IBD Watch^®

^{Timely Information for Practicing Physicians}

  JUNE 2005 

ABSTRACT HIGHLIGHTS OF DIGESTIVE DISEASE WEEK^®

May 14–19, 2005

INFLAMMATORY BOWEL DISEASE (IBD)

Outcomes of pregnancy during thiopurine therapy.  C Dejaco and colleagues followed 33 pregnancies in 25 women with IBD treated with thiopurine therapy (azathioprine, 6 mercaptopurine, or thioguanine) and 35 pregnancies in 28 women with IBD who did not receive immunosuppressive therapy. No significant differences in outcomes (abortions, stillbirths, per-term births, low birth weight, malformations, or perinatal infections) were observed between the 2 groups of IBD patients. Compared with 310,323 control pregnancies from the Austrian birth registry (2000–2003), the duration of pregnancies in IBD patients was shorter (P=0.03).  However, no difference in birth weight was detected. These data provide evidence of the safety of thiopurine maintenance therapy in patients with IBD during pregnancy.  (Abstract 62)

Risk factors for colorectal neoplasia (CRN).  T Jess and colleagues conducted a nested case-control study of CRN risk factors in 2 well-described IBD cohorts from Copenhagen County (Denmark) and Olmstead County (Minn., USA). A diagnosis of primary sclerosing cholangitis, presence of clinically active disease (during at least 20% of the disease course), and >1 year of continuous symptoms were found to be significantly associated with CRN. In addition, a greater number of endoscopies and higher cumulative doses of sulfasalazine, mesalamine, and steroids also were associated with a greater risk for CRN. More surgical resections reduced the odds for CRN. Smoking was not observed to be a risk factor. These data suggest that the surgical removal of high-risk bowel segments may be the only protective factor against CRN in patients with active IBD.  (Abstract 780)

CROHN'S DISEASE (CD)

Medical management of CD: Top-down vs step-up strategies. Current guidelines for CD treatment restrict use of immuno-modulators to patients who fail corticosteroids. Daniel Hommes and others conducted a randomized controlled trial to introduce more potent immunomodulators earlier in the course of the disease with the objective of altering long-term prognosis. Patients in the study (N=129) had active and newly diagnosed CD, or a CD history of no more than 4 years during which no steroids or immuno-modulatory drugs were taken. They were randomized to a “top-down” (TD) group (n=65), receiving infliximab (IFX) 5 mg/kg (weeks 0, 2, and 6) plus azathioprine (AZA) 2.5 mg/kg, or to a “step-up” (SU) group (n=64), receiving corticosteroids, initially at 40 mg/d, tapered over 8 weeks. Disease recurrence was treated with IFX and/or methotrexate (MTX) in the TD arm, and with repeated corticosteroids in the SU arm; patients failing repeated steroids were allowed AZA. The prospectively defined endpoints were remission (CDAI <150 and no corticosteroid therapy) at 6 and 12 months. More patients achieved the primary outcome in the TD group (74.5% vs 48.1%) due primarily to the proportion of patients in the SU group who remained on corticosteroids (32.7% vs 0%). There was no difference in the proportion of patients with CDAI scores of >150; similarly, health-related quality of life assessments by IBDQ and Eurqol scores showed no differences between the 2 strategies. At 26 weeks, the proportion of patients on MTX, AZA, or 6-MP was significantly higher in the TD group (86.8% vs 40.4%). Thus, the introduction of infliximab and azathioprine early in the course of CD is more effective (steroid sparing) than the traditional approach using corticosteroids followed by immunomodulators in relapsing or nonresponding patients. (Abstract W1017)

Prolonged immunosuppressive therapy during infliximab therapy does not prevent relapse.  G van Assche and others studied 57 patients with CD who had been successfully treated for ≥6 months with infliximab 5 mg/kg iv plus immunosuppressive therapy, randomizing them to either continue or discontinue immunosuppressive agents during maintenance infliximab treatments every 8 weeks. Baseline characteristics were similar between the 2 treatment groups. After a median follow-up of 7 months, 21% and 33% of patients who continued or discontinued immunosuppressives, respectively, had experienced a disease flare (P=0.24).  Mean CRP values and mean increase in CRP at the time of disease flare were not different between the 2 groups. These findings demonstrated that the continuation of immunosuppressive therapy beyond 6 months in patients receiving maintenance infliximab treatments may not be necessary to prolong maintenance of remission.  (Abstract 147)

Treatment with IL-10-producing Lactococcus lactis.  Studies in animal models indicate that the topical application of IL-10 using genetically modified bacteria can reduce CD activity. These data led Henri Braat and others to treat 10 patients with CD for 7 days with Lactococcus lactis genetically modified to produce IL-10. Treatment with the bacterium was associated with only minor adverse events. Fecal collections on day 4 of treatment were found to contain the largest amounts of the modified bacterium DNA sequences. These DNA sequences were no longer detectable 2 days after the termination of treatment. In addition, dissemination of the transgene to other microorganisms was not observed. An average decrease in CDAI of 71.7 resulted after the 1 week of study duration (P<0.002). These data demonstrated that short-term treatment with IL-10–producing Lactococcus lactis is safe and may be effective. The authors suggest that this therapy may be most suitable for maintenance treatments of CD.  (Abstract 685)

Ciprofloxacin treatment of perianal fistulas.  RL West and coworkers conducted a double-blind study in which 24 patients with perianal fistulizing CD who were undergoing therapy with infliximab 5 mg/kg (weeks 6, 8, and 12) were randomized to receive ciprofloxacin 500 mg bid or placebo for 12 weeks. No difference in clinical response rates was seen at 6 weeks. However, at weeks 8, 12, and 18, clinical response rates were higher in the ciprofloxacin group than in the placebo group; logistic regression analysis showed a tendency for patients treated with infliximab and ciprofloxacin to respond better than patients treated with infliximab and placebo (P=0.07). Fistula tracts remained visible on hydrogen peroxide–enhanced 3D-endoanal ultrasonography despite clinical response.  (Abstract W1075)

ULCERATIVE COLITIS (UC)

Oral tacrolimus therapy.  H Ogata and colleagues conducted a double-blind study in which 60 patients with refractory UC were randomized to receive low trough levels of tacrolimus (LTG), high trough levels of tacrolimus (HTG), or placebo for 2 weeks. At 2 weeks, response rates were 68.4%, 38.1%, and 10% in the HTG, LTG, and placebo groups, respectively. Compared with placebo, HTG therapy yielded improvement (P<0.001). In the open-label phase of the study, former LTG and placebo patients received HTG therapy, and their response rates improved significantly. The mean doses of prednisolone were significantly reduced with HTG therapy. These results suggest that tacrolimus is an effective treatment option for patients with refractory UC.  (Abstract 489)

New therapies.  Two studies reported the use of alicaforsen, an antisense inhibitor of ICAM-1, in patients with UC. In the first double-blind study, 112 patients with mild to moderate UC were randomized to one of 4 alicaforsen-enema dosing regimens or to placebo given over a 6-week period. Dosing regimens utilizing <240 mg of alicaforsen failed to demonstrate improvement over placebo. However, patients receiving alicaforsen enemas 240 mg daily had a better response rate than placebo patients at weeks 18 and 30 (P=0.04 and 0.03, respectively); median duration of response was ≥6 months. In a second study, 159 patients with mild to moderate UC were randomized to receive alicaforsen enemas 120 mg, alicaforsen enemas 240 mg, or mesalamine enemas 4 g daily for 6 weeks. During the 6-week treatment period, the clinical response rates for alicaforsen 240 mg and the mesalamine enemas were comparable (both were superior to the alicaforsen 120 mg group). A trend toward a longer median duration of response in the alicaforsen 240 mg group, compared with the mesalamine group, was observed (6 months vs <4 months; P=0.20).  In addition, the results of 53 patients with UC refractory to iv steroids (34 EBV– and 19 EBV+) randomized to receive doses of 5, 7.5, 10, or 12.5 mg/kg of visilizumab, a humanized anti-CD3 monoclonal antibody, for 2 consecutive days were reported by SR Targan and colleagues. All visilizumab doses were well tolerated and induced rapid and durable responses in a majority of patients.  No increase in the incidence of infection or difference in clinical response was observed in EBV+ patients.  (Abstracts 490, 491, 493)

Phase III trials of infliximab.  Two phase III trials, ACT 1 (N = 364) and ACT 2 (N = 364), investigated the efficacy and safety of infliximab for the treatment of active UC resistant to corticosteroids and/or 6-MP/AZA. In ACT 1, patients were randomized to receive infliximab 5 mg/kg, infliximab 10 mg/kg, or placebo at weeks 0, 2, and 6, and then every 8 weeks up to week 46. In ACT 2, patients were randomized to receive infliximab 5 mg/kg, 10 mg/kg, or placebo at weeks 0, 2, 6, 14, and 22. In both studies, significantly higher proportions of patients receiving infliximab 5 mg/kg and 10 mg/kg, as compared with patients receiving placebo, achieved clinical responses and remissions at week 8. These differences in response and remission rates persisted at week 30. In addition, a significantly greater proportion of patients in both infliximab treatment groups than patients in the placebo groups in both studies developed mucosal healing at week 8 that persisted to week 30. Infliximab was well tolerated. These studies confirm that infliximab is an effective and safe therapy for patients with active UC.  (Abstracts 688, 689)

Detection of dysplasia and colorectal cancers.  DT Rubin and coworkers retrospectively reviewed 1,339 surveillance exams performed in 622 UC patients in the University of Chicago IBD Surveillance Database. In total, 44 patients were found to have dysplasia or cancer at a median age of 47.5 years and a median duration of UC of 20 years. Per-patient sensitivities for dysplasia and cancer were 75% and 100%, respectively. These findings showed that dysplasia and cancer in UC are reliably identified during surveillance examinations in most patients. The authors concluded that future guidelines should emphasize additional biopsies of abnormal mucosa. A second study was conducted by R Kesslich and others in which 153 patients with long-standing UC were randomized to undergo conventional colonoscopy or chromoendoscopy plus confocal laser endoscopy to detect intraepithelial neoplasias and cancer. Significantly more intraepithelial neoplasias were detected by chromoendoscopy in conjunction with endomicroscopy than with conventional colonoscopy (P=0.007), and the presence of neoplastic changes was predicted with high accuracy by endomicroscopy (sensitivity: 94.7%; specificity: 98.3%; accuracy: 97.8%). These findings suggest that chromo-endoscopy with endomicroscopy may lead to improvement in the surveillance and clinical management of patients with UC.  (Abstracts 779, 483)  

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