Vedolizumab in the treatment of chronic, antibiotic-dependent or refractory pouchitis.

BACKGROUND: The most common complication after ileal pouch anal anastomosis in up to 50% of patients is an acute pouchitis. The majority of patients respond to antibiotic treatment. However, 10%-15% develops chronic antibiotic-dependent or refractory pouchitis which is usually hard to treat. AIM: To evaluate the effectiveness of vedolizumab in patients with chronic pouchitis. METHODS: Patients with chronic antibiotic-dependent or refractory pouchitis were treated with vedolizumab (300 mg at week 0, 2, 6 and 10) in 10 IBD centres and retrospectively registered. Data were recorded until week 14 of vedolizumab treatment. In total 20 patients (12 male, median age 43 years) were included for analysis. The effectiveness was measured using the Oresland Score (OS) at week 2, 6, 10 and 14 and the pouch disease activity index (PDAI) at week 0 and 14. RESULTS: The mean OS declined from 6.8 (range 2-12) to 3.4 (range 0-11). Concordantly, the mean PDAI after 14 weeks of treatment dropped from 10 (range 5-18) to 3 (range 0-10). Only three patients reported moderate side effects. No serious side effects were recorded. In addition, symptomatic co-medication such as loperamide and tincture of opium could be terminated in 8 out of 12 patients as well as antibiotic treatment could be stopped in 17 out of 19 patients. CONCLUSION: Our data indicate that vedolizumab could be an option in the treatment of patients with chronic, antibiotic-dependent or refractory pouchitis.

Comorbidity in acute pancreatitis relates to organ failure but not to local complications.

OBJECTIVE: Organ failure and local complications contribute to morbidity and mortality in acute pancreatitis. Comorbidity is known to be related to organ failure. The impact of comorbidity on local complications has not yet been delineated. Moreover, it is not clear if the outcome of first-attacks and acute-on-chronic episodes, respectively, differs from outcome in all episodes. METHODS: Consecutive cases of confirmed acute pancreatitis in a four-year period were reviewed. Charlson comorbidity index (CCI), complications (organ failure and local complications), disease severity (according to the revised Atlanta Classification), need for intensive care, and mortality were derived from the charts. RESULTS: A total of 391 episodes of acute pancreatitis were included. Patients with organ failure were significantly older (P< 0.001) und had a higher CCI (P< 0.001) than patients without organ failure. Patients with and without local complications did not significantly differ in age or CCI. The complication rate of the entire cohort (n = 391; 47.1 %) was comparable with the complication rate of first-attacks (n = 269; 46.8 %) and acute-on-chronic episodes (n = 68; 47.1 %). The majority of the twelve deceased patients had been old and/or chronically ill. Six of these patients had an advanced malignant disease. CONCLUSIONS: Comorbidity and age clearly are contributors to organ failure and mortality. Local complications occur independently of age and concomitant diseases. The overall complication rate is not significantly influenced by preceding inflammation of the pancreas. To further improve care in patients with acute pancreatitis special attention should be given to old and multi-morbid patients.

Ischemic colitis following uncomplicated colonoscopy.

BACKGROUND/OBJECTIVE: Ischemic colitis is a disorder of the intestine arising from a multitude of reasons thus representing a challenge for causal research. Our aim was to shed further light on the course, etiology and triggers of non-occlusive ischemic colitis by presenting an atypical complication after colonoscopy. DESIGN: We present the case report of a 77-year-old male patient presenting with ischemic colitis after an uneventful outpatient colonoscopy two days prior to onset of symptoms. RESULTS: So far only few cases of post-colonoscopy ischemic colitis have been reported. In the present case no single reason was identified. It remains to be assumed that a combination of predisposing conditions with a modest decrease of blood pressure and short-term increased intraluminal pressure during colonoscopy may have led to ischemic colitis. CONCLUSION: Awareness of ischemic colitis as a complication in comparable settings is favorable. So far, early countermeasures against even modest hypotension in patients with comparable past history may be considered on an individual basis depending on the entirety of risk factors. However, prospective studies are necessary to evaluate potential risk profiles for ischemic colitis in terms of colonoscopy.

Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues.

BACKGROUND AND AIMS: Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment. METHODS: In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months. RESULTS: We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died. CONCLUSIONS: Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.

Benefit of Contrast-Enhanced Ultrasound (CEUS) in the Follow-Up Care of Patients with Colon Cancer: A Prospective Multicenter Study.

PURPOSE: According to the German guidelines on colorectal cancer, unenhanced ultrasound is recommended for follow-up. On the other hand, ultrasound and radiology societies specify the use of contrast-enhanced ultrasound for ruling out liver metastases. Studies focusing on the follow-up of cancer patients are lacking. The goal of this multicenter study initiated by the German Ultrasound Society (DEGUM) was to determine the potential benefit of contrast-enhanced ultrasound in the follow-up of patients with colon cancer. MATERIALS AND METHODS: Follow-up patients with colon cancer (UICC > IIa) were investigated. As scheduled according to the German guidelines, unenhanced ultrasound was performed followed by contrast-enhanced ultrasound. All liver lesions were recorded. In case of additional metastases detected on contrast-enhanced ultrasound, contrast-enhanced CT, MRI or biopsy was performed to confirm additional liver metastases. RESULTS: A total of 45 liver metastases were detected in 26/290 patients (= 9 %) using unenhanced ultrasound. A further 28 metastases were detected on contrast-enhanced ultrasound in these 26 patients. In 18 patients showing no liver metastases, 40 additional metastases were detected on unenhanced ultrasound. This means that 44 patients with a total of 113 liver metastases were detected on contrast-enhanced ultrasound (p = 0.0006). CONCLUSION: Contrast-enhanced ultrasound should be recommended in the follow-up of patients with colon cancer in addition to unenhanced ultrasound - the up-to-date standard.

[Therapy of chronic inflammatory bowel diseases. Standards, controversies and perspectives]. / Therapie chronisch-entzündlicher Darmerkrankungen. Standards, Kontroversen und Perspektiven.

Crohn's disease and ulcerative colitis are the most common forms of chronic inflammatory bowel disease. The therapeutic algorithm is complex and individualized especially in complicated courses of the disease. This article gives a comprehensive overview on the typical courses of disease and the standard therapy of both diseases. Furthermore, ongoing controversies will be highlighted including early immunosuppression and immunomodulation as well as new therapeutic goals, such as mucosal healing. Finally, a perspective on future therapeutic options is given focusing especially on vedolizumab, the new antibody against the bowel-specific α4ß7-integrin.

Inflammatory bowel diseases influence major histocompatibility complex class I (MHC I) and II compartments in intestinal epithelial cells.

Antigen presentation by intestinal epithelial cells (IEC) is crucial for intestinal homeostasis. Disturbances of major histocompatibility complex class I (MHC I)- and II-related presentation pathways in IEC appear to be involved in an altered activation of CD4(+) and CD8(+) T cells in inflammatory bowel disease. However, a comprehensive analysis of MHC I- and II-enriched compartments in IEC of the small and large bowel in the healthy state as opposed to inflammatory bowel diseases is lacking. The aim of this study was to characterize the subcellular expression of MHC I and II in the endocytic pathway of IEC throughout all parts of the intestinal tract, and to identify differences between the healthy state and inflammatory bowel diseases. Biopsies were taken by endoscopy from the duodenum, jejunum, ileum and colon in healthy individuals (n = 20). In Crohn's disease (CD), biopsies were obtained from the ileum and colon and within the colon from ulcerative colitis (UC) patients (n = 15). Analysis of IEC was performed by immunoelectron microscopy. MHC I and II were identified in early endosomes and multi-vesicular, multi-lamellar, electrondense and vacuolar late endosomes. Both molecules were enriched in multi-vesicular bodies. No differences were found between the distinct parts of the gut axis. In CD and UC the expression of MHC I and II showed a shift from multi-vesicular bodies towards the basolateral membranes. Within the multi-vesicular bodies, MHC I and II moved from internal vesicles to the limiting membranes upon inflammation in CD and UC. MHC I- and II-enriched compartments in IEC were identical in all parts of the small and large bowel. CD and UC appear to modulate the MHC I- and II-related presentation pathways of exogenous antigens in IEC.

Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis - experience in 130 patients.

BACKGROUND: Steroid-refractory ulcerative colitis (UC) remains a challenging condition warranting surgery upon failure of pharmacological treatment. Calcineurin inhibitors or infliximab are alternatives in this situation. Data on the efficacy and safety of tacrolimus in this setting are limited. AIM: To study the short-term efficacy and safety of tacrolimus in moderate-to-severe steroid-refractory UC. The role of thiopurines in this situation and predictors of colectomy were evaluated. METHODS: In three centers, all charts from tacrolimus-treated patients with steroid-refractory UC were reviewed. Efficacy was assessed by colectomy-free survival and clinical remission at 3 months. RESULTS: We identified 130 patients with pancolitis in 75 (59%), left-sided disease in 35 (27%) and proctitis in 18 patients (14%) (disease localisation not obtainable in two patients). The median age was 40 (range: 18-81). Clinical activity according to the median Lichtiger score decreased from 13 (range: 4-17) at baseline to 3 (0-14) at week 12. Eighteen patients underwent colectomy within the first 3 months of treatment with tacrolimus (14%). Clinical remission was achieved in 94 patients (72%) in this period. Thiopurines given in parallel to tacrolimus tended to limit colectomy and significantly increased remission (P = 0.002) in the short-term. No other predictors of colectomy or remission were identified. Side effects were noticed in 53% of patients and no severe events occurred. CONCLUSION: This large survey confirms the efficacy and safety of tacrolimus in patients with steroid-refractory ulcerative colitis.

Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study.

BACKGROUND: Vidofludimus (SC12267) is a novel oral immunomodulator inhibiting dihydroorotate dehydrogenase (DHODH) and the expression of proinflammatory cytokines including interleukin-17 (IL17A and IL17F) and interferon-gamma. The objective of the study was to explore the efficacy, safety and tolerability of vidofludimus in steroid-dependent inflammatory bowel disease (IBD). METHODS: The open label uncontrolled ENTRANCE study (ClinicalTrials.gov NCT00820365) has been conducted at 13 study centers in Germany, Bulgaria and Romania. Thirty-four steroid-dependent patients with a confirmed diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were treated with a once daily 35mg oral dose of vidofludimus over 12weeks. Steroids were tapered during the first 8weeks followed by a steroid-free treatment period of 4weeks. Complete response was defined as steroid-free clinical remission at week 12; partial response was defined as being in remission at steroid dose equal or lower than the individual patient's threshold dose for relapse. RESULTS: Of the thirty-four patients enrolled in this trial 26 were evaluable for primary efficacy assessment. After completion of the 12weeks treatment phase 8 out of 14 (57.1%) patients with CD and 6 out of 12 (50.0%) patients with UC were in steroid-free remission (complete responders). Another 4 (28.6%) patients in CD and 5 (41.7%) patients in UC were partial responders. Vidofludimus was well tolerated, no drug-related serious adverse events were observed. CONCLUSIONS: This trial provides first evidence of clinical efficacy of vidofludimus in IBD. Although the safety and tolerability profile seems favorable, long-term controlled studies are needed to further investigate its potential as novel IBD therapy.

[CEUS as a tool to uncover an unusual cause of obstructive jaundice]. / KM-verstärkter Ultraschall zur Erkennung der seltenen Ursache eines obstruktiven Ikterus.

Aneurysms within the visceral arteries are rare. Among these, aneurysms of the splenic artery occur most frequently followed by aneurysms of the hepatic arteries. An early diagnosis is easily missed and almost all patients become symptomatic with an acute rupture associated with high mortality. Here we demonstrate the case of a 76-year-old patient who presented with acute upper abdominal pain accompanied by a single episode of vomiting and pyrexia of 39 °C. Laboratory results presented the picture of an obstructive jaundice without evidence for accompanying pancreatitis. Inflammatory markers were within normal limits at onset, but increased dramatically within the next few days. An acute calculous cholecystitis was diagnosed on abdominal ultrasound whereas gastroscopy revealed no relevant changes. Computed tomography was suspicious for pancreatitis of the head with obstruction of the bile duct. Choledocholithiasis was ruled out by ERCP, but symptoms persisted despite papillotomy. Due to raising inflammatory markers and an ongoing impairment of the patients condition, an abdominal CT scan was repeated which revealed the suspicion of a ruptured aneurysm of the common hepatic artery. At the time of transferral we were able to confirm the diagnosis by contrast-enhanced ultrasound and angiography. The patient was immediately forwarded to surgery due to lack of satisfactory endovascular procedures. In summary, the patient suffered from a ruptured spurial aneurysm of the right gastric artery thereby obstructing the common bile duct. Beside CT scans and angiography, this case documents a pivotal role for contrast-enhanced ultrasound in the work-up of visceral artery aneurysms.

[Intensive care and inflammatory bowel diseases (IBD). The severe and fulminant flare]. / Intensivmedizin und chronisch entzündliche Darmerkrankungen (CED). Schwerer und fulminanter Schub.

Inflammatory bowel disease (IBD) is a non-curable disease. Although we seem to have a definitive surgical solution for ulcerative colitis, patients are at risk of suffering from acute and chronic pouchitis as well as peri- and postoperative complications. In Crohn's disease medical treatment is able to prolong surgery-free survival, but no definitive healing strategy is as yet at hand. Moreover, effective medication exposes patients to potentially life-threatening complications. The severely compromised patient in particular needs careful surveillance and requires a balanced treatment strategy endorsed by gastroenterologists and surgeons. Treatment is still aimed at suppressing immune mechanisms and is far from being causal. Nevertheless, this approach has resulted in a reduction in surgical procedures and hospitalizations. The following overview covers special issues related to strategies for severe and fulminant flares of inflammatory bowel disease.

ABCB1 single-nucleotide polymorphisms determine tacrolimus response in patients with ulcerative colitis.

Tacrolimus (Tac) is effective in the treatment of steroid-refractory ulcerative colitis (UC); however, nonresponse and unpredictable side effects are major limitations. Because Tac response in patients who have undergone solid-organ transplantation has been associated with the presence of variants in CYP3A and ABCB1, we elucidated the contributions of CYP3A4*1B and CYP3A5*3 and of ABCB1 1236C>T, 2677G>T,A, and 3435C>T polymorphisms to Tac response in 89 patients with UC. Short-term remission and response were achieved in 61 and 14% of the patients, respectively, and were associated with colectomy-free survival. In a linear logistic regression model, patients with homozygous variants for one of the three ABCB1 alleles showed significantly higher short-term remission rates as compared with those of other genotypes. The effects held true after multivariate analysis including multiple comparisons and were more pronounced after correction for dose-adjusted Tac blood trough levels. We suggest that ABCB1, but not CYP3A5, may predict short-term remission of Tac in steroid-refractory UC.

Infliximab as rescue medication for patients with severe ulcerative/indeterminate colitis refractory to tacrolimus.

BACKGROUND: The calcineurin inhibitor tacrolimus and the anti-TNF-antibody infliximab are established options in steroid-refractory ulcerative colitis (UC). AIM: To evaluate the efficacy of infliximab-salvage therapy in patients with refractory UC failing to respond to tacrolimus. METHODS: Twenty-four patients were enrolled in this evaluation. Reasons for tacrolimus therapy were steroid-refractory disease in 19 patients and steroid-dependency in five patients. All patients receiving infliximab had tacrolimus-refractory active disease (Lichtiger score >10) and were treated with 5 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter, if tolerated. RESULTS: Six of 24 patients (25%) achieved remission following infliximab infusion and four of 24 (17%) had an initial response only, but underwent proctocolectomy later because of loss of response (3) or development of a delayed hypersensitivity reaction (1). Fourteen patients (58%) completely failed to respond with 10 undergoing colectomy. Eight patients experienced side effects under infliximab, including two infectious complications (herpes zoster and herpes pneumonia). CONCLUSIONS: Infliximab offers a therapeutic option as rescue therapy in about a quarter of patients with active UC after failing to respond to tacrolimus. This benefit has to be weighed against the risks of infectious complications.

Influence of standard treatment on ileal and colonic antimicrobial defensin expression in active Crohn's disease.

BACKGROUND: Crohn's Disease (CD), a chronic intestinal inflammation, is currently treated primarily by therapeutics which are directed against inflammatory responses. Recent findings though suggest a central role of the innate immune barrier in the pathophysiology. Important factors providing this barrier are antimicrobial peptides like the alpha- and beta-defensins. Little is known about in vivo effects of common drugs on their expression. AIM: To analyse the influence of corticosteroids, azathioprine and aminosalicylate treatment on ileal and colonic antimicrobial peptides in active CD and also assess the role of inflammation. METHODS: We measured the expression of antimicrobial peptides and pro-inflammatory cytokines in 75 patients with active CD. RESULTS: Ileal and colonic alpha- and beta-defensins as well as LL37 remained unaffected by corticosteroids, azathioprine or aminosalicylate treatment. Additionally, we did not observe a negative coherency between Paneth cell alpha-defensins and any measured cytokines. HBD2 and LL37 unlike HBD1 levels were linked to inflammatory cytokines and increased in highly inflamed samples. CONCLUSIONS: Current oral drug treatment seems to have no major effect on the expression of antimicrobial peptides. In contrast to HBD2 and LL37, ileal levels of HD5 and HD6 and colonic HBD1 level are independent of current inflammation. Innovative drugs should aim to strengthen protective innate immunity.

Clinical trial: cyclophosphamide pulse therapy - a promising therapeutic alternative in refractory Crohn's disease.

BACKGROUND: In severe steroid-refractory Crohn's disease (CD), established therapies fail in a relevant proportion of patients. Recent pilot studies indicated the efficacy of cyclophosphamide pulse therapy in these patients. AIM: To provide further and substantial evidence for the rationale to apply cyclophosphamide pulse therapy as therapeutic option in severe courses of CD. METHODS: Fifteen patients with steroid-refractory (n = 13) or steroid-dependent (n = 2) CD received 2-6 (median 3) monthly pulses of 750 mg cyclophosphamide in an open-label fashion. Eleven patients were on concomitant immunosuppression (azathioprine/mercaptopurine n = 9; methotrexate n = 2). RESULTS: Thirteen of 15 patients (87%) had a clinical response (CDAI decrease >100). Ten patients (67%) went into remission (CDAI <150) after 8 weeks. Steroid-free remission was achieved in eight patients (54%). Two patients (13%) failed to respond. Median CDAI decreased from 420 (245-550) to 100 (26-538) at week 8. Remission lasted 16 months (median, range 4-40). In three patients, arthritis, erythema nodosum and episcleritis completely resolved. Cyclophosphamide pulse therapy administration was well tolerated in all subjects. CONCLUSIONS: Cyclophosphamide pulse therapy is safe and highly effective for induction and maintenance of remission in steroid-refractory/-dependent CD. There is a strong need for additional experience to improve the setting of the encouraging cyclophosphamide treatment in CD.

Probiotic E. coli treatment mediates antimicrobial human beta-defensin synthesis and fecal excretion in humans.

Inducible epithelial human beta-defensins (hBD) play an important role in intestinal barrier function. In vitro studies showed that clinically effective probiotics induce antimicrobial hBD-2. Here, we aimed to assess the in vivo effect in healthy volunteers and also addressed how defensins affect probiotic survival. Symbioflor 2 containing one strain of several viable genotypes of Escherichia coli was administered to 23 healthy individuals. After 3 weeks, fecal hBD-2 peptide was increased in 78% (mean 3.7-fold; P<0.0001). Interestingly, the fecal hBD-2 peptide was still elevated 9 weeks after treatment (P=0.008). In vitro studies revealed that this effect was mediated by only one out of three tested E. coli genotypes and comparable to probiotic E. coli Nissle 1917 (10- to 15-fold). Functional assays showed that all tested bacteria were similarly killed by defensins allowing to speculate about a suicidal character of this effect. Defensin induction seems to be a common and important mechanism of probiotic treatment.

Defensin-immunology in inflammatory bowel disease.

Defensins are endogenous antibiotics with microbicidal activity against Gram-negative and Gram-positive bacteria, fungi, enveloped viruses and protozoa. A disturbed antimicrobial defense, as provided by Paneth- and other epithelial cell defensins, seems to be a critical factor in the pathogenesis of inflammatory bowel diseases. Conspicuously, there is a relative lack of Paneth cell beta-defensins HD-5 and HD-6 in ileal Crohn's disease, both in the absence of a pattern recognition receptor NOD2 mutation and, even more pronounced, in its presence. This deficit is independent of concurrent active inflammation and results in a diminished antibacterial killing by the mucosa. The Crohn's disease mucosa has not only a significant lack in killing different Escherichia coli but also an impaired ability in clearing Staphylococcus aureus as well as anaerobic micro-organisms. Thus, this dysfunction in antibacterial barrier seems to be broad and is not restricted to a single bacterial strain. In addition to directly controlling barrier function, Paneth cell defensins also regulate the composition of the bacterial stool flora. In the majority of patients, the Paneth cell deficiency is mediated by WNT signalling which suggests a disturbed Paneth cell differentiation in ileal Crohn's disease. In contrast, colonic Crohn's disease is characterised by an impaired induction of mucosal beta-defensins, partly due to a low copy number of the beta-defensin gene cluster. Therefore it seems plausible that bacteria take advantage of a niche formed by defensin deficiency. This would represent a paradigm shift in understanding Crohn's disease and provides a target for future therapeutic strategies.

Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2.

Recent evidence suggests that probiotic bacteria may stabilize gut barrier function via induction of anti-microbial peptides such as defensins. This study aimed to elucidate the induction mechanism of the human beta defensin-2 (hBD-2) gene by different probiotic lactobacillus strains. The expression of hBD-2 mRNA peaked at 6 h of incubation upon treatment of Caco-2 cells and increased with higher dosage of various probiotic bacteria. Deletion of nuclear factor (NF)-kappaB and activator protein-1 (AP-1) binding sites on the hBD-2 promoter resulted in a complete abrogation of promoter activation by probiotics. As revealed by the use of specific mitogen-activated protein kinase (MAPK) inhibitors the hBD-2 induction was dependent on the MAPK extracellular regulated kinase (ERK 1/2), p38 and c-Jun N-terminal kinase (JNK), although to varying degrees. Several Lactobacillus strains and VSL#3, a probiotic cocktail of four lactobacilli, three bifidum and one streptococcus species, induced the secretion of the hBD-2 peptide into the culture media as shown by enzyme-linked immunosorbent assay (ELISA). Thus, the present study suggests that lactobacilli and the VSL#3 bacterial mixture strengthen intestinal barrier functions through the up-regulation of hBD-2 via induction of proinflammatory pathways including NF-kappaB and AP-1 as well as MAPKs.