Lactobacillus GG in inducing and maintaining remission of Crohn's disease

Background  

Experimental studies have shown that luminal antigens are involved in chronic intestinal inflammatory disorders such as Crohn's disease and ulcerative colitis. Alteration of the intestinal microflora by antibiotic or probiotic therapy may induce and maintain remission. The aim of this randomized, placebo-controlled trial was to determine the effect of oral Lactobacillus GG (L. GG) to induce or maintain medically induced remission.     

Low-dose oral methotrexate for maintaining Crohn's disease remission: where we stand

Methotrexate has been considered a second-line immunomodulating therapy, behind azathioprine (AZA) or its metabolite 6-mercaptopurine (6-MP), for the treatment of Crohn's disease (CD). Approximately 27% to 50% of patients with refractory CD are intolerant or resistant to AZA or 6-MP. Two well-designed randomized double-blind placebo-controlled trials have demonstrated that low-dose methotrexate (<25 mg/wk), given intramuscularly (IM), is effective in inducing and maintaining remission in CD. In clinical practice, IM injection involves an inconvenience for patients and higher costs. Furthermore, frequent IM injections increase the risk of complications such as peripheral nerve injury, local irritation, pain, bleeding, fibrosis, abscess formation, gangrene, and contractures. Alternatively, subcutaneous (SQ) injection has been advocated because it has been shown to have similar pharmacokinetics to IM injection. However, because of a recent and ongoing national shortage of parenteral methotrexate, patients who were receiving IM methotrexate had to switch to the oral form until the parenteral formulation becomes available. Oral methotrexate has been used with great success in treatment of rheumatoid arthritis and psoriasis for the past 50 years. However, the data on the usage of low-dose oral methotrexate in maintaining CD remission are scanty and controversial. The purpose of this article is to review the mechanism of action, absorption, and the objective evidence in supporting the use of oral methotrexate in maintaining CD remission.     

Stopping immunomodulators and biologics in inflammatory bowel disease patients in remission

The emergence of biologic response modifiers and earlier use of immunomodulators for inflammatory bowel disease (IBD) patients have improved outcomes. Durable remissions have been achieved in many IBD patients on these treatments, but the duration of treatment and identifying which patients may stop therapy is yet unresolved. Recently, the term very deep remission (defined as clinical remission [CDAI < 150] and endoscopic remission) has been applied to patients on immunomodulators/biologics who have no clinical symptoms or objective signs of inflammatory disease. Whether or not patients who achieve and maintain a very deep remission may successfully stop treatment is not known. This article will review the current data on stopping treatment in IBD and identify certain factors that are associated with a high relapse rate after discontinuing treatment. Where evidence-based data are lacking, the authors provide their opinion.     

Microinflammation in patients with Crohn's disease in clinical remission

Background and aimsIt is not clear whether Crohn's disease patients in clinical remission (Crohn's disease activity index < 150) display normal concentrations of inflammation sensitive biomarkers. Our goal in this work was to explore the intensity of the microinflammatory response in a group of Crohn's disease patients in clinical remission.MethodsHigh sensitivity C-reactive protein, quantitative fibrinogen, erythrocyte sedimentation rate as well as platelet and leukocyte counts were examined in a group of 76 patients with Crohn's disease in remission and in 228 matched controls.ResultsCrohn's disease patients in clinical remission displayed a statistically significant (p < 0.001) elevated concentration of hs-CRP (4.83 ± 3.8 mg/l) compared to controls (1.05 ± 2.9 mg/l). All other bio-markers were also significantly higher in Crohn's disease patients in remission compared to controls. Similar results were obtained in a subgroup of Crohn's disease patients with very low disease activity — CDAI < 75.ConclusionsClinical remission is not equivalent to biochemical remission raising a question concerning the true definition of remission in Crohn's disease.     

Nutritional deficiencies in patients with Crohn's disease in remission

BACKGROUND: Patients with Crohn's disease (CD) are at risk of developing nutritional deficiencies, especially because of restrictive diets. The aim of our study was to assess food intake and the status for vitamins and trace elements in nonselected CD patients in clinical remission. METHODS: A total of 54 consecutive CD patients (28 females, 26 males, 39 +/- 2 years of age [mean +/- SD]) in clinical remission for >3 months underwent body composition, resting energy expenditure, nutrient intake, and plasma concentration assessment, and were compared with 25 healthy controls (16 females, 9 males, 38 +/- 3 years old). RESULTS: According to the nutritional risk index, 37 patients (70%) were not malnourished, 12 were at moderate risk, and 4 were at severe risk for malnutrition. Fat mass was lower in patients in remission compared with controls (P = 0.04). The mean daily energy intake was comparable between patients (2218 +/- 92 kcal/day) and controls (2066 +/- 101 kcal/day), covering their needs. No significant difference was observed for macronutrient intake in comparison with controls; compared to controls, female CD patients had lower intakes of beta-carotene (P < 0.005), vitamins B1 (P < 0.05), B6 (P < 0.01), and C (P < 0.005), and magnesium (P < 0.01). They had significantly higher intakes of zinc (P < 0.01). Male CD patients had lower intakes of beta-carotene and vitamin C (P < 0.05). More than 50% of patients had low plasma concentrations of vitamin C (84%), copper (84%), niacin (77%), and zinc (65%). CONCLUSIONS: In CD patients in remission, macronutrient needs are usually covered by food intake. However, micronutrient deficiencies are frequent and call for specific screening and treatment.     

Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial

BACKGROUND & AIMS: The aim of this study was to evaluate the usefulness of short-term infliximab combined with azathioprine (AZA) or 6-mercaptopurine (6-MP) in steroid-dependent Crohn's disease patients. METHODS: Patients with active disease despite prednisone given for more than 6 months were eligible and were stratified as follows: the failure stratum consisted of patients receiving AZA/6-MP at a stable dose for more than 6 months, and the naive stratum consisted of patients not treated previously with AZA/6-MP. Patients were randomized to infliximab 5 mg/kg or placebo at weeks 0, 2, and 6. All patients were treated with AZA/6-MP maintained at a stable dose throughout the 52 weeks of the study. The primary end point was remission off steroids at week 24. RESULTS: Among the 113 enrolled patients (55 in the failure stratum), 57 were assigned to infliximab. At week 24, the success rate (intent-to-treat analysis) was higher in the infliximab group than in the placebo group (57% vs 29%; P = .003); at weeks 12 and 52, the corresponding rates were 75% vs 38% (P < .001) and 40% vs 22% (P = .04), respectively. In each stratum, the success rate was significantly higher in the infliximab group at weeks 12 and 24, and a trend was found at week 52. In the failure stratum, only 27% of the patients in the infliximab group were still in remission off steroids, compared with 52% in the naive stratum. Steroid resistance was less common and the cumulative dose of prednisone was lower in the infliximab group. CONCLUSIONS: Infliximab plus AZA/6-MP is more effective than AZA/6-MP alone in steroid-dependent Crohn's disease patients.     

Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn's disease: A systematic review and meta-analysis

Background and aimsCombination therapy with infliximab and azathioprine has been shown to be superior to either treatment alone in Crohn's disease (CD). However, the benefit of combining adalimumab with an immunomodulator remains controversial.The aim of this study was to compare the efficacy of adalimumab monotherapy with combination therapy for induction and maintenance of response and remission in CD using a meta-analysis of the current literature.MethodsWe performed a systematic literature search using Medline, Embase, Cochrane and several other databases. Prospective randomized controlled trials, retrospective cohort and case-controlled studies were included. The primary outcomes included induction of response and remission (up to week 12), maintenance of clinical response and remission (1 year) and the need for dose escalation. Several subgroup and sensitivity analyses were performed.ResultsEighteen out of 2743 retrieved studies were included. A meta-analysis of 7 studies assessing induction of remission (n = 1984) showed that ADA monotherapy was inferior to combination therapy [OR = 0.78 (0.64–0.96), p = 0.02]. A meta-analysis of 4 studies revealed that combination therapy was not statistically different from ADA for maintenance of remission [OR = 1.08 (0.79–1.48), p = 0.48]. Combination therapy was also not different from ADA monotherapy in terms of requirement for dose escalation [OR = 1.13 (0.69–1.85), p = 0.62].ConclusionsCombination therapy with ADA and immunomodulator was mildly superior to ADA monotherapy for induction of remission in CD. The rate of remission at 1 year and the need for dose escalation were similar in both groups. These findings should be interpreted with caution in view of possible confounders and should be further validated by randomized controlled trials.     

Budesonide for maintenance of remission in patients with Crohn's disease in medically induced remission: a predetermined pooled analysis of four randomized, double-blind, placebo-controlled trials

OBJECTIVES: To evaluate the efficacy and safety of oral budesonide for maintenance of remission in patients with mild to moderately active Crohn's disease (CD) of the ileum and/or ascending colon. METHODS: Four double-blind, placebo-controlled trials with identical protocols were combined according to a predetermined analysis plan. Three hundred eighty patients with CD in medically induced remission (CD activity index [CDAI]< or =150) were randomized to receive oral budesonide 3 mg, 6 mg, or placebo daily for 12 months. The primary outcome measure was time to relapse (increase in CDAI of 60 points above baseline and >150). RESULTS: The median time to relapse was 268, 170, and 154 days for budesonide 6 mg, budesonide 3 mg, and placebo groups, respectively (p= 0.0072). The frequency of adverse events and glucocorticosteroid side effects were similar in all groups. CONCLUSION: Budesonide 6 mg/day is effective for prolonging time to relapse and for significantly reducing rates of relapse at 3 and 6 months but not 12 months in patients with CD in medically induced remission.