Systematic review: the role of tacrolimus in the management of Crohn's disease.

BACKGROUND Several published studies have evaluated the efficacy of tacrolimus in the management of Crohn's disease with variable conclusions. AIM To review systematically the evidence examining the efficacy and safety of tacrolimus in treating Crohn's disease. METHODS The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PUBMED) and EMBASE (1984 to January 2011) were searched. Also, references from selected articles were examined. Case series (five or more patients), cohort and randomised controlled trials were eligible for inclusion, incorporating oral, intravenous or topical tacrolimus therapy. The primary outcome was induction of remission of active Crohn's disease. RESULTS Eleven studies met the inclusion criteria which included 163 patients, of which 127 received tacrolimus therapy. In patients with luminal Crohn's disease, the crude pooled remission rate for tacrolimus was 44.3% (range, 7-69%) and the crude pooled response rate was 37.1% (range, 14-57%). For patients with perianal disease using systemic tacrolimus, crude pooled remission rate was 28.6% (range, 0-64%) and crude pooled response rate was 38.8% (range, 0-57%). Combining data from two studies using topical tacrolimus, 35.7% of patients achieved remission and 28.6% partial response. Nonserious adverse effects are common, particularly tremor, paraesthesia and headache. Reversible nephrotoxity occurred in 16% of patients. CONCLUSIONS The current evidence; although of a poor quality, appears to support the use of tacrolimus in Crohn's disease. High quality randomised controlled trials are needed.

Not just a rash!

Henoch-Schonlein Purpura (HSP) is the most common systemic vasculitis in childhood and can present in adults. It is a self-limiting disease characterised by a tetrad of manifestations including the mandated typical cutaneous hallmark. We present a classic case of HSP complicated by gastrointestinal haemorrhage associated with hidradenitis suppurativa.

Clinical trial: randomized study of clarithromycin versus placebo in active Crohn's disease.

BACKGROUND: Crohn's disease is characterized by defective innate immune responses to intestinal bacteria. Clarithromycin is a broad-spectrum antibiotic that has good penetration into macrophages. AIM: To assess the efficacy of clarithromycin in active Crohn's disease. METHODS: Patients with Crohn's disease activity index > 200 and serum C-reactive protein > or = 10 mg/L were randomized to receive clarithromycin 1 g o.d. or placebo for 3 months. Patients taking more than 10 mg/day prednisolone or 3 mg/day budesonide were excluded. Primary outcome was remission (CDAI < or = 150) or response (fall in CDAI > or = 70 from pre-treatment level) at 3 months. RESULTS: The trial was stopped after 41 patients had been recruited because of poor overall efficacy. There was no difference in combined remission or response rates at 3 months between clarithromycin: 26% (five of 19) and placebo: 27% (six of 22) (P = 1.00). The mean (s.d.) fall in Crohn's disease activity index was 35 (80) clarithromycin and -2 (114) placebo (P = 0.24). However, post hoc analysis showed a significant difference in response/remission determined by Crohn's disease activity index after 1 month: 53% (10 of 19) clarithromycin vs. 14% (three of 22) placebo (P = 0.01). CONCLUSION: Clarithromycin 1 g for 3 months is ineffective in active Crohn's disease but possible benefit was observed at 1 month, suggesting that an initial effect may be attenuated by subsequent bacterial resistance.

Treatment of radiation proctitis.

Late complications of pelvic radiotherapy occur in 5-20% of patients, particularly chronic radiation proctitis (CRP). Rectal bleeding is the most common symptom. Other symptoms include difficulty in defaecation or tenesmus because of loss of distensibility of the rectum or rectal structuring. Treatment options of CRP include oral therapy (5-aminosalicylates, metronidazole), rectal instillation therapy (hydrocortisone, sucralfate, 5-aminosalicylates, formalin), thermal therapy (argon plasma coagulation, heater probe or laser) and hyperbaric oxygen. It is difficult to recommend evidence-based therapy. There are no adequately powered studies of the treatment of CRP and most data are uncontrolled, non-blinded observation studies from single sites. There are no standard evaluation tools (including endoscopic grading, symptom scores and quality-of-life scores), adequate description of preceding radiotherapy dose or adequate follow-up in most studies. Many studies have poor documentation of complications and few are carried out prospectively. A pragmatic approach is to use sucralfate enemas and oral metronidazole. Thermal methods seem to be effective and safe. Simple heater probe treatment or argon plasma coagulation are the preferred methods due to their better safety profile. Intra-rectal formalin seems to be effective, but possibly has a higher rate of complications. For resistant disease, hyperbaric oxygen may be an option.

Low molecular weight heparin (tinzaparin) vs. placebo in the treatment of mild to moderately active ulcerative colitis.

BACKGROUND: Heparin has anti-inflammatory and immunomodulatory activity which may be of therapeutic benefit in the treatment of ulcerative colitis. AIM: To test whether low molecular weight heparin, given subcutaneously, would provide a significant therapeutic response compared with placebo in the treatment of mild to moderate ulcerative colitis. STUDY DESIGN: A prospective, double-blind, randomized, placebo-controlled, multi-centre trial comparing tinzaparin 175 anti-Xa IU/kg/day (innohep, LEO Pharma) subcutaneously for 14 days followed by tinzaparin 4500 anti-Xa IU/day subcutaneously for 28 days with placebo, administered subcutaneously once daily for up to 42 days. The primary outcome measure was the mean change in colitis activity from baseline to the end of study treatment assessed by the sum of scores of stool frequency, rectal bleeding, sigmoidoscopic appearance and histology. Secondary outcome measures included changes in individual activity indices and laboratory parameters. Patients were assessed at weekly intervals for 6 weeks and within 1 week of completing treatment. RESULTS: One hundred patients with active ulcerative colitis (up to six bloody stools per day, no fever, no tachycardia or systemic disturbances) were randomized. Forty-eight received tinzaparin and 52 received placebo. The difference in the mean percentage change in colitis activity from baseline to end of treatment (tinzaparin-placebo) was not statistically significant (P = 0.84). There was no difference between tinzaparin and placebo in any secondary outcome measure. One major bleed (rectal), occurred in a patient receiving placebo. CONCLUSION: This is the largest trial to date of heparin in ulcerative colitis. The results show no benefit of low molecular weight heparin over placebo in mild to moderately active ulcerative colitis.

Treatment of oesophago-gastric tumours.

The incidence of oesophageal adenocarcinoma continues to rise rapidly in the West whereas cancer of the stomach is becoming less common. Most patients present with advanced disease that is not amenable to curative treatment. This review focuses on recent evidence on the endoscopic therapy of oesophago-gastric cancer. Although there are many treatment modalities available, there is a paucity of good quality randomised trial evidence on which to base palliative treatment decisions. Furthermore, although palliation of dysphagia may be improved by expandable metal stents or ablative therapy, there is no evidence that this improves survival and each of these therapies has a high frequency of complications particularly in longterm survivors. Exciting developments have however been reported in the therapy of early stage oesophago-gastric cancer. Endoscopic mucosal resection is particularly promising with high rates of complete removal of early cancer or high grade dysplasia. Long-term follow up of these patients is required because of high rates of metachronous tumour formation and at present there are no randomised trial data comparing endoscopic mucosal resection with conventional surgery.

A randomised controlled trial of high versus low long chain triglyceride whole protein feed in active Crohn's disease.

BACKGROUND: Polymeric feeds have shown variable efficacy in active Crohn's disease (CD) with remission rates from 36% to 82%. Meta-analyses of elemental, peptide, and whole protein feeds have shown a strong negative correlation between remission rate in CD and the long chain triglyceride (LCT) content of the feed. We performed a randomised controlled double blind trial in patients with active CD comparing two single whole protein feeds with LCT supplying 5% or 30% of the total energy. METHODS: Fifty four patients with active CD (Crohn's disease activity index (CDAI) >200, serum C reactive protein (CRP) 10 mg/l) were randomised to a high or low LCT feed for three weeks. The total amount of energy supplied by fat was identical in the two feeds. Remission was defined as a CDAI < or =150 and response as a fall in CDAI of > or =70 or a CRP <10 mg/l. RESULTS: Overall remission rate by intention to treat was 26% for the low LCT feed and 33% for the high LCT feed (p=0.38). Response was achieved in 33% with the low LCT and in 52% with the high LCT feed (p=0.27). CRP <10 mg/l was achieved in 30% in the low LCT and 33% in the high LCT group (p=0.99). Thirty nine per cent (21/54) of patients withdrew before three weeks because of inability to tolerate the diet. Excluding patients unable to tolerate the diet, remission rates were 46% for low LCT and 45% for high LCT (p=0.99). DISCUSSION: This trial has shown no difference in the effect of low and high LCT whole protein feeds in active CD. The previously reported correlation between LCT content of diet and response in active CD is unlikely to be due to LCT itself and may be due to some other component of high LCT feeds.

Interaction between bacterial peptides, neutrophils and goblet cells: a possible mechanism for neutrophil recruitment and goblet cell depletion in colitis.

Goblet cell depletion occurs in various forms of colitis, but its mechanism is unknown. We have investigated two linked hypotheses: (i) that bacterial peptides, such as formyl-methionyl-leucyl-phenylalanine (fMLP), interact with epithelial cells inducing the release of chemokines, including interleukin-8 (IL-8), which in turn leads to the recruitment of neutrophils which release mucin secretagogues; (ii) that fMLP acts directly on epithelial cells to cause mucus secretion. Studies were performed to measure the effects of fMLP on the synthesis and secretion of IL-8 and mucus by the goblet cell differentiated colon cancer cell lines HT29-MTX (methotrexate-conditioned HT29 colonic adenocarcinoma cell line) and LS174T, and to assess the effects of neutrophil-derived secretagogues on goblet cell secretion in these cell lines. fMLP (0.1 microM) increased the secretion of IL-8 by 105% (P<0.0001) in HT29-MTX cells and by 401% (P<0.0001) in LS174T cells. fMLP also increased the synthesis and secretion of mucins by these cell lines, with maximal effects of 65% above control values for synthesis (P<0.01) and 73% for secretion (P<0.01). A dose-related increase (up to 67%; P<0.01) in mucin secretion was demonstrated in HT29-MTX cells in response to incubation with supernatant from activated neutrophils. This effect was largely (83%; P<0.02) inhibited by ICI 200,355, a specific inhibitor of neutrophil elastase. In conclusion, the bacterial peptide fMLP and neutrophil elastase are both potent mucus secretagogues for colon epithelial cells. fMLP also elicits release of the potent neutrophil chemoattractant IL-8 from colon epithelial cells. These findings support the hypothesis that the mucosal inflammation and mucus depletion seen in ulcerative colitis could result from interaction between bacterial peptides and the mucosa.

Increasing the intra-Golgi pH of cultured LS174T goblet-differentiated cells mimics the decreased mucin sulfation and increased Thomsen-Friedenreich antigen (Gal beta1-3GalNac alpha-) expression seen in colon cancer.

Mucins in ulcerative colitis and colon cancer share common properties of reduced sulfation and increased oncofetal carbohydrate antigen expression. It has previously been shown that there is no simple correlation between these changes and the activity of the relevant glycosyl-, sialyl-, and sulfo-transferases. We examined mucin sulfation and expression of oncofetal Thomsen-Friedenreich (TF) antigen (galactosyl beta1-3N-acetylgalactosamine alpha-) in the goblet cell-differentiated human colon cancer cell line LS174T following treatment with bafilomycin A(1, )which raises intra-Golgi pH, or monensin, which disrupts medial-trans Golgi transport. Cells were dual-labeled with sodium [(35)S]-sulfate and D-[6-(3)H(N)]-glucosamine hydrochloride, or labeled with L-[U-(14)C]-threonine alone. Mucin was purified using Sepharose CL-4B gel filtration. Mucin sulfo-Lewis(a) and TF antigen expression were assessed using the F2 anti-sulfo-Lewis(a) monoclonal antibody and peanut agglutinin binding respectively. Bafilomycin (0.01 microM; 48 h) reduced total mucin sulfation, expressed relative to incorporation of glucosamine, to 0.50 +/- 0.04 d.p.m. [(35)S]-sulfate per d.p.m. [(3)H]-glucosamine compared to control, 0.84 +/- 0.05 (p < 0.001, n = 16). This was accompanied by 50.3 +/- 8.0% increased expression of TF antigen (p < 0.01) and 50.1 +/- 5.5% decreased expression of sulfo-Lewis(a) (p < 0.01). The reduced sulfate:glucosamine ratio was largely due to increased incorporation of glucosamine into newly synthesized mucin rather than reduction in total sulfate incorporation. In contrast, monensin only reduced total mucin glycosylation at concentrations > 0.1 microM and had no significant effect on mucin sulfation or TF expression. Intra-Golgi alkalinization affects mucin glycosylation, resulting in decreased mucin sulfation and increased expression of TF antigen, changes that mimic those seen in cancerous and premalignant human colonic epithelium.

Open label trial of oral clarithromycin in active Crohn's disease.

BACKGROUND: Crohn's disease seems likely to be due in some way to bacteria. Clarithromycin is a broad spectrum macrolide antibiotic with good penetration into macrophages and may be effective in eradicating the organisms that are presumed to be at the centre of the granulomatous reaction in Crohn's disease. METHODS: Twenty-five patients with active Crohn's disease were treated with oral clarithromycin 250 mg b.d. in an open label study. Treatment was for an initial 4-week period, continued to 12 weeks in patients who had shown a partial or complete response. The patients had a median age of 30 years (range 17-72), and disease duration of 5 years (range 2 months-28 years); 14 had ileocolonic, four small bowel, seven colonic disease and 10 had previous resections. Twenty patients were receiving a 5-ASA preparation, 15 corticosteroids (prednisolone median dose 10 mg range 2-30 mg) and nine azathioprine. All patients receiving corticosteroids or azathioprine had been on unchanged treatment for at least 12 weeks. RESULTS: Median pre-treatment Harvey Bradshaw index (HBI) was 9 (range 5-16) and median serum C-reactive protein was 21.5 mg/L (range < 5-117). By 4 weeks the median HBI had decreased to 5 (range 0-18) (P < 0.001) and median CRP to 17 mg/L (range < 5-157) (P=0.16). Sixteen patients (64%) had at least a 3 point fall in HBI and remission (defined as a HBI less than or equal to 4) was achieved in 12 patients (48%). By 12 weeks median HBI was 5 (range 0-18) (P < 0.001) and median CRP was 14.5 mg/L (range < 5-157) (P=0.05). Eleven of the 25 patients studied continued on oral clarithromycin after 12 weeks for a median of 28 weeks (range 20-60). Eight (73%) remained in remission on treatment. When treatment with clarithromycin was stopped three remained in remission and five relapsed after a median of 5 months (range 4-9). Two patients withdrew due to non-serious side-effects. Treatment was well tolerated in the remaining patients. CONCLUSION: This open label study has shown an impressive response to clarithromycin in a group of patients with active Crohn's disease, many of whom had been resistant to other therapy. A formal randomized controlled trial of clarithromycin in active Crohn's disease is needed.

Behavior of a cell line derived from normal human hepatocytes on non-physiological and physiological-type substrates: evidence for enhancement of secretion of liver-specific proteins by a three-dimensional growth pattern.

The behavior of a recently described cell line, HH25, derived from normal human hepatocytes, has been investigated on several different substrates--tissue-culture plastic, glass, a thin layer of rat-tail collagen I, and thin layers or thick gels of extracellular matrix derived from the Engelbreth-Holm-Swarm murine sarcoma (EHS matrix). Cellular morphology, proliferation, and secretion of three hepatocyte-specific proteins (albumin, alpha1 acid glycoprotein, and alpha1 antitrypsin) have been examined. There were no differences in morphology, proliferation, or differentiated function in the cells on either plastic, glass, collagen, I, or a thin layer of EHS matrix, but on a thick EHS matrix gel the cells altered their morphology (forming three-dimensional colonies with canalicular-like structures) and their production of albumin and alpha1 acid glycoprotein was enhanced. This suggests that the enhanced differentiated function is associated with the morphological change (occurring only on the thick EHS gel) rather than with receptor-mediated cell-matrix interactions (which can also occur on the thin layer of EHS matrix). This cell line is therefore a good in vitro cellular model for the investigation of the roles of morphological changes and of cell-cell and cell-matrix interactions in the control of human hepatocyte behavior without the need for an extensive source of primary tissue.

Adjuvant post-operative therapy.

About 90% of patients with Crohn's disease require surgery at some time in their lives but the clinical recurrence rate after surgery is about 50% within 5 years, with 50% requiring further surgery within 10 years. Endoscopic evidence of relapse can be found in 75% within 12 weeks of resection. There is therefore a major problem to be solved. The solution is less clear. Retrospective studies suggest that smoking is a major factor determining a poor prognosis after surgery and it is most important that patients are encouraged to stop. There is strong evidence linking diet with Crohn's disease but the mechanism and nature of this link remains unclear. A low total fat intake, possibly supplemented with eudragitcoated n-3 fatty acid (fish oil) looks reasonable on current evidence but not proven. Mesalazine and metronidazole are the drugs for which most supportive evidence is available. The individual trials of mesalazine have generally proved inconclusive and meta-analyses have been needed to demonstrate a significant beneficial effect (approximately halving the relapse rate at 1 year). More recent large controlled studies performed after the meta-analyses however have again proved negative and the benefit is probably more modest than the meta-analyses suggested. Metronidazole, 20 mg/day for the first 3 months after surgery, has been shown to reduce relapse by just over one-third with a beneficial effect that was surprisingly sustained throughout a 3 year follow-up period. Peripheral neuropathy is a problem and further studies are needed at lower dosage. Azathioprine, 1.5-2 mg/kg/day is effective as maintenance therapy but there is insufficient evidence to recommend its routine post-operative use, moreover it takes up to 3 months to have an effect. Although budesonide has been shown to delay the time to relapse in non-operated patients it, like other corticosteroids, has been shown to be no better than placebo when maintenance is assessed according to the proportion of patients who remain relapse-free after 1 year. Patients undergoing operation for Crohn's disease should therefore be strongly advised to stop smoking. A 3 month course of oral metronidazole plus continued maintenance with oral mesalazine can be justified on current evidence but further studies are needed.

Management of the first presentation of severe acute colitis.

Prompt diagnosis and exclusion of infection requires a minimum of rigid sigmoidoscopy, rectal mucosal biopsy and stool culture. Admission to hospital is mandatory for patients with features of severe disease, or who are in their first attack of ulcerative colitis and have bloody diarrhoea, even if the criteria for severe disease are not met. Once admitted, the patient should be monitored by plain abdominal X-ray, full blood count, serum albumin and C reactive protein on alternate days; temperature and pulse rate should be recorded four times per day. Treatment should be instituted as soon as the diagnosis is made with an intravenous corticosteroid (hydrocortisone 100 mg intravenously, four times daily, or equivalent). Antibiotics may be included if infection cannot be confidently excluded. Free diet can be allowed but attention should be given to nutritional, fluid and electrolyte status with intravenous replacement if necessary. Any evidence of colonic dilatation occurring despite maximal therapy should be regarded as an absolute indication for colectomy. The patient should be kept fully informed from an early stage about the likely natural history of the condition and about the possible therapeutic options including surgery. Cyclosporin therapy should be reserved for patients who have a poor response to the first 3-4 days of corticosteroid therapy, particularly those with serum C reactive protein > 45 mg/l and who do not yet have absolute indications for colectomy. Most patients who have not convincingly responded within 10 days of starting full medical therapy should undergo colectomy, although partial responders who are afebrile may reasonably continue for up to 14 days before a final decision. Approximately 30-40% of patients with severe colitis will need colectomy within the first 6 months. With optimal management, mortality should be zero, but better medical therapies are urgently needed to reduce the colectomy rate.

Tissue plasminogen activator, plasminogen activator inhibitors, and activator-inhibitor complex in liver disease.

AIMS: To identify the relative contribution of plasminogen activators, particularly tissue plasminogen activator (t-PA) and specific plasminogen activator inhibitors (PAI-1, PAI-2), to the fibrinolytic changes associated with various types of liver disease or severe chemical and physical damage to the liver. METHODS: Platelet rich (PRP) and platelet poor plasma (PFP) from patients with alcoholic cirrhosis, primary biliary cirrhosis, hepatic malignancy, or paracetamol overdose, or who were undergoing partial hepatectomy or liver transplantation, were assayed for t-PA, PAI-1, t-PA-PAI-1 complex and PAI-2 antigen values using specific enzyme linked immunosorbent assays (ELISAs) developed in this laboratory. RESULTS: Appreciable increases in the plasma concentration of t-PA, PAI-1, and t-PA-PAI-1 were seen in patients with alcoholic cirrhosis, primary biliary cirrhosis, and hepatic malignancy. Liver damage due to paracetamol overdose and partial hepatectomy both resulted in a striking increase in plasma PAI-1 concentration, although concentrations of t-PA and t-PA-PAI-1 complex were less affected. Concentrations of t-PA, PAI-1, and t-PA-PAI-1 complex returned to near normal values after successful liver transplantation in a patient with chronic active hepatitis. PAI-2 was also detected in several patients with chronic liver disorders. CONCLUSIONS: Haemorrhage due to fibrinolytic bleeding is commonly associated with liver disease. The patients studied here all had appreciable increases in circulating t-PA antigen concentrations. This was associated with increased concentrations of PAI-1 antigen and t-PA-PAI-1 complex and the balance between activator and inhibitor did not result in systemic plasmin generation. Reduced PAI-1 activity in cirrhosis or a critical difference in the ratio of t-PA to PAI-1 concentrations may explain the enhanced plasminogen activator activity previously noted in cirrhosis but not metastatic disease. Reduced hepatic clearance of t-PA and t-PA-PAI-1 complex due to impaired liver function may account for increased concentrations of free and complexed t-PA.