Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

AIM：To investigate the efficacy of 6-mercaptopurine （6-MP） in cases of azathioprine （AZA） hypersensitivity in patients with inflammatory bowel disease. METHODS： Twenty nine previously confirmed Crohn’s disease （CD） （n = 14） and ulcerative colitis （UC） （n = 15） patients with a known previous （AZA） hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies （CDAI/CAI）, laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS： In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 （8 UC, 4 CD） patients, and after the first year in 9 （6 UC, 3 CD） patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts （P = 0.01）, CRP （P = 0.02）, and serum iron （P = 0.05） values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION： About one-third of the previously AZA- intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.     

Endoscopic findings can predict the efficacy of leukocytapheresis for steroid-naive patients with moderately active ulcerative colitis

AIM：To investigate the therapeutic usefulness of leukocytapheresis （LCAP; Cellsoba） in steroid-naive patients with moderately active ulcerative colitis （UC）. METHODS： Eighteen steroid-naive patients with moderately active UC received one LCAP session every week for fi ve consecutive weeks. RESULTS： The remission rate 8 weeks after the last LCAP session was 61.1% （11/18）. All three patients with deep ulcers showed worsening after LCAP. For the remaining 15 patients, who had erosions or geographic ulcers, the average clinical activity index （CAI） score dropped significantly from 9.4 to 3.8 eight weeks after the last LCAP session （t = 4.89, P = 0.001）. The average C-reactive protein （CRP） levels before and after LCAP were 1.2 mg/dL and 1.0 mg/dL, respectively. Of the patients with erosions, geographic ulcers, and deep ulcers, 100% （9/9）, 33.3% （2/6）, and 0% （0/3） were in remission 8 weeks after the last LCAP session, respectively （χ2 = 7.65, P 〈 0.005）. Forty- eight weeks after the last LCAP session, the remission rates for patients with erosions and geographic ulcers were 44.4% （4/9） and 16.7% （1/6）, respectively. Only one patient suffered a mild adverse event after LCAP （nausea）. CONCLUSION： LCAP is a useful and safe therapyfor steroid-naive UC patients with moderate disease activity. Moreover, the effi cacy of the treatment can be predicted on the basis of endoscopic fi ndings.     

Use of mycophenolate mofetil in inflammatory bowel disease

AIM： To assess the efficacy and safety of mycophenolate mofetil （MMF） prospectively in inflammatory bowel disease （IBD） patients intolerant or refractory to conventional medical therapy.
METHODS： Crohn＇s disease （CD） or ulcerative colitis/ IBD unclassified （UC/IBDU） patients intolerant or refractory to conventional medical therapy received MMF （500-2000 mg bid）. Clinical response was assessed by the Harvey Bradshaw index （HBI） or colitis activity index （CAI） after 2, 6 and 12 mo of therapy, as were steroid usage and adverse effects.
RESULTS： Fourteen patients （9 CD/5 UC/IBDU; 8M/6F; mean age 50.4 years, range 28-67 years） were treated and prospectively assessed for their response to oral MMF. Of the 11 patients who were not in remission on commencing MMF, 7/11 （63.6%） achieved remission by 8 wk. All 3 patients in remission on commencing MMF maintained their remission. Ten patients were still on MMF at 6 mo with 9/14 （64.3%） in remission, while of 12 patients followed for 12 mo, 8 were in remission without dose escalation （66.7%）. Three patients were withdrawn from the MMF due to drug intolerance. There were no serious adverse events attributed due to the medication.
CONCLUSION： MMF demonstrated efficacy in the management of difficult IBD. MMF appeared safe, well tolerated and efficacious for both short and long-term therapy, without the need for dose escalation. Further evaluation of MMF comparing it to conventional immunosuppressants is required.     

Comparison of the efficacy of granulocyte and monocyte/macrophage adsorptive apheresis and leukocytapheresis in active ulcerative colitis patients: a prospective randomized study

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with recurring inflammation of the colorectal mucosa. Recently, cytapheresis has emerged as a new treatment for patients with UC. Removal methods are mainly performed with beads [granulocyte and monocyte/macrophage adsorptive apheresis (GMCAP)] or filters [leukocytapheresis (LCAP)]. Both treatments have been reported to be effective for active UC. There have been few trials, however, comparing the efficacy of GMCAP and LCAP. In this study, we prospectively evaluated the efficacy of LCAP and GMCAP for the treatment of active UC. METHODS: Thirty-nine patients [18 male, 21 female; mean age 38.7 years; duration of disease 6 years; clinical activity index (CAI) >6 points] with moderate-to-severe active UC were randomly assigned to the LCAP (n=21) or GMCAP group (n=17). Adacolumn (cellulose acetate beads; Japan Immunoresearch Laboratories, Takasaki, Japan) for GMCAP and Cellsorba EX (polyethylene phthalate fibers; Asahi Medical Co. Ltd, Tokyo, Japan) for LCAP were used for leukocyte removal. Patients received two sessions of cytapheresis in the first week, followed by four weekly administrations. Steroid doses were tapered if patients achieved clinical improvement. When the CAI score had decreased by 5 points or more, the patient was considered to have improved. RESULTS: Thirteen patients in the GMCAP group and 14 in the LCAP group achieved clinical improvement. No significant difference was found in clinical response and clinical course between LCAP and GMCAP. Hemoglobin levels were significantly decreased immediately after one session of cytapheresis in the LCAP group. No severe adverse effects were observed in any of the patients. No significant differences were observed in any clinical parameters predictive of a response to either LCAP or GMCAP. But in all patients receiving cytapheresis, a high CAI score was a significant risk factor for treatment failure. All of the cytapheresis nonresponders had CAI scores >or=16. CONCLUSION: Both GMCAP and LCAP were effective treatments for active UC. Patients with severe UC and a high CAI score were, however, refractory to treatment.     

Granulocytapheresis is useful as an alternative therapy in patients with steroid-refractory or -dependent ulcerative colitis

BACKGROUND: Recently, granulocyte and monocyte adsorption apheresis (GCAP) has been shown to be safe and effective for active ulcerative colitis (UC). We analyzed the safety and efficacy of GCAP (G-1 Adacolumn) in patients with steroid-refractory and -dependent UC. G-1 Adacolumn is filled with cellulose acetate carriers that selectively adsorb granulocytes and monocytes/macrophages. METHODS: Forty-four patients with UC were treated with GCAP. These patients received 5 apheresis sessions over 4 weeks. Twenty patients had steroid-refractory UC (group 1) and 10 had steroid-dependent UC (group 2). Fourteen patients who did not want readministration of steroids were treated with GCAP at the time of relapse, just after discontinuation of steroid therapy (group 3). RESULTS: Of 44 patients treated with GCAP, 24 (55%) obtained remission (CAI < or = 4), 9 (20%) showed a clinical response, and 11 (25%) remained unchanged. Only 2 of 10 patients (20%) with severe steroid-refractory UC (CAI > or = 12) achieved remission, whereas 7 of 10 patients (70%) with moderate steroid-refractory UC achieved remission (p < 0.05). The dose of corticosteroids was tapered in 9 of 10 (90%) patients with steroid-dependent UC after GCAP therapy. Twelve (86%) of 14 patients in group 3 showed an improvement in symptoms and could avoid re-administration of steroids after GCAP. No severe adverse effects occurred. CONCLUSIONS: The findings of this study suggest that GCAP may be a useful alternative therapy for patients with moderate steroid-refractory or -dependent UC, although cyclosporin A or colectomy is necessary in patients with severe UC. GCAP may also be useful for avoiding re-administration of steroids at the time of relapse. Randomized, controlled clinical trials are needed to confirm these findings.     

Selective Granulocyte and Monocyte Adsorptive Apheresis as a First-Line Treatment for Steroid Naïve Patients with Active Ulcerative Colitis: A Prospective Uncontrolled Study

Corticosteroid therapy of ulcerative colitis (UC) is associated with frequent adverse side effects and poor quality of life. Recently, adsorptive granulocyte and monocyte/macrophage apheresis has shown efficacy in patients with severe steroid refractory UC. The objective of this study was to investigate if, instead of corticosteroids, adsorptive leukocytapheresis has efficacy as the first-line therapy for steroid-naïve patients with active UC. Twenty patients, aged 15–49 years, with a mean clinical activity index (CAI) of 8.6 were recruited. Adsorptive leukocytapheresis was done with Adacolumn, which contains cellulose acetate beads as adsorptive carriers for granulocytes and monocytes (FcγR and complement receptors expressing leukocytes). Each patient received 6 to 10 leukocytapheresis sessions of 60-min duration, at 2 sessions/week. Efficacy was assessed 1 week after the last session. Post treatment, the mean CAI was 3.0 (P = 0001), and 17 of 20 patients (85%) were in remission. There were significant falls in C-reactive protein (P = 0.0003), total white cell counts (P = 0.003), neutrophils (P = 0.0029), and monocytes (P = 0.0038), an increase in lymphocytes (P = 0.001), and increases in the blood levels of soluble TNF-α receptors I (P = 0.0007) and II (P = 0.0045) in the column outflow (blood return to the patients). Further, at 8 months, 60% of patients had maintained their remission. No severe side effects were reported. In conclusion, adsorptive leukocytapheresis should reduce corticosteroid therapy in patients with moderate UC; cases with early-stage active disease may benefit most.     

Effect of probiotics on pro-inflammatory cytokines and NF-��B activation in ulcerative colitis

AIM:To demonstrate the therapeutic effect of probiotics in patients with ulcerative colitis(UC),and their effect on inflammatory mediators and nuclear factor(NF)κB activation in these patients.METHODS:Thirty patients with mild to moderate UC were randomly classified into two groups:sulfasalazine group,who received sulfasalazine 2400 mg/d;and probiotic group,who received sulfasalazine 2400 mg/d with probiotic.The patients were investigated before and after 8 wk of treatment with probiotic(Lactobacillus delbr...     

Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis

BACKGROUND/AIM: Active ulcerative colitis (UC) is often associated with increased peripheral granulocytes and monocytes/macrophages which show activation behavior and prolonged survival time. Further, mucosal granulocyte level parallels intestinal inflammation and can predict UC relapse. Accordingly, our aim was to see if adsorptive granulocyte/monocyte apheresis (GMA) can promote remission and spare steroid in patients with steroid-dependent (SD) UC. METHODS: 69 SD patients, at the time of relapse, were randomly assigned to groups I (n = 46) and II (n = 23). The mean dose of prednisolone (PSL) was 12 mg/day/patient, CAI (clinical activity index) 9.2 in both groups. Group I patients were given up to 11 GMA sessions over 10 weeks with Adacolumn; in group II, the mean dose of PSL was increased to 30 mg/day/patient. RESULTS: At week 12, 83% of group I and 65% of group II patients were in remission, CAI in group I was 1.7 (p < 0.001) and in group II, 2.5 (p < 0.001). Further, during the 12 weeks of treatment, the cumulative amount of PSL received per patient was 1,157 mg in group I and 1,938 mg in group II (p = 0.001). CONCLUSIONS: GMA appeared to be an effective adjunct to standard drug therapy of moderately severe UC by promoting remission and sparing steroids.     

Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis

AIM:To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis(UC)patients.METHODS:This was a prospective,multicenter,observational study.Between May 2010 and August 2012,49 steroid-refractory UC patients(55 flare-ups)were consecutively enrolled.All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1mg/kg per day.The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/m L for the first 2 wk.Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger’s clinical activity index(CAI).RESULTS:The mean CAI was 12.6±3.6 at onset.Within the first 7 d,93.5%of patients maintained high trough levels(10-15 ng/m L).The CAI significantly decreased beginning 2 d after treatment initiation.At 2wk,73.1%of patients experienced clinical responses.After tacrolimus initiation,31.4%and 75.6%of patients achieved clinical remission at 2 and 4 wk,respectively.Treatment was well tolerated.CONCLUSION:Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation.Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.     

Dose-escalation, phase I/II study of azithromycin and pyrimethamine for the treatment of toxoplasmic encephalitis in AIDS

OBJECTIVE: To assess the safety, tolerance and activity of increasing doses of azithromycin in combination with pyrimethamine for the treatment of toxoplasmic encephalitis (TE) in patients with AIDS. DESIGN: A phase I/II dose-escalation study of oral azithromycin in combination with pyrimethamine. SETTING: Eight clinical sites in the United States. PATIENTS: Forty-two adult HIV-infected patients with confirmed or presumed acute TE. METHODS: Patients were enrolled into three successive cohorts receiving azithromycin 900, 1200 and 1500 mg a day with pyrimethamine as induction therapy. The induction period was 6 weeks followed by 24 weeks of maintenance therapy. MAIN OUTCOME MEASURES: Patient response was evaluated clinically and radiologically. RESULTS: Of the 30 evaluable patients, 20 (67%) responded to therapy during the induction period. Ten experienced disease progression. Of the 15 patients who received maintenance therapy, seven (47%) relapsed. Six patients discontinued treatment during the induction period as a result of reversible toxicities. Treatment-terminating adverse events occurred most frequently among the patients receiving the 1500 mg dose. CONCLUSION: The combination of azithromycin (900-1200 mg a day) and pyrimethamine may be useful as an alternative therapy for TE among patients intolerant of sulfonamides and clindamycin, but maintenance therapy with this combination was associated with a high relapse rate. The combination was safe, but low-grade adverse events were common.     

Effects of adacolumn selective leukocytapheresis on plasma cytokines during active disease in patients with active ulcerative colitis

AIM: To investigate the relationship between ulcerative colitis (UC) clinical activity index (CAI) and circulating levels of IL-1ra, IL-10, IL-6 and IL-18. METHODS: Blood levels of IL-lra, IL-10, IL-6 and IL-18 were measured in 31 patients with active UC, the mean CAI was 11.1, ranging from 5-25; and 12 healthy individuals as controls. Patients were given granulocyte and monocyte adsorptive apheresis (GMA) with Adacol-umn. Leucocytes which bear the FcyR and complement receptors were adsorbed to the column leucocytapher-esis carriers. Each patient could receive up to 11 GMA sessions over 8 wk. RESULTS: We found strong correlations between CAI and IL-10 (r = 0.827, P < 0.001), IL-6 (r = 0.785, P < 0.001) and IL-18 (r = 0.791, P < 0.001). IL-lra was not correlated with CAI. Following GMA therapy, 24 of the 31 patients achieved remission and the levels of all 4 cytokines fell to the levels in healthy controls. Further, blood levels of IL-lra and IL-10 increased at the column outflow and inflow at 60 min suggesting release from leucocytes that adhered to the carriers. CONCLUSION: Elevated blood levels of IL-6 and IL-18 together with peripheral blood granulocytes and mono-cytes/macrophages in patients with active UC show acti-vative behaviour and increased survival time can be pro-inflammatory and the targets of GMA therapy.     

Use of infliximab in the prevention and delay of colectomy in severe steroid dependant and refractory ulcerative colitis

AIM： To determine if infliximab can prevent or delay surgery in refractory ulcerative colitis （UC）. METHODS： UC patients who failed to have their disease controlled with conventional therapies and were to undergo colectomy if infliximab failed to induce a clinical improvement were reviewed. Patients were primarily treated with a single 5 mg/kg infliximab dose. The Colitis Activity Index （CAI） was used to determine response and remission. Data of 8 wk response and colectomy rates at 6 mo and 12 mo were collected. RESULTS： Fifteen patients were included, 7 with UC unresponsive or intolerant to Ⅳ hydrocortisone, and 8 with active disease despite oral steroids （all but one with therapeutic dosage and duration of immunomodulation）. All the Ⅳ hydrocortisone-resistant/intolerant patients had been on azathioprine/6-MP 〈 8 wk. At 8 wk, infliximab induced a response in 86.7% （13/15） with 40% in remission （6/15）. Within 6 mo of treatment 26.7% （4/15） had undergone colectomy and surgery was avoided in 46.6% （7/15） at 12 mo. The colectomy rate at 12 mo in those on immunomodulatory therapy 〈 8 wk at time of infliximab was 12.5% （1/8） compared with 100% （7/7） in patients who were on long-term maintenance immunomodulators （P 〈 0.02）. CONCLUSION： Infliximab prevented colectomy due to active disease in immunomodulatory-na？ve, refractory UC patients comparable to the use of Cyclosporine. In patients, however, on effective dosage and duration of immunomodulation at time of infliximab therapy colectomy was not avoided.     

Efficacy and Safety of Adsorptive Granulocyte and Monocyte Apheresis in Elderly and Pregnant Patients With Ulcerative Colitis

In patients with active ulcerative colitis (UC), adsorptive granulocyte/monocyte apheresis (GMA) is expected to promote remission. We conducted a retrospective cohort study to evaluate the efficacy and safety of GMA in patients with active UC. Twenty‐one UC patients including five pregnant or lactating mothers and four elderly patients (aged >60 years) received up to 10 GMA sessions. UC severity was evaluated at baseline and after GMA therapy according to Lichtiger's Clinical Activity Index (CAI). We defined clinical remission as CAI ≤4. Overall, the median CAI score after GMA therapy had decreased from 9 to 4 (P < 0.001). The clinical remission rate was 62%, but in the elderly and pregnant or lactating mothers, the remission rates were 100% and 60%, respectively. No severe adverse effects were seen in this study. Our results may support GMA as an effective and safe treatment for active UC patients, including elderly patients and pregnant cases.     

Leukocyte adsorptive apheresis for the treatment of active ulcerative colitis: a prospective, uncontrolled, pilot study.

BACKGROUND AND AIMS: Active ulcerative colitis (UC) is characterized by infiltration of activated granulocytes and monocytes/macrophages (GM) within the large bowel mucosa. GM are major sources of inflammatory cytokines, and in UC they are elevated with increased survival time. We investigated the possibility that reducing the level of these cells might promote remission of active UC. METHODS: Thirty-one patients with active corticosteroid refractory (refractory) UC, mean age of 42 years, duration of UC 6 years, clinical activity index (CAI) of 15, disease activity index (DAI) of 10, and 8 corticosteroid naive patients (naive), mean age of 36 years, duration of UC 2 years, CAI of 11, DAI of 8 were recruited. Each patient was treated with up to 11 cycles of granulocyte and monocyte adsorptive apheresis over 11 weeks by using a 335-mL capacity column filled with cellulose acetate beads that adsorb GM. RESULTS: At week 12, 81% of refractory (CAI, 3; P < 0.001 and DAI, 4; P < 0.001) and 88% of naive (CAI, 1; P = 0.012 and DAI, 3; P = 0.011) patients achieved remission. Early relapse was not a feature, and at 12 months, 26 of 33 patients had maintained their remission. The treatment was well tolerated, and no severe side effects were observed. CONCLUSIONS: The outcome of this study suggests that reduction of circulating granulocytes and monocytes results in alleviation of inflammation and promotes clinical remission in patients with severe active UC that has not responded to intensive corticosteroid treatment. These data suggest that formal controlled studies are warranted.     

Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC). METHODS: Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up. RESULTS: Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P=.040). Recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (P=.049). Furthermore, curcumin improved both CAI (P=.038) and EI (P=.0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed. CONCLUSIONS: Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.     

Effects of an angiotensin-converting enzyme inhibitor (ramipril) on inflammatory markers in secondary prevention patients: RAICES Study

AIMS: To evaluate the hypothesis that angiotensin-converting enzyme inhibitor therapy with ramipril reduces baseline levels of C-reactive protein in patients at high cardiovascular risk. METHODS: Secondary prevention patients were screened for eligibility and treated with ramipril for 6 month. Baseline and 6-month highly sensitive C-reactive protein levels were determined. RESULTS: A total of 77 patients were analyzed. The median highly sensitive C-reactive protein concentration at baseline was 2.17 mg/l (interquartile interval 0.97-4.54); whereas in post-treatment, the median was 1.70 mg/l (interquartile interval 0.88-3.41), P=0.0009. Patients were stratified according to risk level determined by baseline highly sensitive C-reactive protein levels: low-risk (<1 mg/l), intermediate risk (1-3 mg/l) and high risk (>3 mg/l) The reduction in highly sensitive C-reactive protein occurred at the expense of the high-risk group (baseline 5.02 mg/l, post-treatment 3.3 mg/l, P<0.0001), with no differences in the other groups. In multiple regression analysis, the reduction observed in the high-risk group could not be explained by baseline treatment or change in any of the variables analyzed. CONCLUSION: Highly sensitive C-reactive protein levels were reduced after a 6-month ramipril therapy in secondary prevention patients, suggesting an anti-inflammatory effect of angiotensin-converting enzyme inhibitors. Future investigations will be done to confirm these results, and to investigate how angiotensin-converting enzyme inhibitor treatment elicits anti-inflammatory effects.     

Successful treatment of steroid refractory active ulcerative colitis with natural interferon-beta--an open long-term trial

INTRODUCTION: In some steroid refractory patients with active ulcerative colitis (UC), treatment with immunosuppressive agents, such as cyclosporin, azathioprine or 6-mercaptopurin is effective. However, there are patients who fail to respond to these treatment options or who cannot tolerate them. Application of natural interferon-beta (nIFN-beta) may offer an alternative. Following our positive results with nIFN-beta in a previously published open-labeled study, the present study was designed as an extension with the hypothesis that administration of higher dosage of nIFN-beta (1.0 vs. 0.5 MIU) could result in fewer relapse events. PATIENTS AND METHODS: 46 steroid refractory patients with active UC and a mean clinical activity index (CAI) of 13.2 +/- 3.7 (range 9-23) were treated with nIFN-beta in addition to existing basic medication (5-ASA/SASP plus corticosteroids). During an induction period of eight weeks, 18 patients (group A) received 0.5 MIU nIFN-beta daily and 28 patients (group B), 1.0 MIU nIFN-beta daily intravenously as a bolus injection. Patients who achieved complete remission (decrease of CAI to < or = 4) during the induction period received maintenance therapy with nIFN-beta at the same dose level three times a week and corticosteroids were withdrawn. Remissions and maintenance of remissions were evaluated. RESULTS: In both groups, a comparable number of complete remissions occurred during the induction period: in 16 / 18 patients (89 %) in group A and in 24 / 28 patients (86 %) in group B. Duration of maintenance treatment was 60.0 +/- 90.0 weeks in group A and 52.7 +/- 9.6 weeks in group B. Under this treatment, relapses (increase of CAI to > or = 6) occurred in 5 / 16 patients (31 %) vs. 1 / 24 patients (4 %) (p < or = 0.05). Hence, regarding maintaining remissions, the 1.0 MIU group outscored the 0.5 MIU group. Apart from known flu-like side effects, the therapy was well tolerated by all patients in both groups. CONCLUSION: nIFN-beta may be a safe and effective alternative to induce and maintain remissions in patients with steroid refractory active UC. To validate the presented results, its effect has to be investigated in a randomized, placebo-controlled dose-finding trial.     

A polymorphism in the macrophage migration inhibitory factor gene is involved in the genetic predisposition of Crohn's disease and associated with cumulative steroid doses

BACKGROUND/AIMS: Macrophage migration inhibitory factor (MIF) is an important cytokine involved in the regulation of the innate immune system in IBD. Secreted MIF is able to induce the production of pro-inflammatory cytokines and counteracts anti-inflammatory effects of steroids. We evaluated whether the single nucleotide polymorphism (SNP) G/C at position -173 of the MIF gene contributes to the predisposition to IBD and higher amounts of steroid therapy. METHODOLOGY: We genotyped the SNP G/C at position -173 of the MIF gene in 157 patients with Crohn's disease (CD), 102 patients with ulcerative colitis (UC) and 489 healthy controls. Allele frequencies and cumulative steroid doses were compared. RESULTS: C allele and CC genotype frequencies were significantly decreased in CD patients compared to controls (p < 0.012 and p < 0.022, respectively). No significant differences were found in UC patients compared to controls. Cumulative corticosteroid dose was significantly higher in CD patients with the CC genotype [12300mg/yr (0-40000mg/yr), p < 0.021] compared with the GC genotype [220mg/yr (0-450mg/yr) and the GG genotype (310mg/yr (100-500mg/yr)]. In contrast, there were no significant differences between the genotypes in UC patients. CONCLUSIONS: Our data demonstrate the counterregulatory effects of MIF in CD patients and indicate the important role of the SNP G/C at position -173 of the MIF gene for the anti-inflammatory therapy with glucocorticoids.     

Ranitidine therapy in patients with idiopathic gastric acid hypersecretion

One hundred twenty-four patients with idiopathic gastric acid hypersecretion (basal acid output greater than 10.0 meq/hr) were prospectively evaluated and treated with ranitidine twice a day. Fifty-four patients (44%) required standard doses of ranitidine 300 mg/day for adequate treatment, and the other 70 patients (56%) required increased doses of ranitidine (mean 994 mg/day, range 600–3000 mg/day). Mean basal acid outputs for these two groups were 14.0 and 16.6 meq/hr, respectively, which were not significantly different. Nevertheless, there was a significant correlation between basal acid output and daily ranitidine dose required for therapy (r=0.18,P=0.05). The duration of ranitidine therapy consisted of: <1 year (N=46), 1 year (N=16), 2 years (N=19), 3 years (N=22), 4 years (N=15), 5 years (N=6). Only five patients required progressive increases in ranitidine during the time of treatment, which consisted of an average of 0.5 dose adjustments per year. No side effects occurred with any of these high doses of ranitidine. These results indicate that, as in Zollinger-Ellison syndrome, ranitidine is effective therapy for patients with idiopathic gastric acid hypersecretion; however, markedly increased doses as large as 3000 mg/day may be required.     

Ciclosporin use in acute ulcerative colitis: a long-term experience

BACKGROUND: Within a lifetime, approximately 15% of ulcerative colitis (UC) patients will have a severe relapse necessitating admission to hospital. Despite intravenous steroid treatment, approximately 25% will require either surgery or ciclosporin (CsA) rescue therapy. Initial response rates to CsA have been encouraging, but remission rates have been disappointing. There is a paucity of long-term data on UC patients who have been brought into remission with CsA. OBJECTIVES: To report our 7 year experience on the use of CsA in acute UC and to highlight long-term follow-up data on these patients. PATIENTS AND METHODS: A retrospective database of 76 UC patients requiring CsA between 1996 and 2003 was constructed. CsA was started on the basis of their C-reactive protein (CRP) and/or stool frequency after 3 days or after 5-7 days of i.v. hydrocortisone. The patients (33 female, 43 male, mean age 44.5 years) were followed up for a median 2.9 years (range 0.2-7.0 years). Fifty-four patients received i.v. CsA (4 mg/kg), while 22 received oral CsA (5 mg/kg). Long-term outcome was evaluated by Kaplan-Meier survival analysis: time to first relapse and time to surgery. RESULTS: Median disease duration was 6.6 years. Median CRP and stool frequency at day 3 was 20 mg/l and 6 per day, respectively. Fifty-six patients (74%) achieved initial remission. CsA was discontinued in only four patients due to side effects. Duration of i.v. steroids or the addition of AZA did not improve time to first relapse or time to surgery. Comparison between i.v. CsA and oral CsA revealed a statistically significant difference in time to first relapse (P < 0.01) and time to surgery (P < 0.05) in favour of oral CsA. CONCLUSIONS: These data describe the long-term outcome of the largest series of patients so far reported that have had treatment with CsA for severe refractory UC. If patients achieved initial remission with CsA, after 1 year, 65% had relapsed and after 3 years 90% had relapsed. After 7 years, 58% had come to colectomy. Minor side effects were frequent, but none were life threatening. There was no increase in post-operative complications in those who came to colectomy.