Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn's disease

BACKGROUND & AIMS: Because the reoperation rate for Crohn's disease is high after resective surgery, use of conservative surgery has increased. Mesalamine was investigated for the prevention of postoperative relapse, with disappointing results. The role of azathioprine in the postoperative setting is unknown. We aimed to compare the efficacy and safety of azathioprine and mesalamine in the prevention of clinical and surgical relapse in patients who have undergone conservative surgery for Crohn's disease. METHODS: In a prospective, open-label, randomized study, 142 patients received azathioprine (2 mg. kg -1. day -1 ) or mesalamine (3 g/day) for 24 months. Clinical relapse was defined as the presence of symptoms with a Crohn's Disease Activity Index score >200 and surgical relapse as the presence of symptoms refractory to medical treatment or complications requiring surgery. RESULTS: After 24 months, the risk of clinical relapse was comparable in the azathioprine and mesalamine groups, both on intention-to-treat (odds ratio [OR], 2.04; 95% confidence interval [CI], 0.89-4.67) and per-protocol analyses (OR, 1.79; 95% CI, 0.80-3.97). No difference was observed with respect to surgical relapse at 24 months between the 2 groups. In a subgroup analysis, azathioprine was more effective than mesalamine in preventing clinical relapse in patients with previous intestinal resections (OR, 4.83; 95% CI, 1.47-15.8). More patients receiving azathioprine withdrew from treatment due to adverse events than those receiving mesalamine (22% vs. 8%; P = 0.04). CONCLUSIONS: While no difference was observed in the efficacy of azathioprine and mesalamine in preventing clinical and surgical relapses after conservative surgery, azathioprine is more effective in those patients who have undergone previous intestinal resection.     

Disodium cromoglycate in the treatment of ulcerative colitis and Crohn''s disease

A controlled clinical study on disodium cromoglycate (DSCG) at a dose of 800 mg per day versus placebo was carried out in 141 patients with ulcerative colitis and 25 patients with Crohn's disease. Those of the ulcerative colitis patients who had been on sulphasalazine treatment continued that treatment during the trial (101 patients). Forty patients were intolerant of sulphasalazine. No patient received steroids during the last month before the study. Patients with Crohn's disease had their possible sulphasalazine treatment stopped before the trial. No beneficial effect of DSCG as compared with placebo was found, as the DSCG and the placebo group showed the same number of relapses in patients with a clinically inactive ulcerative colitis at the start of the trial and the same number of patients improving, deteriorating, and maintaining steady state in patients with clinically active ulcerative colitis at the start of the trial. There was no difference between relapse rate in DSCG and placebo groups in patients with Crohn's disease. No correlation between the eosinophil count in rectal mucosa and the outcome of the attack of ulcerative colitis could be demonstrated.     

Intestinal permeability test as a predictor of clinical course in Crohn''s disease

OBJECTIVE: The clinical course of Crohn's disease is often unpredictable. The aim of this study was to select the most useful parameters able to predict clinical relapses. METHODS: One hundred-thirty Crohn's disease patients in clinical remission were followed every 4 months for 2 yr or until clinical relapse. Demographic and clinical data were recorded and intestinal permeability (lactulose/mannitol [L/M] test) and biochemical tests (white blood cell count, erythrocyte sedimentation rate, C-reactive protein, alpha1 acid glycoprotein, and serum iron) were performed at study entry. A subgroup of 54 patients had clinical follow-up and repeated tests every 4 months. RESULTS: Fifty-two patients (40%) relapsed during the 2-yr follow-up. A significant correlation was found between relapse and gender (p = 0.030) but not between relapse and age, extent and type of disease, previous surgery, or therapy. Increased L/M test (p = 0.0001) and decreased serum iron level (p = 0.0057) were associated with clinical relapse. Time-dependent analysis, performed on patients receiving serial evaluation, showed that L/M test alteration was the only variable that could predict a relapse (RR 8.84, 95% confidence interval [CI] 1.41-53.37; p < 0.05). CONCLUSIONS: The L/M test identifies Crohn's disease patients in apparent remission, but with a high risk of clinical relapse, better than clinical and biochemical indices. Different treatment strategies might be suggested for this subgroup of patients.     

Clinical relapse of Crohn's disease under standardized conservative treatment and after excisional surgery

The course of 205 patients with Crohn's disease at one gastroenterological center was studied in patients with conservative drug treatment or with operative management of their disease. The decision for one or the other treatment regimen was made by an interdisciplinary team of gastroenterologists and surgeons. Using life-table analysis the 205 patients showed a clinical relapse rate of 27% after two years and 38% after four years. Clinical relapse was defined by a Crohn's disease activity index (CDAI) over 150. We used a standardized drug regimen of salazosulfapyridin and prednisone; the indication for excisional surgery was limited strictly to life-threatening situations, absolute nonresponse to drug treatment, and severe intervisceralfistulae. The operated patients (N=93) had a lower relapse rate than the patients treated conservatively (N=112), 20% and 51%, respectively, after four years. There were considerably fewer relapses in Crohn's colitis patients who were operated upon than in conservatively treated patients (18% versus 67% after four years); the same was found for ileocolitis (20% vs 49% after four years), but there was no difference between the treatment groups in ileitis (25–30% relapses for both after four years). In addition the patients with Crohn's disease of the colon had a more favorable course after resection with respect to symptoms, clinical and laboratory findings, and CDAI in remission. This paper gives data only for surgery in severe clinical situations and does not give a rationale for earlier surgery. This problem should now be studied in a randomized trial.     

Prophylaxis of postoperative relapse in Crohn's disease with mesalamine: European Cooperative Crohn's Disease Study VI

BACKGROUND & AIMS: This study investigated if long-term treatment with high-dose mesalamine reduces the risk of clinical relapse of Crohn's disease after surgical resection. METHODS: In a prospective, randomized, double-blind, multicenter study, 4 g of mesalamine (Pentasa; Ferring A/S, Vanlose, Denmark) daily was compared with placebo in 318 patients. Treatment was started within 10 days after resective surgery and continued for 18 months. Primary outcome parameter was clinical relapse as defined by an increase in Crohn's Disease Activity Index, reoperation, septic complication, or newly developed fistula. Risk factors for recurrence were prospectively defined to be analyzed in a stepwise proportional hazards model. RESULTS: Cumulative relapse rates (+/-SE) after 18 months were 24.5% +/- 3.6% and 31.4% +/- 3.7% in the mesalamine (n = 152) and placebo (n = 166) groups, respectively (P = 0.10, log-rank test, 1-sided). Retrospective analysis showed a significantly reduced relapse rate with mesalamine only in a subgroup of patients with isolated small bowel disease (n = 124; 21.8% +/- 5.6% vs. 39.7% +/- 6.1%; P = 0.02, log-rank test). Probability of relapse was predominantly influenced by the duration of disease (P = 0.0006) and steroid intake before surgery (additional risk, P = 0.0003). CONCLUSIONS: Eighteen months of mesalamine, 4 g daily, did not significantly affect the postoperative course of Crohn's disease. Some relapse-preventing effect was found in patients with isolated small bowel disease.     

Acid, motility, and ulcers: a comparison of cisapride with placebo in the prevention of duodenal ulcer relapse.

In a single centre double blind study of 66 patients, the value of cisapride (10 mg twice daily) was compared with placebo in the prevention of duodenal ulcer relapse. Patients who remained ulcer free attended for clinical review every two months and had a mandatory endoscopy at 0, 4, 8, and 12 months or if symptoms suggestive of ulcer recurrence developed. The 12 month crude relapse rates (that underestimate the probability of ulcer recurrence) showed that cisapride was superior to placebo (34% (11/32) relapsed on cisapride v 68% (23/34) on placebo, p = 0.007). This finding was confirmed using lifetable analysis, with a 35% reduction (95% confidence intervals 10-59%, p < 0.05) in the proportion of ulcer relapses in patients who had received cisapride compared with those treated with placebo. These results are similar to those reported in maintenance trials of H2 receptor antagonists analysed by the same method. Drug related adverse clinical events were mainly trivial, but led to three patients on cisapride and one on placebo withdrawing from the trial.     

Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn's disease. The Italian IBD Study Group.

A randomized, placebo-controlled multicenter trial was conducted to evaluate the efficacy and safety of a delayed-release formulation of 5-aminosalicylic acid (5-ASA) (Asacol; Giuliani & Bracco, Milan, Italy) for prevention of clinical relapse in 125 patients with inactive Crohn's disease. Patients in remission [Crohn's Disease Activity Index (CDAI) less than 150] between 3 months and 2 years were randomly allocated to receive either 800 mg 5-ASA three times daily (n = 64) or placebo (n = 61) for up to 12 months or until relapse of symptoms. Relapse was defined by a CDAI greater than 150, with a minimum increase of 100 points over the baseline value. The cumulative relapse rates were 12% in the 5-ASA group and 22% in the placebo group at 3 months [95% confidence interval (CI) for the difference, -4 to 24]; 28% and 41%, respectively, at 6 months (95% CI, -4 to 30); and 34% and 55%, respectively, at 12 months (95% CI, 3-39; P = 0.02, log rank test). Significant decrease in the risk of relapse was found in patients with ileitis, in those with previous bowel resection and, in those with prolonged prestudy remission. Eight patients (5 on 5-ASA, 3 on placebo) withdrew from the study because of adverse reactions, but no major clinical or laboratory adverse effect was observed. It is concluded that oral 5-ASA coated with Eudragit S (Rohn Pharma GmbH, Wieterstadt, Germany), 2.4 g daily, is safe and seems superior to placebo in preventing or delaying clinical relapse in Crohn's disease, especially in milder cases and in ileal disease.     

Zinc supplementation tightens "leaky gut" in Crohn's disease

OBJECTIVES: Small intestinal permeability is often increased in patients with Crohn's disease and may be pathogenic for clinical relapses. No effective prophylactic treatment is available for these patients. The aim of this study was to ascertain whether zinc supplementation may improve intestinal permeability. METHODS: We studied 12 patients with quiescent Crohn's disease who had been in remission for at least 3 months and had increased intestinal permeability on two separate occasions within the last 2 months. Patients received oral zinc sulfate supplements (110 mg three times a day) for 8 weeks and were followed-up for 12 months thereafter to monitor relapses. RESULTS: We found that the lactulose/mannitol ratio was significantly higher before supplementation than after (0.041 +/- 0.003 versus 0.026 +/- 0.005). During follow-up, 10 patients had normal intestinal permeability and did not relapse; of the remaining two who had increased intestinal permeability, one relapsed. CONCLUSIONS: Our findings show that zinc supplementation can resolve permeability alterations in patients with Crohn's disease in remission. Improving intestinal barrier function may contribute to reduce the risk of relapse in Crohn's disease.     

Can calprotectin predict relapse risk in inflammatory bowel disease?

OBJECTIVE:  Assessing the clinical course of inflammatory bowel disease (IBD) patients consists of periodical clinical evaluations and laboratory tests. We aimed to assess the role of calprotectin tests in predicting clinical relapse in IBD patients.
METHODS:  Ninety-seven patients with ulcerative colitis (UC) and 65 with Crohn's disease (CD) in clinical remission were prospectively included in the study. A 10-g stool sample was collected for calprotectin assay. The cutoff level was set at 130 mg/kg of feces. Patients were followed up for 1 yr after the test or until relapse. The cumulative proportion of relapses was estimated by the Kaplan-Meier analysis. Statistics for equality of survival distribution were tested using the log-rank test.
RESULTS:  The calprotectin test was positive in 44 UC patients and 26 of them relapsed within a year, while 11 of 53 UC patients with a negative calprotectin test relapsed within the same time frame. Thirty CD patients had a positive calprotectin test and 13 of them relapsed within a year, as did 7 of the 35 with a negative test result. A significant correlation emerged between a positive calprotectin test and the probability of relapse in UC patients ( P = 0.000). In CD patients, only cases of colonic CD showed a significant correlation between a positive calprotectin test and the probability of relapse, i.e ., 6 colonic CD patients were positive for the calprotectin test and 4 relapsed ( P = 0.02).
CONCLUSIONS:  Measuring calprotectin may help to identify UC and colonic CD patients at higher risk of clinical relapse.     

Olsalazine is not superior to placebo in maintaining remission of inactive Crohn's colitis and ileocolitis: a double blind, parallel, randomised, multicentre study

BACKGROUND AND AIMS: The benefit of 5-aminosalicylic acid therapy for maintenance of remission in Crohn's disease is controversial. The primary aim of this study was to evaluate the prophylactic properties of olsalazine in comparison with placebo for maintenance of remission in quiescent Crohn's colitis and/or ileocolitis. METHODS: In this randomised, double blind, parallel group study of olsalazine versus placebo, 328 patients with quiescent Crohn's colitis and/or ileocolitis were recruited. Treatment consisted of olsalazine 2.0 g daily or placebo for 52 weeks. The primary end point of efficacy was relapse, as defined by the Crohn's disease activity index (CDAI) and by clinical relapse. Laboratory and clinical disease activity indicators were also measured. Safety analysis consisted of documentation of adverse events and laboratory values. RESULTS: No differences in the frequency of termination due to relapse or time to termination due to relapse were noted between the two treatment groups (olsalazine 48.5% v placebo 45%) for either colitis or ileocolitis. The failure rate, defined as not completing the study, was significantly higher in olsalazine treated patients compared with placebo treated patients for the overall population (colitis and/or ileocolitis: olsalazine 65.4% v 53.9%; p=0.038). Similar failure rates were seen for patients with colitis. A significantly higher percentage of olsalazine treated patients experienced adverse gastrointestinal events. Drug attributed adverse events were reported more frequently in the olsalazine treated group with gastrointestinal symptoms being causally related to olsalazine treatment (olsalazine 40.7% v placebo 26.9%; p=0.010). Back pain was reported significantly more often by the placebo treated group. However, serious medical events did not differ between the two groups. Adverse events led to more early withdrawals in the olsalazine treated group than in the placebo treated group; thus average time in the study for patients in the olsalazine treatment group was significantly shorter than that of patients in the placebo group. CONCLUSIONS: Patients treated with olsalazine were more likely to terminate their participation in the trial than those taking placebo. This difference was not related to relapse of disease, as measured by CDAI and clinical measures, but rather was due to the development of intolerable adverse medical events of a non-serious nature related to the gastrointestinal tract. The gastrointestinal related events in the olsalazine treated group may be due to the difference in gastrointestinal status at baseline which favoured the placebo treatment group.     

Chloroquine for the maintenance of remission of autoimmune hepatitis: results of a pilot study

BACKGROUND: Due to the risks related to long-term treatment with prednisone and azathioprine, most clinicians try to withdraw these drugs when patients with autoimmune hepatitis are in remission. However, there is a high probability of relapse, and most patients end up receiving maintenance treatment. AIM: To evaluate the safety and efficacy of maintenance treatment with chloroquine in the prevention of autoimmune hepatitis relapses. METHODS: Classical treatment was stopped after achievement of biochemical and histological remission of autoimmune hepatitis. Chloroquine diphosphate, 250 mg daily, was given for at least 12 months or until the occurrence of relapses defined by levels of aminotransferases at least twice the upper normal values. RESULTS: Fourteen patients were consecutively treated and compared with 18 historical controls. There was a 6.49 (1.38-30.30) greater chance of relapse in the historical controls when compared with patients treated with chloroquine (72.2% x 23.5%; 0.031). CONCLUSIONS: The group treated with chloroquine had a lower frequency of relapses. Chloroquine was safe in patients with autoimmune hepatitis and hepatic cirrhosis without decompensation, on 250 mg daily up to 2 years. These preliminary results provide a basis for upcoming controlled studies comparing chloroquine with placebo or for maintenance treatment with prednisone and/or azathioprine for the prevention of autoimmune hepatitis relapses.     

The relapse of Trypanosoma brucei brucei infections after chemotherapy in rabbits

Infections of T. brucei in the rabbit were found to relapse after chemotherapy. The results indicated that 25 mg/kg diminazene aceturate given 3 days after infection resulted in a complete cure but if given 7 days after infection relapses frequently occurred. However, treatment was apparently successful if delayed until 14 or 21 days. Six of the rabbits originally treated with diminazene aceturate on day 7 were treated with suramin 21 days later; in 3 rabbits the infections relapsed. In all rabbits in which drug treatment was not curative, the clinical condition nevertheless improved. An attempt to locate a cryptic focus of infection in rabbits was unsuccessful.     

Comparison of relapse rates and of mucosal abnormalities after healing of duodenal ulceration and after one year's maintenance with cimetidine or sucralfate: a light and electron microscopy study.

Forty six patients with endoscopically diagnosed duodenal ulceration were randomly allocated to treatment with either sucralfate 1 g qds (n = 24) or cimetidine 200 mg tds and 400 mg nocte (n = 22). When the ulcers healed, a maintenance dose of sucralfate 1 g bd or cimetidine 400 mg nocte was given for one year (or until relapse if earlier). Biopsies of duodenal mucosa adjacent to ulcer sites for light and electron microscopy were obtained before and after healing and again after one year's maintenance if the ulcer remained healed. Duodenal biopsies were also taken from 20 age and sex matched controls. Rates of healing and relapse during maintenance did not differ between the two treatments, although relapses occurred earlier with cimetidine. In the three year post-maintenance follow up period 10/13 cimetidine patients relapsed compared with four of 11 sucralfate patients (p less than 0.05), the relapses occurring significantly earlier in the cimetidine treated patients (p less than 0.05). Mucosal biopsies from both treatment groups still showed considerable abnormalities after healing. During maintenance, however, the sucralfate scores fell significantly (p less than 0.02) to near control levels unlike the cimetidine scores which remained raised at pretreatment values. The histological and ultrastructural changes were not predictive of later relapse. These findings favour the use of sucralfate in preference to cimetidine for maintenance treatment in the prevention of relapse of healed duodenal ulcers.     

Double-blind trial of the use of transfer factor in the treatment of Crohn's disease.

We have undertaken a double-blind controlled trial of the use of transfer factor in Crohn's disease. Thirty-three patients with known Crohn's disease completed the trial in which half the patients had three injections of transfer factor and the other half were given saline. After six months there was no significant difference in the clinical condition of either of the two groups compared with before receiving treatment. There was also no difference in their in vitro lymphocyte function, although a number of patients exhibited altered responsiveness to skin testing with tuberculin or streptokinase/streptodornase. A signficant fall on Crohn's disease activity index score occurred over the initial 'acclimatising period' before the trial was started, probably related to overcoming initial introspection and the placebo effect of being part of a trial.     

CDP571, a humanised monoclonal antibody to tumour necrosis factor alpha, for moderate to severe Crohn's disease: a randomised, double blind, placebo controlled trial

BACKGROUND: Targeting tumour necrosis factor alpha (TNF-alpha) has demonstrated efficacy in Crohn's disease. AIM: To evaluate CDP571, a humanised antibody to TNF-alpha, for treating active Crohn's disease. PATIENTS: A total of 396 patients with moderate to severe Crohn's disease. METHODS: In a 28 week, randomised, double blind, placebo controlled trial, patients received intravenous CDP571 (10 mg/kg) or placebo every eight weeks to week 24. The primary outcome measure was clinical response (a decrease in the Crohn's disease activity index (CDAI) to > or =100 points or remission (CDAI score < or =150 points)) at week 28. A secondary outcome measure was clinical response (using the same definition) at week 2. RESULTS: Clinical response occurred at week 28 in 80/263 (30.4%) CDP571 patients and 31/132 (23.5%) placebo patients (p = 0.102). Clinical response at week 2 occurred in 90/263 (34.2%) CDP571 patients and 28/132 (21.2%) placebo patients (p = 0.011). Post hoc exploratory subgroup analysis of 159 patients with baseline C reactive protein (CRP) > or =10 mg/l demonstrated significant differences between CDP571 and placebo in clinical response rates at weeks 2 (CDP571, 50/101 (49.5%); placebo, 9/58 (15.5%); p<0.001) and 28 (CDP571, 29/101 (28.7%); placebo, 7/58 (12.1%); p = 0.018). Adverse events occurred at similar frequencies in both treatment groups. CONCLUSIONS: CDP571 is modestly effective for short but not long term treatment of unselected patients with moderate to severe Crohn's disease. The clinical relevance of this short term effect is unclear. Post hoc analysis suggests both short and long term efficacy of CDP571 in patients with elevated baseline CRP (> or =10 mg/l). CDP571 is well tolerated.     

Thymosin alpha-1 with peginterferon alfa-2a/ribavirin for chronic hepatitis C not responsive to IFN/ribavirin: an adjuvant role?

This study was conducted to determine whether the adding thymosin alpha-1 to standard of care for re-treatment of nonresponding hepatitis C infections can improve sustained viral response (SVR) rates. Patients (n = 552) with hepatitis C infections not responding to the combination of Peginterferon alfa-2a or 2b with ribavirin (RBV)were randomized to receive peginterferon alfa-2a 180 mg/week with RBV 800-1200 mg/daily plus either thymosin alpha-1 1.6 mg SC twice weekly (n = 275) or placebo (n = 277) for 48 weeks. Eighty-eight per cent of patients had HCV genotype 1, 6.6% type 4, 2.2% type 2 and 3.6% type 3. SVR rates in the intention to treat population were similar between thymosin alpha-1 and placebo (12.7%vs 10.5%; P = 0.407). Among patients who completed all 48 weeks of therapy, the SVR rate was significantly higher in the thymosin alpha-1 group at 41.0% (34/83) compared with 26.3% (26/99) in the placebo group (P = 0.048). No significant difference was observed between treatment groups in the incidence of adverse events. The addition of thymosin alpha-1 to the standard of care did not increase the on-treatment HCV viral response. Thymosin alpha-1 seems to play no role in the primary therapy of the disease. This study raises the hypothesis that thymosin alpha-1 may have a secondary therapeutic role as an adjuvant in the prevention of relapses in patients achieving a virologic response during therapy.     

Placebo-controlled trial of oral 5-ASA in relapse prevention of Crohn's disease

Treatment of Crohn's disease (CD) in clinical remission is still a debated issue. Previous studies have shown a high risk of relapse for patients with CD in clinical remission (CDAI less than 150) but with some abnormally high laboratory parameters as well as a possible beneficial role of low-dosage steroid treatment in this group of patients. Furthermore, good results have been reported on the efficacy of 5-aminosalicylic acid (5-ASA) in moderately active CD. In our study we verified the efficacy of a slow-release oral 5-ASA preparation in preventing relapses in a group of patients in clinical remission but with raised laboratory parameters. Forty-four patients were randomized in a double-blind manner to receive either 5-ASA (2 g/day) or placebo for four months. Location of disease and previous steroid treatment were similar in both groups. One patient in the 5-ASA group discontinued the drug because of uterine bleeding. During the study period, 13 of 22 placebo-treated patients and 11 of 21 5-ASA-treated patients relapsed (corrected chi square = NS). Considering the location of disease, three of 10 patients in the 5-ASA group and six of nine patients in the placebo group with ileal CD relapsed (therapeutic gain with 5-ASA: 36.6%; 95% allowance for error from -6% to 79.2%). Moreover, in seven patients with ileal CD who remained in remission, we found a statistically significant decrease in alpha 1 acid glycoprotein and C-reactive protein from the second month of the study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients

Reports of clinical relapse occurring after apparently successful antibiotic treatment of Whipple's disease prompted this review of long-term follow-up of treated patients. Follow-up of at least 1 yr after completion of treatment or 2 yr after diagnosis was obtained on 88 patients with documented Whipple's disease by a review of the medical literature, correspondence with the authors as needed, and questionnaires mailed to academic gastroenterology programs in the United States. Relapse was defined on the basis of morphology (preferably) or clinically, or both. Thirty-one patients relapsed, 6 of whom relapsed twice. Fifty-seven patients did not relapse. The mean time to relapse was 4.2 yr. The mean follow-up period of patients who did not relapse was 8.2 yr. The type and number of relapses were as follows: clinical, 16; central nervous system, 13; arthralgia, 5; gastrointestinal, 1; and cardiac, 2. The clinical, arthralgia, and gastrointestinal relapses were evenly distributed between early relapses (occurring less than 2 yr after diagnosis) and late relapses (occurring greater than 2 yr after diagnosis). All cardiac and central nervous system relapses were late. Twenty-one of 49 patients treated with tetracycline alone relapsed. Two relapses were reported in 15 patients treated with penicillin and streptomycin followed by tetracycline. Three relapses developed in 8 patients treated with penicillin alone. Five of the 16 patients treated with other regimens relapsed. Nine of the 13 patients with central nervous system relapse had been initially treated with tetracycline, 2 were treated with penicillin, and 2 were treated with combinations of antibiotics. Results of treatment of central nervous system relapse were poor in 10 of the 11 patients for whom details were available. Results of treatment of non-central-nervous-system relapse were excellent in 19 of 20 patients. It is concluded that tetracycline alone, or penicillin alone, is not adequate initial therapy for Whipple's disease and that central nervous system relapse is resistant to antibiotic therapy. The authors recommend parenteral penicillin and streptomycin followed by 1 yr of oral trimethoprim-sulfamethoxazole therapy or oral trimethoprim-sulfamethoxazole alone for 1 yr as initial therapy for Whipple's disease. Relapse should be defined by demonstration of recurrence of bacilli whenever possible.     

C-reactive protein levels during a relapse of Crohn＇s disease are associated with the clinical course of the disease

AIM： TO explore if C-reactive protein （CRP） levels might serve as a prognostic factor with respect to the clinical course of Crohn＇s disease and might be useful for classification. METHODS： In this retrospective cohort study we enrolled 94 patients from the inflammatory bowel disease （IBD） database of the University Medical Centre Utrecht. CRP levels during relapse were correlated with the number of relapses per year. Severity of relapses was based on endoscopic reports and prednisone use. Furthermore, patients were categorized in a low or high CRP group based on their CRP response during relapse and demographic and clinical features were compared. RESULTS： Overall, a positive correlation between CRP levels, number of relapses, and severity of relapse was found （respectively rs = 0.31, P 〈 0.01 and rs = 0.50, P 〈 0.001）. Employing a cut-off level of 15 mg/L, the index CRP level was found to discriminate patients with respect to the number of relapses per year, as well as for severity of relapses （respectively 0.25 ± 0.16 vs 0.36 ± 0.24, P 〈 0.05 and 4.4 ± 1.2 vs 3.2 ± 1.1 on a 10-point visual analogue scale, P 〈 0.001 for the high CRP and low CRP groups respectively）. In addition, the high CRP group showed more cumulative days of prednisone use per year （107 ± 95 vs 58 ± 48, P 〈 0.05）, as well as a better response to infiiximab （93 % vs 33 %, P = 0.06）. CONCLUSION： A higher CRP level during relapse seems to be associated with a more severe clinical course of disease.     

Oral 4-aminosalicylic acid versus 5-aminosalicylic acid slow release tablets. Double blind, controlled pilot study in the maintenance treatment of Crohn's ileocolitis.

4-Aminosalicylic acid (4-ASA) has been suggested as an effective treatment for both active and quiescent ulcerative colitis. 5-Aminosalicylic acid (5-ASA) is well accepted for the maintenance treatment of inactive ulcerative colitis. Moreover, recent studies suggest that 5-ASA may also be effective in maintaining remission in Crohn's colitis. As treatment with 4-ASA may result in less side effects, the efficacy of a one year's maintenance treatment with oral 4-ASA (1.5 g/d, slow release tablets, n = 19) and oral 5-ASA (1.5 g/d, slow release tablets, n = 21) was compared in a double blind, randomised trial in patients with quiescent Crohn's ileocolitis. Patients with ileocolonic or colonic involvement were enrolled if in stable remission for more than two months but less than one year. Baseline demography and clinical severity were similar in both groups. Total colonoscopy and ileoscopy were performed at enrollment and at the end of the study. After one year seven of 19 patients receiving 4-ASA (36%) and 8 of 21 receiving 5-ASA (38%) had developed a clinical relapse, as defined by a rise in the Crohn's disease activity index (CDAI) of more than 100 points to values higher than 150. The relapse rates between the 4-ASA and the 5-ASA groups were not statistically different although no comparison with the spontaneous relapse rate in a placebo group could be made. Clinical relapse was accompanied by a statistically significant rise in serum concentrations of soluble interleukin 2 receptor and by an increased percentage of activated peripheral blood T cells. There were no statistical differences between the 4-ASA and the 5-ASA groups regarding the height of rise in CDAI or of soluble interleukin 2 receptor concentrations during relapse, thus showing a similar severity relapsed disease activity. In conclusion, 4-ASA maybe as effective as 5-ASA in the maintenance treatment of quiescent Crohn's disease and there were no differences in the severity of relapse between both treatment groups.