid peroxidase antibodies >1000 U/mL, so diagnosis of Haschimoto thyroiditis was confirmed. Persistent hypotension and fatigue, recurrent hypoglycemic crises indicated a possible presence of hypo-function of adrenal glands. After complete withdrawal of corticosteroid therapy, low cortisol levels (69.4 nmol/L) and positive tetracosactide stimulation test proved adrenal cortex failure. Regardless of the intensive treatment for diabetes, hypothyroidism, adrenal insufficiency and Crohn's disease, it was extremely difficult to achieve and maintain control of all four diseases.

Clinical and pathological tools for identifying microsatellite instability in colorectal cancer.

AIM: To assess practical accuracy of revised Bethesda criteria (BGrev), pathological predictive model (MsPath), and histopathological parameters for detection of high-frequency of microsatellite instability (MSI-H) phenotype in patients with colorectal carcinoma (CRC). METHOD: Tumors from 150 patients with CRC were analyzed for MSI using a fluorescence-based pentaplex polymerase chain reaction technique. For all patients, we evaluated age, sex, family history of cancer, localization, tumor differentiation, mucin production, lymphocytic infiltration (TIL), and Union for International Cancer Control stage. Patients were classified according to the BGrev, and the groups were compared. The utility of the BGrev, MsPath, and clinical and histopathological parameters for predicting microsatellite tumor status were assessed by univariate logistic regression analysis and by calculating the sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values. RESULTS: Fifteen out of 45 patients who met and 4 of 105 patients who did not meet the BGrev criteria had MSI-H CRC. Sensitivity, specificity, PPV, and NPV for BGrev were 78.9%, 77%, 30%, and 70%, respectively. MSI histology (the third BGrev criterion without age limit) was as sensitive as BGrev, but more specific. MsPath model was more sensitive than BGrev (86%), with similar specificity. Any BGrev criterion fulfillment, mucinous differentiation, and right-sided CRC were singled out as independent factors to identify MSI-H colorectal cancer. CONCLUSION: The BGrev, MsPath model, and MSI histology are useful tools for selecting patients for MSI testing.

Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis.

BACKGROUND AND AIMS: It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC. METHODS: A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment. RESULTS: The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events. CONCLUSIONS: Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.

Different levels of humoral immunoreactivity to different wheat cultivars gliadin are present in patients with celiac disease and in patients with multiple myeloma.

BACKGROUND: Immunity to food antigens (gliadin, cow's milk proteins) is in the centre of the attention of modern medicine focused on the prevention of diseases, prevention which is based on the use of appropriate restriction diet. Detection of the enhanced levels of the immune reactions to antigen(s) present in food is from this point of view of great importance because there are reports that some of health disturbances, like celiac disease (CD) and some premalignant conditions, like monoclonal gammopathy of undetermined significance (MGUS), were vanished after the appropriate restriction diets. It is well known that gliadin is toxic to small bowel mucosa of relatively small population of genetically predisposed individuals, who under this toxic action develop celiac disease (CD). As the quantity of immunogenic gliadin could vary between different wheat species, the first aim of this work was to determine the percentage of immunogenic gliadin in ten bread wheat cultivars and in three commercially grown durum wheat cultivars. The second part of the study was initiated by results of previous publication, reporting that sera of some of multiple myeloma (MM) patients showed the presence of elevated levels of anti-gliadin IgA, without the enhanced levels of anti-gliadin IgG antibodies, determined with commercial ELISA test. It was designed to assess is it possible to reveal is there any hidden, especially anti-gliadin IgG immunoreactivity, in serum of mentioned group of patients. For this purpose we tested MM patients sera, as well as celiac disease (CD) patients sera for the immunoreaction with the native gliadin isolated from wheat species used for bread and pasta making in corresponding geographic region. RESULTS: Gliadin was isolated from wheat flour by two step 60% ehanolic extraction. Its content was determined by commercial R5 Mendez Elisa using PWG gliadin as the standard. Results obtained showed that immunogenic gliadin content varies between 50.4 and 65.4 mg/g in bread wheat cultivars and between 20 and 25.6 mg/g in durum wheat cultivars. Anti-gliadin IgA and IgG immunoreactivity of patients' sera in (IU/ml) was firstly determined by commercial diagnostic Binding Site ELISA test, and then additionally by non-commercial ELISA tests, using standardized ethanol wheat extracts -gliadin as the antigen. In both patients groups IgA immunoreactivity to gliadin from different cultivars was almost homogenous and in correlation with results from commercial test (except for one patient with IgA(lambda) myeloma, they were more then five times higher). But, results for IgG immunoreactivity were more frequently inhomogeneous, and especially for few MM patients, they were more then five times higher and did not correlate with results obtained using Binding Site test. CONCLUSION: Results obtained showed different content of immunogenic gliadin epitopes in various species of wheat. They also point for new effort to elucidate is there a need to develop new standard antigen, the representative mixture of gliadin isolated from local wheat species used for bread production in corresponding geographic region for ELISA diagnostic tests.

CARD15 gene polymorphisms in Serbian patients with Crohn's disease: genotype-phenotype analysis.

OBJECTIVE: Genetic heterogeneity and incomplete phenotype penetrance complicate genetic analysis of Crohn's disease (CD). Studies in western Europe have shown that CARD15 polymorphisms increase susceptibility to CD, but frequencies vary within different European populations. The aim here was to evaluate the prevalence of CARD15 mutations and their phenotypic correlation in a Serbian population. MATERIALS AND METHODS: 131 patients with CD, 65 patients with ulcerative colitis, and 88 healthy controls were genotyped for three common mutations (R702W, G908R, Leu1007insC) by PCR-restriction fragment length polymorphism. chi and Student's t-test were used for statistical assessment. RESULTS: At least one CARD15 disease-associated allele was found in 35.11% patients with CD, 14.77% of healthy controls (P=0.001), and 7.69% patients with ulcerative colitis (P=0.0001). The L1007fs mutation showed a significant association with CD (P<0.0001). The frequency of R702W mutant allele was almost equal in the control group and CD patients Univariate analyses established that CARD15 carriers had a significantly higher risk of isolated ileal location [P=0.042; odds ratio (OR) 2.30; 95% confidence interval (CI): 1.02-5.19], fibrostenotic behavior (P<0.0001; OR 9.86; 95% CI: 4.29-22.62), surgical resection (P=0.036; OR 2.2; CI, 1.046-4.626), and earlier onset of disease (P=0.026). CONCLUSION: This study confirms that CARD15 carriers, especially L1007fs mutants, in central Europeans have an increased risk of CD and it is associated with earlier onset, ileal, fibrostenotic disease and a higher risk of surgery. Any influence of latitude is not matched by an east-west divide on the genotype frequency and phenotype of CD within Europe.

Mechanism of diarrhea in microscopic colitis.

AIM: To search the pathophysiological mechanism of diarrhea based on daily stool weights, fecal electrolytes, osmotic gap and pH. METHODS: Seventy-six patients were included: 51 with microscopic colitis (MC) (40 with lymphocytic colitis (LC); 11 with collagenous colitis (CC)); 7 with MC without diarrhea and 18 as a control group (CG). They collected stool for 3 d. Sodium and potassium concentration were determined by flame photometry and chloride concentration by titration method of Schales. Fecal osmotic gap was calculated from the difference of osmolarity of fecal fluid and double sum of sodium and potassium concentration. RESULTS: Fecal fluid sodium concentration was significantly increased in LC 58.11+/-5.38 mmol/L (P<0.01) and CC 54.14+/-8.42 mmol/L (P<0.05) than in CG 34.28+/-2.98 mmol/L. Potassium concentration in LC 74.65+/-5.29 mmol/L (P<0.01) and CC 75.53+/-8.78 mmol/L (P<0.05) was significantly less compared to CG 92.67+/-2.99 mmol/L. Chloride concentration in CC 36.07+/-7.29 mmol/L was significantly higher than in CG 24.11+/-2.05 mmol/L (P<0.05). Forty-four (86.7%) patients had a secretory diarrhea compared to fecal osmotic gap. Seven (13.3%) patients had osmotic diarrhea. CONCLUSION: Diarrhea in MC mostly belongs to the secretory type. The major pathophysiological mechanism in LC could be explained by a decrease of active sodium absorption. In CC, decreased Cl/HCO3 exchange rate and increased chloride secretion are coexistent pathways.

Circulating insulin-like growth factors in patients infected with Helicobacter pylori.

OBJECTIVES: The level of insulin-like growth factors (IGFs) and their binding proteins may change in acutely ill humans. The aim of this work was to examine the changes in the IGF system in patients suffering from infection induced by Helicobacter pylori (H. pylori). DESIGN AND METHODS: The serum concentrations of IGF-I, IGF-II and cortisol were measured by radioimmunoassay. IGFBP patterns were characterized by ligand-affinity blotting, and a lectin-binding assay was used to investigate the possible changes in the glycocomponent of IGFBP-3. RESULTS: Both IGF-I and IGF-II concentrations were significantly lower in patients with H. pylori infection (P < 0.001 for IGF-I and P = 0.016 for IGF-II) compared to healthy individuals, whereas the level of cortisol was significantly elevated in analyzed patients (P < 0.001). Autoradiography demonstrated the increased presence of IGFBP-2 and IGFBP-1, together with a decreased level of IGFBP-3. CONCLUSIONS: The circulating IGF/IGFBP system is altered in patients infected with H. pylori. The increased level of cortisol suggests the involvement of the hypothalamic/pituitary/adrenal axis that stimulates the elevation of blood glucose, probably in coordination with decreased IGF activity to minimize anabolic metabolism.

Primary malignant mesothelioma of the peritoneum.

Mesothelioma of the peritoneum represents an extremely rare malignancy of the abdominal cavity and forms about 10% of all mesotheliomas. The annual incidence of the tumor in the general population is 1-2 cases per million. The causative relationship between chronic exposure to asbestos and mesothelioma has been proved. Since the symptomatology of the tumor is usually not specific, the diagnosis is made in the advanced stages of the disease, which is the limiting factor for therapy. Most patients die within 2 years from the diagnosis. We report a case of a primary malignant mesothelioma of the peritoneum in a 60-year old male, who presented with three-month history of ascites, weakness and appetite loss. The patient gave the information that he had been living for 15 years in a loft which was insulated by material consisting of asbestos. After investigations, primary neoplasm of the peritoneum was suspected, which was confirmed by the biopsy and the morphopathological examination. Due to the advanced spread of the tumor and the poor general condition, the patient underwent palliative therapy. The patient died 3 months after the diagnosis. Epidemiological data for chronic exposure to asbestos have to be considered as the etiological factor of disease in this particular patient.