Efficacy of Infliximab after Failure of Subcutaneous Anti-TNF Agents in Patients with Moderate to Severe Ulcerative Colitis

Aim: To assess the efficacy of infliximab in ulcerative colitis (UC) patients who had failed therapy with adalimumab or golimumab. Methods: Retrospective analysis of prospectively acquired data of all anti-TNF naive patients with moderate to severe UC who received adalimumab or golimumab in 4 tertiary referral centres. Patients with primary non response or secondary loss of response to adalimumab or golimumab received therapy with infliximab. Clinical response and remission rates were assessed at week 14 and 54 after initiation of infliximab. Results: Between September 2015 and September 2017, 29 of 58 (50%) anti-TNF naive patients with moderate to severe UC failed therapy with adalimumab (n=38) or golimumab (n=20). Twenty one of 29 (72.4%) patients were primary non responders and 8 (27.6%) patients lost response to adalimumab or golimumab. All these 29 patients received infliximab, while 15 (51.7%) were on concomitant azathioprine therapy. Eighteen (62.1%) and 10 (34.5%) patients showed clinical response and clinical remission at week 14 respectively, while 14 (48.3%) patients were on clinical remission at week 54 after initiation of infliximab. Azathioprine co-administration at the start of infliximab was associated with a greater proportion of patients achieving clinical remission at week 54 (10 of 15 patients on combination therapy vs 4 of 14 patients on infliximab monotherapy, p=0.04). Conclusions: A significant proportion of anti-TNF naive patients with moderate to severe UC who have failed 1st course therapy with subcutaneous anti-TNF agents can achieve clinical response and/or remission with 2nd course therapy with infliximab

Helicobacter pylori as a risk factor for the onset of coronary heart disease. The role of the helicobacter pylori-induced proinflammatory cytokines

Introduction: Helicobacter pylori (H. pylori), a Gram-negative, spiral, microaerophilic bacterium, has been associated with a variety of intestinal and extraintestinal disorders, including atherosclerosis. The results, however, originating from related studies are controversial. Objective& Methods: The objectives of the study were to determine the frequency of H. pylori infection among IHD patients and otherwise healthy individuals and examine the effect of the infection on lipids, coagulation, inflammatory indices and determinants of homocysteine levels. IgG and IgA antibody titres against H. pylori were calculated in 248 individuals (134 IHD patients and 114 subjects, all meeting inclusion criteria) by means of an enzyme-linked immunosorbent assay. In order to eliminate confounding factors, subjects exhibiting systemic inflammatory disorders, malignancies, renal insufficiency, cholestasis, thyroid diseases, depression or were under medication that could alter the levels of the tested parameters, were excluded from the study. Based on serology, the study participants were classified into H. pylori-seropositive and seronegative sex, age, body mass index, diabetes mellitus and smoking-matched subgroups. Lipids -total cholesterol, low and high density lipoproteins (LDL, HDL) and triglycerides- caogulation parameters - platelet count, mean platelet volume, prothrombin time, active partial prothrombin time, fibrinogen and D-dimers- inflammatory indices - white blood cell count, C reactive protein, serum amyloid A, ceruloplamin, complement factors C3 and C4- as well as BNP and fetuin A were determined in all study participants (expressed as mean ± SEM). Results: Higher levels of LDL were recorded in seropositive (115.6 ± 4.157mg/dL) compared to seronegative individuals (102.2 ± 2.991mg/dL) (P<0.01). Moreover, H. pylori seropositive subjects tended to exhibit lower HDL levels (46.44 ± 1.349mg/dL) as compared to those found in the seronegative qroup (42.72 ± 1.414mg/dL), although this difference reached only a statistical trend (P=0.06). An upregulation of ceruloplasmin became evident in the seropositive (26.82 ± 0.5181mg/dL) compared to the seronegative (25.36 ± 0.4866mg/dL) participants (P=0.041). Moreover, these elevated ceruloplasmin concentrations correlated with anti-H.pylori IgG titer (r=0.326, P=0.0007). Subjects with a positive serology for H. pylori tended to exhibit lower C3 levels (112.4 ± 2.341mg/dL) compared to those with a negative serology (117.7 ± 1.793mg/dL) (P=0.076). As far as fetuin A levels are concerned, a positive qualitative and quantitative (IgG and IgA titers) link with seropositivity was recorded: 0.7702 ± 0.03357g/L in seropositive and 0.5575 ± 0.02563g/L in seronegative individuals without IHD (P=0.0005), along with a P=0.047, r= 0.249 for IgG and a P=0.001, r=0,395 for ΙgA antibodies. Conclusion: While the changes in the levels of lipids are suggestive of an H. pylori-induced dyslipidemic background, complement activation and the upregulation of ceruloplasmin are indicative of an associated inflammatory, oxidative disequilibrium. The upregulation of fetuin A, on the other hand, suggests the induction of a metabolic dysregulation, that of insulin resistance. Conclusively, our results show that H. pylori infection may predispose to atherosclerosis by sustaining a multivariate atherogenic condition.Εισαγωγή: To Helicobacter pylori (H. pylori), ένα Gram-αρνητικό, σπειροειδές, μικροαερόφιλο βακτήριο έχει συσχετισθεί με ποικίλες διαταραχές, συμπεριλαμβανομένης και της αθηροσκλήρυνσης. Τα αποτελέσματα ωστόσο που προκύπτουν από τις σχετικές μελέτες είναι αντικρουόμενα. Σκοπός&Μέθοδοι: Σκοπός της μελέτης ήταν ο προσδιορισμός της συχνότητας της λοίμωξης από H. pylori σε ασθενείς με στεφανιαία νόσο (ΣΝ), καθώς και η διερεύνηση της επίδρασης της λοίμωξης στα λιπίδια, στην πήξη, στους δείκτες φλεγμονής, καθώς και σε ουσίες - παραμέτρους που σχετίζονται με μυοκαρδιακή αναδιάταξη (remodelling) αλλά και εκείνες που επηρεάζουν τα επίπεδα ομοκυστεΐνης. Οι τίτλοι IgG και IgA αντισωμάτων προσδιορίστηκαν σε 248 άτομα (134 ασθενείς με ΣΝ και 114 κατά τα λοιπά υγιή άτομα μέσω ELISA. Άτομα που έπασχαν από συστηματικά φλεγμονώδη νοσήματα, κακοήθεια, νεφρική ανεπάρκεια, χολοστατικά σύνδρομα, νοσήματα θυρεοειδούς αδένα, κατάθλιψη ή ήταν υπό αγωγή που θα μπορούσε να μεταβάλει τα επίπεδα των μετρούμενων ουσιών, αποκλείστηκαν από τη μελέτη. Με βάση την οροθετικότητα οι μετέχοντες ταξινομήθηκαν σε ομάδες H.pylori-οροθετικές και οροαρνητικές, προτυποποιημένες ως προς το φύλο, ηλικία, δείκτη μάζας σώματος, σακχαρώδη διαβήτη και κάπνισμα. Λιπίδια, τριγλυκερίδια, παράμετροι πήξης, δείκτες φλεγμονής, καθώς και ΒΝΡ αλλά και η φετουΐνη Α, προσδιορίστηκαν σε όλους τους μετέχοντες στην μελέτη (εκφρασμένες ως μέση τιμή ± SEM). Αποτελέσματα: Υψηλότερα επίπεδα LDL καταγράφηκαν σε οροθετικά (115.6 ± 4.157mg/dL) σε σχέση με οροαρνητικά (102.2 ± 2.991mg/dL) άτομα (P<0.01). Επιπλέον, H.pylori-θετικοί ασθενείς εμφάνισαν στατιστική τάση για χαμηλότερα επίπεδα HDL (46.44 ± 1.349mg/dL) σε σύγκριση με τους H. pylori-αρνητικούς (42.72 ± 1.414mg/dL) (P=0.06). Αυξημένες τιμές για τη σερουλοπλασμίνη παρατηρήθηκαν σε οροθετικά (26.82 ± 0.5181mg/dL) σε σχέση με οροαρνητικά άτομα (25.36 ± 0.4866mg/dL) (P=0.041). Μάλιστα, οι αυξημένες αυτές τιμές συσχετίζονταν γραμμικά με τον τίτλο των IgG αντισωμάτων έναντι H.pylori (r=0.326, P=0.0007). Στην ομάδα των οροθετικών ασθενών σημειώθηκε επίσης μια τάση για χαμηλότερα επίπεδα του C3 παράγοντα του συμπληρώματος (112.4 ± 2.341mg/dL) κατά τη σύγκριση με εκείνα των οροαρνητικών (117.7 ± 1.793mg/dL) (P=0.076). Τέλος η οροθετικότητα για H. pylori συνδέθηκε ποιοτικά αλλά και ποσοτικά (τίτλοι IgG και IgA αντισωμάτων κατά H. pylori) με αυξημένα επίπεδα φετουΐνης Α (0.7702 ± 0.03357g/L σε οροθετικούς και 0.5575 ± 0.02563g/L σε οροαρνητικούς χωρίς ΣΝ αντίστοιχα, P=0.0005) (P=0.047, r= 0.249 για τα IgG και P=0.001, r=0,395 για τα ΙgA). Συμπεράσματα: Οι μεταβολές στα επίπεδα των λιπιδίων είναι ενδεικτικές μιας επαγόμενης από το Ελικοβακτηρίδιο του πυλωρού δυσλιπιδαιμίας. Παράλληλα, η ενεργοποίηση του συμπληρώματος και η αύξηση της συγκέντρωσης της σερουλοπλασμίνης υποδηλώνουν μια φλεγμονώδη, οξειδωτική διαταραχή. Η αύξηση της φετουΐνης Α αναδεικνύει μια μεταβολική διαταραχή σχετιζόμενη με αντίσταση στη δράση της ινσουλίνης. Συνολικά, τα αποτελέσματα της μελέτης αναδεικνύουν το ρόλο της λοίμωξης από το Ελικοβακτηρίδιο του πυλωρού ως προδιαθεσικού παράγοντα για την εξέλιξη μιας πολυπαραγοντικής αθηροσκληρυντικής διεργασίας

Liver cirrhosis-effect on QT interval and cardiac autonomic nervous system activity.

AIM: To examine the impact of liver cirrhosis on QT interval and cardiac autonomic neuropathy (CAN). METHODS: A total of 51 patients with cirrhosis and 51 controls were examined. Standard 12-lead electrocardiogram recordings were obtained and QT as well as corrected QT interval (QTc) and their dispersions (dQT, dQTc) were measured and calculated using a computer-based program. The diagnosis of CAN was based upon the battery of the tests proposed by Ewing and Clarke and the consensus statements of the American Diabetes Association. CAN was diagnosed when two out of the four classical Ewing tests were abnormal. RESULTS: QT, QTc and their dispersions were significantly longer (P &lt; 0.01) in patients with cirrhosis than in controls. No significant differences in QT interval were found among the subgroups according to the etiology of cirrhosis. Multivariate regression analysis after controlling for age, gender and duration of cirrhosis demonstrated significant association between QT and presence of diabetes mellitus [standardized regression coefficient (beta) = 0.45, P = 0.02] and treatment with diuretics (beta = 0.55, P = 0.03), but not with the Child-Pugh score (P = 0.54). Prevalence of CAN was common (54.9%) among patients with cirrhosis and its severity was associated with the Child-Pugh score (r = 0.33, P = 0.02). Moreover, patients with decompensated cirrhosis had more severe CAN that those with compensated cirrhosis (P = 0.03). No significant association was found between severity of CAN and QT interval duration. CONCLUSION: Patients with cirrhosis have QT prolongation. Treatment with diuretics is associated with longer QT. CAN is common in patients with cirrhosis and its severity is associated with severity of the disease

Ulcerative Colitis in Hematological Malignancies: Paraneoplastic Manifestation or Coincidental Bystander?

Evidence of coexistence of diverse hematological malignancies—lymphoma, leukemia, multiple myeloma, and myelodysplastic syndromes—and either ulcerative colitis or Crohn’s disease can be found in the literature. However, a more “systemic” effort to reach further and examine the potential of either one as paraneoplastic manifestation has not been performed. Based on these, three cases of ulcerative colitis manifesting before, simultaneously, and after the onset of different hematological malignancies are presented and critically evaluated

Imbalance of tissue inhibitors of metalloproteinases (TIMP)-1 and-4 serum levels, in patients with inflammatory bowel disease

Background: Tissue inhibitors of metalloproteinases (TIMPs) play a key role in tissue degradation and remodeling. Since chronic inflammation is associated with tissue remodeling in inflammatory bowel disease (IBD), we evaluated serum TIMP-1 and TIMP-4 levels in IBD patients, in comparison with healthy controls (HC). Methods: TIMP-1, TIMP-2 and TIMP-4 serum levels were determined in 53 patients with ulcerative colitis (UC), 52 patients with Crohn's disease (CD) and 50 HC, by means of commercially available enzyme-linked immunosorbent assays. The levels of TIMPs were evaluated with regard to the levels of inflammatory markers, such as C reactive protein (CRP) and serum amyloid A (SAA) and the clinical characteristics of patients, so that potential correlations could be recorded. Results: Mean serum TIMP-1 levels were 414.9 +/- 17.6 ng/mL in UC patients, 446.1 +/- 22.8 ng/mL in CD patients and 296.5 +/- 20.6 ng/mL in HC. UC and CD patients had significantly higher serum TIMP-1 levels when compared to HC, (p 0.05 in all cases). Mean serum TIMP-4 levels were 1761.2 +/- 67.7 pg/mL in UC patients, 1708.1 +/- 73.4 pg/mL in CD patients and 5573.4 +/- 1246.3 pg/mL in HC. UC and CD patients had significantly lower serum TIMP-4 levels when compared to HC (p = 0.008 and p = 0.02 respectively). Mean serum TIMP-4 levels were significantly lower in males (2772.9 pg/mL), compared to females (3299.0 pg/mL, p = 0.01). In addition, CRP levels showed a statistically significant correlation with TIMP-1 (r = 0.247, p = 0.01), and TIMP-4 levels (r = 0.217, p = 0.03). Similarly, there was a statistically significant correlation between SAA levels and both TIMP-1 (r = 0.264, p = 0.008) and TIMP-4 serum levels (r = 0.212, p = 0.03). Conclusion: An imbalance between TIMP-1 and TIMP-4 serum levels is present in IBD patients. TIMP-1 levels could be used not only for diagnostic purposes but also for the assessment of activity in IBD. Gender tends to influence TIMP-1 and TIMP-4 serum levels. These new findings bring into question the potential role of TIMPs in IBD, thus underlining the need for future studies which could offer new insight into this matter