Impact of Helicobacter pylori infection and mucosal atrophy on gastric lesions in patients with familial adenomatous polyposis

BACKGROUND: There are limited data on factors predicting response to azathioprine and uncertainty regarding the optimal duration of treatment. PATIENTS AND METHODS: The notes of patients attending the Oxford IBD clinic from 1968 to 1999 were reviewed. Remission was defined as no need for oral steroids for at least three months and relapse was defined as active disease requiring steroids. RESULTS: A total of 622 of 2205 patients were treated with azathioprine (272 Crohn's disease, 346 ulcerative colitis, and four indeterminate colitis). Mean duration of the initial course of treatment was 634 days. The overall remission rates were 45% for Crohn's disease and 58% for ulcerative colitis. For the 424 patients who received more than six months of treatment, remission rates were 64% and 87%, respectively. Factors favouring remission were ulcerative colitis (p=0.0001), lower white blood cell (WBC) or neutrophil count (p=0.0001), higher mean cell volume (p=0.0001), and older age (p=0.05). For Crohn's disease, colonic disease favoured remission (p=0.03). Factors that were not significant were age, sex, lymphocyte count, and dose (mg/kg). The proportion of patients remaining in remission at one, three, and five years was 0.95, 0.69, and 0.55, respectively. The chance of remaining in remission was higher if WBC was less than 5 x 10(9) (p=0.03) and in male patients (p=0.01; Crohn's disease only). There was no difference in relapse rates between Crohn's disease and ulcerative colitis. After stopping azathioprine, the proportion of patients remaining in remission at one, three, and five years was 0.63, 0.44, and 0.35 (222 patients). Duration of azathioprine treatment did not affect the relapse rate after stopping treatment (p=0.68). CONCLUSIONS: Azathioprine is effective treatment for ulcerative colitis and Crohn's disease. The efficacy of azathioprine is reasonably well sustained over five years.     

A report on efficacy and safety of azathioprine in a group of inflammatory bowel disease patients in northwest Greece

BACKGROUND/AIMS: Inflammatory bowel disease has a variable severity and in a group of patients a second-line treatment with immunosuppressive agents, such as azathioprine is required. The aim of the present study was to determine the efficacy and safety of long-term azathioprine treatment in inflammatory bowel disease patients unresponsive to steroids. METHODOLOGY: We investigated the efficacy of azathioprine in controlling the disease relapse (in combination with other drugs) in 29 patients with inflammatory bowel disease (16 with ulcerative colitis and 13 with Crohn's disease). Patients, who were started on azathioprine in combination with steroids, were those who were resistant to steroids. After controlling the acute phase, steroids were discontinued or reduced in very low doses (up to 4 mg methylprednisone per day) and azathioprine was administered in combination with mesalamine for a period of 12-48 months. RESULTS: Azathioprine (in combination with 5-ASA products and steroids) succeeded in controlling the acute relapse in 24 of 29 patients [82.75%, 15/16 (93.7%) with ulcerative colitis and 9/13 (69.2%) with Crohn's disease]. Of the patients who achieved remission, this was maintained for 1 year at least. Only one case of pancreatitis and one with vomiting and diarrhea were noted a few months after the initiation of therapy and azathioprine was discontinued. CONCLUSIONS: Azathioprine is an effective agent which controls acute relapse of inflammatory bowel disease in many cases in combination with other drugs. Long-term remission can be achieved. Side effects are uncommon.     

Azathioprine versus sulfasalazine in maintenance of remission in severe ulcerative colitis.

BACKGROUND: Azathioprine is useful as a steroid-sparing drug in patients with ulcerative colitis. Its role as monotherapy in the maintenance of disease remission has not been evaluated. METHODS: In this prospective, randomized, open-label study, 25 patients with severe ulcerative colitis received either azathioprine (2.5 mg/Kg/day; Group A, n = 12) or sulfasalazine (6 g/day; Group B, n = 13). All patients received oral corticosteroids in a tapering dosage schedule initially. Treatment failure was defined as either disease relapse or drug withdrawal because of adverse effects. RESULTS: Five of 12 patients in Group A and 8 of 13 patients in Group B had sustained remission during the stipulated study period of 18 months (p = ns). Two patients in Group A had to stop azathioprine because of adverse effects (bone marrow suppression and acute pancreatitis). In Group A, all patients who had treatment failure developed it in the first half of the study while in Group B treatment failure occurred in both halves. CONCLUSIONS: The relapse rate of ulcerative colitis on maintenance therapy with azathioprine or sulfasalazine is comparable; there was a trend towards earlier treatment failure with azathioprine.     

Azathioprine or 6-mercaptopurine for inflammatory bowel disease: do risks outweigh benefits?

The treatment of Crohn's disease and ulcerative colitis has evolved and has improved the quality of life of patients afflicted with these disorders. Immune modulators such as azathioprine and 6-mercaptopurine are an important class of medications used for the treatment of patients with inflammatory bowel disease. Controlled studies have demonstrated their efficacy in both induction and maintenance of remission in Crohn's disease, and similarly, for the induction and maintenance of remission in patients with ulcerative colitis. These agents have had an increasing importance in the management of steroid-resistant, steroid-dependent diseases, and fistulizing Crohn's disease. The primary limitations to these agents have been their slow onset of action and their side effect profile. Despite these limitations, these agents have demonstrated efficacy and have become paramount to the management of patients with these incurable potentially disabling disorders. The precise role of azathioprine/6-mercaptopurine, their limitations and their safety are reviewed in this paper.     

Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis

BACKGROUND AND AIMS: There are limited evidence based data concerning the use of azathioprine in ulcerative colitis. We aimed to compare the efficacy of azathioprine and oral 5-aminosalicylic acid in inducing remission of steroid dependent ulcerative colitis. METHODS: Seventy two patients with steroid dependent ulcerative colitis were admitted to this investigator-blind study. Steroid dependence was defined as a requirement for steroid therapy > or =10 mg/day during the preceding six months, with at least two attempts to discontinue the medication. The disease had to be clinically and endoscopically active at study entry, and all patients were taking systemic prednisolone (40 mg/day). Patients were randomised to receive azathioprine 2 mg/kg/day or oral 5-aminosalicylic acid 3.2 g/day, for a six month follow up period. The outcome of the treatment was defined as (1) success, indicating induction of clinical and endoscopic remission and steroid discontinuation, or (2) failure, indicating the absence of clinical and endoscopic remission and therefore the need for at least one further cycle of systemic steroids to control symptoms, apart from the initial one, or colectomy. RESULTS: Significantly more patients in the azathioprine than in the 5-aminosalicylic acid group had clinical and endoscopic remission, and discontinued steroid therapy, both in the intention to treat (azathioprine v 5-aminosalicylic acid: 19/36 patients (53%) v 7/36 (21%); odds ratio (OR) 4.78 (95% confidence interval (CI) 1.57-14.5)) and per protocol (azathioprine v 5-aminosalicylic acid: 19/33 patients (58%) v 7/34 (21%); OR 5.26 (95% CI 1.59-18.1)) analysis. CONCLUSIONS: Azathioprine is significantly more effective than 5-aminosalicylic acid in inducing clinical and endoscopic remission and avoiding steroid requirement in the treatment of steroid dependent ulcerative colitis.     

Budesonide versus mesalamine for maintaining remission in patients refusing other immunomodulators for steroid-dependent Crohn's disease.

BACKGROUND & AIMS: To compare the efficacy of controlled-release budesonide capsules with that of mesalamine for maintaining remission and improving quality of life (QOL) in patients with steroid-dependent Crohn's disease. METHODS: Fifty-seven patients (25 men; mean age, 32 +/- 10.1 yr) with quiescent steroid-dependent Crohn's ileitis, ileocolitis, or colitis (Crohn's disease activity index <150) entered a prospective, investigator-blind trial. Patients were eligible for treatment with azathioprine but had not consented or had developed side effects. Patients were randomized to receive budesonide 6 mg/day (n = 29) or mesalamine 1 g 3 times/day (n = 28). Follow-up assessments were made every 2 months for up to 1 year or until relapse. At each visit, quality of life (QOL) was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: There were no significant differences in baseline clinical characteristics between the study groups. The 1-year relapse rate was significantly lower in the budesonide group than in the mesalamine group (55% vs. 82%; 95% confidence interval, 12.4%-41%; P = 0.045). Patients assigned to budesonide also remained in remission longer (241 +/- 114 days vs. 147 +/- 117 days; 95% confidence interval, 32.7-155.3 days; P = 0.003). Compared with mesalamine, budesonide treatment also was associated with a better QOL throughout the study (mean total IBDQ scores 165 +/- 36 vs. 182 +/- 28, respectively; 95% confidence interval, -0.4 to 34.4, P = 0.0001). This advantage was confirmed in patients' self-assessed QOL scores. CONCLUSIONS: Over a 1-year period, controlled-release budesonide was significantly more effective than mesalamine for maintaining remission and improving the QOL of patients with steroid-dependent Crohn's disease.     

Bone density improves with disease remission in patients with inflammatory bowel disease

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) are at risk of low bone mineral density (BMD). The aim of this cross-sectional study was to investigate (i) whether patients with IBD in long-term remission have greater bone density relative to patients with active disease, (ii) the effect of remission on BMD in ulcerative colitis and Crohn's disease, and (iii) the effect of azathioprine treatment, used to induce remission, on BMD. PATIENTS AND METHODS: BMD relative to the age-standardised mean (Z-score) was measured by dual-energy X-ray absorptiometry at the left femoral neck and lumbar spine in consecutive patients with IBD. Patients were divided into the following groups: (i) active disease, (ii) remission of less than one year, (iii) remission of one to three years, and (iv) remission of more than three years. Active disease was defined as three or more bowel motions per day, treatment with oral or rectal corticosteroids, and/or presence of a fistula. The subgroups with ulcerative colitis and Crohn's disease and the effect of taking azathioprine were compared. All results were controlled for confounding variables.RESULTS A total of 137 (64 ulcerative colitis, 73 Crohn's disease) patients were evaluated. Patients in remission for more than three years had a normal mean Z-score that was significantly higher than those with active disease at both the femoral neck and the lumbar spine for both ulcerative colitis and Crohn's disease. Patients taking azathioprine and in remission had significantly higher mean Z-scores at the lumbar spine than patients with active disease and who were not taking azathioprine. CONCLUSION: In patients with ulcerative colitis and Crohn's disease, age-matched BMD is higher with increasing duration of disease remission and induction of remission by azathioprine.     

Is neutropenia required for effective maintenance of remission during azathioprine therapy in inflammatory bowel disease?

BACKGROUND: Azathioprine is an effective treatment for maintaining remission in inflammatory bowel disease (IBD). It is a matter of debate as to whether neutropenia is required during azathioprine therapy to achieve more effective disease remission. We evaluated whether neutropenia during azathioprine therapy reduced relapse rates in IBD patients. PATIENTS AND METHODS: This retrospective study was based on a total of 173 IBD (96 Crohn's disease (CD), 77 ulcerative colitis (UC)) patients who were stable on azathioprine for a minimum of 6 months. Median duration of follow-up was 4.0 years (range 0.6-21 years). The lowest neutrophil counts during treatment for these patients were recorded. Relapse rates per year of follow-up were compared in non-neutropenic patients (neutrophil count > 2.5 x 10(9), n = 129) and neutropenic patients (neutrophil count < or = 2.5 x 10(9), n = 44) groups, and survival curves for cumulative remission rates compared by log-rank test. RESULTS: Mean relapse rate per year of follow-up for the non-neutropenic group was 0.19/year (SD = 0.37/year) compared with the neutropenic group 0.28/year (SD = 0.43/year) (P = NS). Analysis was performed on UC and CD subgroups, and relapse rates were not significantly different. The cumulative remission per cent determined by Kaplan-Meier survival analysis showed no difference between non-neutropenic and neutropenic groups by log-rank analysis, for UC and CD as well as for all IBD patients. CONCLUSION: Neutropenia < or = 2.5 x 10(9) while on azathioprine does not reduce the relapse rates of IBD patients who were established on azathioprine therapy compared with neutrophil counts > 2.5 x 10(9).     

Effective maintenance of inflammatory bowel disease remission by azathioprine does not require concurrent 5-aminosalicylate therapy.

OBJECTIVES: To assess the effect of 5-aminosalicylate treatment in conjunction with azathioprine on remission maintenance in inflammatory bowel disease patients. METHOD: This retrospective study was based on a total of 186 inflammatory bowel disease patients (104 with Crohn's disease; 82 with ulcerative colitis), who were stable on azathioprine for a minimum of 6 months. The median duration of follow-up was 4.3 years (range 0.6-15.5 years). Relapse rates per year of follow-up were compared in an azathioprine + 5-aminosalicylate group (n = 103) and an azathioprine alone group (n = 83); survival curves for cumulative remission rates were compared by log-rank test. Discontinuation of azathioprine in both groups was also recorded, as was the incidence of malignancy. RESULTS: In ulcerative colitis patients (n = 82), mean relapse rates for the azathioprine + 5-aminosalicylate group were 0.21/year compared with 0.19/year for the azathioprine alone group (P = not significant). In Crohn's disease patients (n = 104), mean relapse rates for the azathioprine + 5-aminosalicylate group were 0.27/year compared with 0.3/year for the azathioprine alone group (P = not significant). The cumulative remission percentage (determined from time to first relapse) was used in Kaplan-Meier survival analysis and showed no difference between the azathioprine + 5-aminosalicylate group and the azathioprine alone group by log-rank analysis, for ulcerative colitis and Crohn's disease as well as for all inflammatory bowel disease patients. Concurrent use of 5-aminosalicylates was no more frequent in patients who discontinued azathioprine due to adverse events. The only malignancy recorded was Waldenstr?m's macroglobulinaemia after 7 years of azathioprine therapy. CONCLUSION: Concurrent use of 5-aminosalicylate drugs did not reduce the relapse rates of inflammatory bowel disease patients who were established on azathioprine therapy. The use of 5-aminosalicylate drugs did not lead to any increase in discontinuation of azathioprine due to adverse events.     

The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study

BACKGROUND & AIMS: The aim of this study was to determine the 1-year outcome after the first course of corticosteroids in an inception cohort of patients with inflammatory bowel disease. METHODS: All patients in Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 173) or ulcerative colitis (n = 185) from 1970 to 1993 who were treated with systemic corticosteroids were identified (4 denied research authorization). Immediate outcome (30 days) and 1-year outcome after the first course of corticosteroids were determined. RESULTS: Seventy-four (43%) patients with Crohn's disease and 63 (34%) with ulcerative colitis were treated with corticosteroids. Immediate outcomes for Crohn's disease were complete remission in 43 (58%), partial remission in 19 (26%), and no response in 12 (16%). Immediate outcomes for ulcerative colitis were complete remission in 34 (54%), partial remission in 19 (30%), and no response in 10 (16%). One-year outcomes for Crohn's disease were prolonged response in 24 (32%), corticosteroid dependence in 21 (28%), operation in 28 (38%), and lost to follow-up in 1 (1%). One-year outcomes for ulcerative colitis were prolonged response in 31 (49%), corticosteroid dependence in 14 (22%), and operation in 18 (29%). CONCLUSIONS: Most patients with Crohn's disease and ulcerative colitis initially respond to corticosteroids. At 1 year, 32% of patients with Crohn's disease and 48% with ulcerative colitis are corticosteroid free without operation.     

Efficacy and safety of azathioprine maintenance therapy in a group of Crohn's disease patients in China.

OBJECTIVE: To evaluate the efficacy and the safety of long-term azathioprine maintenance therapy in a group of Chinese patients with Crohn's disease. METHODS: The efficacy of azathioprine (2.0 mg/kg/day) in controlling the disease relapse in 13 patients with Crohn's disease following clinical remission by prednisone or surgery were investigated. The Crohn's disease activity index (CDAI) and the Harvey-Bradshaw index, the reduction of steroid dosage and side-effects for an average of 18 months follow up were analyzed. RESULTS: Azathioprine was effective in controlling the disease relapse in 10 (by CDAI scores) or 11 (by Harvey -Bradshaw index) of 13 patients (76.9% and 84.6%, respectively) for at least 6 months. Azathioprine was not discontinued in a patient who experienced a temporary and mild elevation of aminotransferases 14 months after the initiation of therapy. However one patient who was co-administered with azathioprine and mesalamine (Pentasa) developed an episode of bone marrow suppression that ultimately required the withdrawal of both medications. CONCLUSION: Azathioprine is an effective agent which controls the relapse of Crohn's disease in most patients. Long-term remission can be achieved. Side-effects, including severe leukopenia, myelo-suppression and the mild elevation of hepatic enzymes, may occur in a small number of patients.     

Granulocyte, monocyte/macrophage apheresis for inflammatory bowel disease: the first 100 patients treated in Scandinavia

OBJECTIVE: Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohn's disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated. MATERIAL AND METHODS: Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5-30). RESULTS: The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohn's disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohn's disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7). CONCLUSIONS: Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.     

State-of-the-art: Immunosuppression and biologic therapy

Azathioprine and 6-mercaptopurine are orally administered immunosuppressive drugs which are effective for the treatment of Crohn's disease and ulcerative colitis. Azathioprine is rapidly converted to 6-mercaptopurine after administration. 6-Mercaptopurine is then either converted to the putative active metabolites, the 6-thioguinine nucleotides, or inactivated by the enzyme xanthine oxidase to 6-thiouric acid or alternatively inactivated to 6-methylmercaptopurine by the enzyme thiopurine methyltransferase. Thiopurine methyltransferase activity is genetically determined, with one in 300 patients having low or absent enzyme activity, one in 10 patients having intermediate enzyme activity, and 9 in 10 patients having normal enzyme activity. Patients with intermediate or low thiopurine methyltransferase activity are at risk for early leukopenia. Higher erythrocyte 6-thioguinine nucleotide concentrations are associated with a greater likelihood of clinical response. Azathioprine is modestly effective for Crohn's disease and ulcerative colitis. Toxicity associated with azathioprine includes infection and lymphoma. Anti-TNF therapy with infliximab, adalimumab, and certolizumab pegol is effective for induction and maintenance treatment of Crohn's disease, and infliximab is effective for ulcerative colitis. Toxicity associated with anti-TNF therapy includes infection and lymphoma. Combination therapy with infliximab and azathioprine is more effective for inducing and maintaining steroid-free remission and mucosal healing then monotherapy with either drug alone. Strategies to reduce immunogenicity of anti-TNF agents include combination therapy with azathioprine and administration of a loading dose followed by systematic maintenance dosing. Higher serum trough concentrations of infliximab occur more frequently in patients receiving combination therapy with azathioprine and are associated with better clinical outcomes. Combination therapy is associated with an increased relative risk of opportunistic infection, but is not associated with an increased absolute risk of serious infection. Clinical practice should change such that combination therapy with an anti-TNF agent and azathioprine replace azathioprine in patients failing first line therapy with mesalamine and/or steroids.     

Adverse effects of azathioprine in the treatment of inflammatory bowel disease.

OBJECTIVE: To know the type, frequency and time course for the occurrence of adverse events in our series of patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. PATIENTS AND METHOD: 92 consecutive patients were treated with azathioprine. 70 of them (55 Crohn's disease, 14 ulcerative colitis and 1 undetermined colitis) were suitable for analysis. RESULTS: We observed 23 adverse reactions in 21 patients. Adverse events were as follows: haematological 11.4%, digestive intolerance 11.4%, infection 7.1%, and pancreatitis 2.8%. The prevalence was increased among ulcerative colitis patients (57.8 vs. 21.8%) (p = 0.02). There were no statistical differences in the prevalence of adverse events respective of the age, gender or location of disease. Digestive intolerance and pancreatitis occurred within the first 6 months of therapy, whereas haematological side effects occurred between 3 months and 4 years after therapy onset. Early occurrence (but not late occurrence) was associated with thiopurine methyltransferase (TMPT) activity levels. All infections took place between 8 months and 5 years of treatment. Azathioprine was definitively withdrawn due to side effects in 9 cases (12.8%). CONCLUSIONS: The frequency of adverse events in our study is similar to that reported in previous studies. Azathioprine withdrawal is required in almost half of the cases because of toxicity. Frequency of side effects is increased in patients with ulcerative colitis. The variability in time course makes clinical-biological monitoring mandatory.     

6-mercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine

OBJECTIVE: Azathioprine and 6-mercaptopurine are useful therapies in inflammatory bowel diseases. Despite their efficacy, their use is limited owing to treatment intolerance or toxicity in 10-15% of patients. It has been suggested that both drugs could be interchangeable. MATERIAL AND METHODS: All patients treated with 6-mercaptopurine because of previous digestive intolerance of azathioprine in four Spanish hospitals were reviewed. Tolerance of 6-mercaptopurine therapy was assessed. RESULTS: Fifteen patients (11 Crohn's disease, 4 ulcerative colitis) were included. Immunosuppressant therapy was prescribed for steroid-dependent disease in 13 cases, and for perianal disease in 2. Main symptoms of digestive intolerance were epigastric pain, nausea and vomiting, which developed within the first weeks of treatment. Acute pancreatitis was ruled out in all the cases. Five patients commenced 6-mercaptopurine immediately after azathioprine discontinuation and 7 patients within the first month. Eleven patients (73.3%) tolerated 6-mercaptopurine and reached the therapeutic goals; only two patients had to discontinue 6-mercaptopurine because of adverse effects. CONCLUSIONS: Treatment with 6-mercaptopurine is a safe alternative in patients with inflammatory bowel diseases and previous digestive intolerance of azathioprine.     

Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn’s disease: a randomised, investigator-blind study

BACKGROUND AND AIMS: The efficacy of azathioprine in the treatment of chronic active Crohn's disease is well established. However, this drug has a long onset of action. Methotrexate has also been shown to be effective in chronic active Crohn's disease. The aim of this study was to evaluate the efficacy and safety of methotrexate in comparison with azathioprine, and to establish whether methotrexate has a shorter onset of action in this setting. METHODS: Patients with chronic active Crohn's disease were admitted to this investigator-blind study. Chronicity was defined as the need for steroid therapy of > or = 10 mg/day for at least 4 months during the preceding 12 months, with at least one attempt to discontinue treatment. The disease had to be clinically active at entry, with a Crohn's Disease Activity Index of > or = 200. Six patients treated with azathioprine and methotrexate, respectively, were found to have enterocutaneous and perianal fistulas. At entry, all patients received prednisolone (40 mg once a day) which was tapered over a period of 12 weeks unless their clinical condition deteriorated. All patients were randomised to receive i.v. methotrexate 25 mg/week, or oral azathioprine 2 mg/kg per day, for a 6-month follow-up period. After the first 3 months, methotrexate was switched to oral administration maintaining the same dose. The primary efficacy outcome considered was the proportion of patients entering first remission after 3 and 6 months of therapy. Clinical remission was defined as the lack of need for steroid treatment and a Crohn's Disease Activity Index score of < or = 150 points at each scheduled visit. RESULTS: In the 54 patients (26 F, 28 M, mean age 34 years, range 18-60) randomly assigned to methotrexate (n=27) or azathioprine (n=27), no statistically significant difference was found between the two treatment regimens with respect to remission rate after 3 (methotrexate 44%, azathioprine 33%, p=0.28, (95% CI, 0.369-0.147), and 6 months (methotrexate 56%, azathioprine 63%, p=0.39, 95% CI, 0.187-0.335), respectively. Six patients withdrew from therapy due to adverse events: 3/27 (11%) in methotrexate and 3/27 (11%) in azathioprine. Drug-related adverse events (asthenia, nausea and vomiting) that did not require withdrawal from therapy were more frequent in the methotrexate group (azathioprine: 2/27 (7%); methotrexate: 12/27 (44%), p=0.00009). The frequency of these adverse events was comparable during the intravenous or oral administration of the drug. CONCLUSIONS: This study confirms that methotrexate is effective in inducing remission in patients with chronic active Crohn's disease, therapeutic efficacy being comparable, but not faster, than that of azathioprine.     

Retrospective case series analysis of patients with inflammatory bowel disease on azathioprine. A district general hospital experience

OBJECTIVES: The aim of this study was to look at our practice of using azathioprine and to compare our results with those in published trials both from the point of view of response and also the side-effect profile. DESIGN: A retrospective case series analysis was done on patients with inflammatory bowel disease (IBD) who were on azathioprine at Leicester General Hospital. METHODS: 111 patients (47 males, 64 females, mean age 35.3 years) were included from gastroenterology outpatients records between November 1997 and August 1998. Clinical and demographic details were collected. Response in Crohn's disease was determined using the Harvey-Bradshaw index. In case of ulcerative colitis the following parameters were used: stool frequency; rectal bleeding, weight gain, and general well-being. Logistic regression was performed to look at the influence of age, sex and diagnosis in relation to the response/relapse rate. RESULTS: The average duration of treatment with azathioprine was 28.6 months. The starting dose of 1.53 mg/kg was similar to the maintenance dose (1.51 mg/kg). 58 patients had Crohn's disease and 53 patients were diagnosed with ulcerative colitis. 85 patients were steroid-dependent, 9 steroid-resistant, and 17 patients were started on azathioprine on the basis of extensive disease either seen at the time of endoscopy or radiologically. Improvement in clinical features at 3, 6 and 12 months was 69.5, 77 and 84.1%, respectively. 74% patients showed an improvement in relapse rates during the first year on azathioprine compared to 1 year prior to treatment. 68% patients who had shown improvement at 1 year were no longer taking steroids (p = 0.002). Logistic regression did not show any statistically significant influence of age, sex or diagnosis on response. 4.5% patients had leukopenia requiring dose reductions. Severe leukopenia (leukocyte count <2.5 x 10(9)/l) occurred in 3.6% patients. CONCLUSIONS: Response rates in our IBD patients on azathioprine are comparable with those of the published data despite using a relatively smaller dose.     

Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement

INTRODUCTION: Despite the explosion of biological therapies, the old immunosuppressants continue to play a pivotal role in the management of inflammatory bowel diseases. AIM: To assess the appropriateness of immunosuppressants-azathioprine, 6-mercaptopurine, methotrexate, cyclosporine A, tacrolimus (FK506), mycophenolate mofetil and thalidomide-in the treatment of inflammatory bowel disease by using RAND/University of California Appropriateness Method. METHODS: The RAND method consists of a combination of evidence from the literature and experts' opinions. Appropriateness has been defined to mean that the expected health benefit exceeds the expected negative consequences by a sufficiently wide margin. A panel of 10 experts from the Italian Group for Inflammatory Bowel Disease has rated, in two rounds, on a scale from 1 to 9, the appropriateness of each indication selected by the Promoter Centre, on the basis of their own clinical experience. An indication was considered appropriate if the median of the panelists' ratings fell within the area 7-9, inappropriate in the area 1-3 and uncertain in the area 4-6. A total of 2781 indications were grouped into 13 categories (mild to moderate Crohn's disease; severe Crohn's disease; fistulizing Crohn's disease; steroid-dependant and -resistant Crohn's disease; maintenance of remission induced by medical treatment in Crohn's disease; maintenance of remission induced by surgery in Crohn's disease; mild to moderate ulcerative colitis; severe ulcerative colitis; steroid-dependant and -resistant ulcerative colitis; maintenance of remission induced by medical treatment in ulcerative colitis; extra-intestinal manifestations in inflammatory bowel disease; pregnancy and inflammatory bowel disease; azathioprine-resistant or -intolerant inflammatory bowel disease patients). RESULTS: Of the 2781 scenarios, 212 (7.6%) were rated appropriate, 645 (23.2%) uncertain and 1924 (69.2%) inappropriate. The most relevant results were: in steroid-dependant or -resistant Crohn's disease, azathioprine, 6-mercaptopurine and methotrexate were defined as appropriate in 25 (86.2%) and 14 (48.3%) of the 29 scenarios respectively; in Crohn's disease, azathioprine and 6-mercaptopurine were defined as appropriate combined with Infliximab (bridge therapy); in steroid-dependant or -resistant ulcerative colitis, azathioprine and 6-mercaptopurine were defined as appropriate in 45 (77.6%) out of 58 scenarios, while methotrexate was defined appropriate only after previous azathioprine failure; in severe ulcerative colitis, cyclosporine A was defined as appropriate only after previous failure with steroids; in azathioprine-intolerant or -resistant inflammatory bowel disease patients, methotrexate was appropriate in 20 (66.7%) out of 30 scenarios; it is inappropriate to stop azathioprine treatment before conception in the presence of active disease. The use of FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate or uncertain. CONCLUSIONS: Results of this study show that only azathioprine, 6-mercaptopurine and methotrexate are appropriate in the treatment of inflammatory bowel diseases. Cyclosporine A was found to be appropriate only in severe ulcerative colitis after the failure of steroids. FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate but experience with these agents is somewhat limited.     

Intravenous azathioprine in severe ulcerative colitis: a pilot study

OBJECTIVE: Azathioprine use in acute ulcerative colitis has been limited by its perceived long onset of action. The aim of this study was to determine the safety and clinical effect of an i.v. loading dose of azathioprine in the setting of severe steroid refractory ulcerative colitis. METHODS: Nine hospitalized patients with severe steroid refractory ulcerative colitis were enrolled. Patients 1-3 received 20 mg/kg i.v. azathioprine over 36 h. Patients 4-6 received 40 mg/kg i.v. azathioprine over 36 h. Patients 7-9 received 40 mg/kg i.v. azathioprine as three 8-h infusions over 3 days. Clinical remission was defined as steroid withdrawal and an Ulcerative Colitis Disease Activity Index score of 0. The Inflammatory Bowel Disease Questionnaire was obtained at each visit. White blood cell concentrations and erythrocyte concentrations of 6-thioguanine were obtained. RESULTS: Five of nine patients (56%) had a response and avoided colectomy. Three of nine patients (33%) met the definition for clinical remission. Response was seen within 4 wk. The mean 6-thioguanine concentration for those five patients at 12 wk after infusion was 148.2 pmol/8 x 10(8). Two patients had transient leukopenia and one had transient hepatotoxicity. CONCLUSIONS: Intravenous azathioprine appears to be safe and of clinical benefit in inducing response and avoiding colectomy in severe steroid refractory ulcerative colitis. Data from an i.v. azathioprine trial in Crohn's disease suggests oral dosing alone may obtain the same results. The role of oral dosing alone in severe ulcerative colitis and the role of azathioprine metabolite levels in monitoring efficacy should be investigated further.     

Antibodies against laminaribioside and chitobioside are novel serologic markers in Crohn's disease

BACKGROUND & AIMS: New serologic markers of inflammatory bowel disease may be useful for differentiating between Crohn's disease and ulcerative colitis and for disease stratification. We profiled sugar-binding antibodies to identify novel antiglycan antibodies that may be associated with inflammatory bowel disease. METHODS: Serum samples were obtained from patients with diagnosed Crohn's disease or ulcerative colitis and from control patients. The presence of antiglycan antibodies was evaluated using either a glycan array (GlycoChip; Glycominds, Ltd, Lod, Israel) in patients with Crohn's disease (n = 72) or ulcerative colitis (n = 56) and in healthy controls (n = 41) or using an enzyme-linked immunosorbent assay in patients with Crohn's disease (n = 124), ulcerative colitis (n = 106), and in control patients (n = 101). RESULTS: Inaddition to antibodies against mannan, antibodies to laminaribioside (Glc[beta1,3]Glc[beta]) and chitobioside (GlcNAc[beta1,4]GlcNAc[beta]) had the highest discriminative capability between Crohn's disease and ulcerative colitis (P < .001 and P < .05, respectively). Importantly, 44% (12/27) of anti-Saccharomyces cerevisiae antibody-negative Crohn's disease patients were positive for antilaminaribioside or antichitobioside. In patients with inflammatory bowel disease positive for antibodies against either laminaribioside, chitobioside, or mannan, the diagnosis of Crohn's disease was suggested with a sensitivity of 77.4% and specificity of 90.6%. Having at least 2 of these antibodies increased the specificity to 99.1%. In Crohn's disease, higher levels of antibodies against laminaribioside or mannan were significantly associated with small intestinal disease (P = .03 and P < .0001, respectively). CONCLUSIONS: Antilaminaribioside and antichitobioside carbohydrate antibodies are novel serologic markers associated with Crohn's disease. These antibodies may contribute to the diagnosis and improved stratification of Crohn's disease.