Faculty Bibliography

BACKGROUND & AIMS: Interleukin-12 and interleukin-23 are inflammatory cytokines implicated in Crohn's disease pathophysiology. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12/23. METHODS: We performed a double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohn's disease (population 1). Patients were given subcutaneous placebo at weeks 0-3, then ustekinumab at weeks 8-11; subcutaneous ustekinumab at weeks 0-3, then placebo at weeks 8-11; intravenous placebo at week 0, then ustekinumab at week 8; or intravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an open-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2). RESULTS: In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and 6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (P < .05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in patients given ustekinumab through week 8 compared with placebo. CONCLUSIONS: Ustekinumab induced a clinical response in patients with moderate-to-severe Crohn's disease, especially in patients previously given infliximab

As the baby-boomer generation enters the ranks of the elderly (defined as patients over 60 years of age), the increased burden of managing older inflammatory bowel disease (IBD) patients requires recognition of the impact of comorbid disease, polypharmacy, and surgical candidacy criteria. There is a surprisingly positive response to newer therapies and surgery, provided that a distinction is made between 'fit elderly' and 'frail elderly' patients. The former group should not be denied access to the newer biologics, clinical trials, or surgical alternatives on the basis of age alone. There is a need for clinicians caring for elderly IBD patients to be cognizant of the multiple and often disguised conditions contributing to disease management as well as the importance for careful allocation of health resources

Most physicians believe that the drugs they prescribe will work in their patients and thus have made little preparation for alternative strategies in the event of failure. In the treatment of inflammatory bowel disease (IBD), achieving a remission rate of 20% to 30% or a response rate of 50% to 60% is highly acceptable. This review focuses primarily on placebo-controlled trials that evaluated 'usual' treatments for IBD in terms of induction and maintenance of remission, and identifies the 'gaps' (ie, the percentage of patients lacking any benefit) in currently available treatments for IBD. Approximately, 40% to 60% of patients will not benefit from the available treatments, indicating a considerable unmet need for new, more effective therapies

BACKGROUND: Natalizumab, a humanized monoclonal IgG(4) antibody to alpha4 integrin, was investigated as a treatment of active Crohn's disease (CD). The safety of natalizumab given in combination with infliximab has not previously been studied. METHODS: Seventy-nine adult patients with active CD (Crohn's Disease Activity Index [CDAI] score > or = 150) despite ongoing infliximab treatment were randomized 2:1 to receive 3 intravenous infusions of natalizumab (300 mg; n = 52) or placebo (n = 27) every 4 weeks. Patients received infliximab (5 mg/kg) every 8 weeks for at least 10 weeks before randomization and throughout the study. The primary objective was to assess the short-term safety and tolerability of natalizumab in patients concurrently receiving infliximab. Secondary and tertiary objectives included measures of efficacy, health-related quality of life (HRQoL), and effects on inflammatory markers. A subset of patients also participated in a pharmacokinetic/pharmacodynamic (PK/PD) analysis of the effects of concurrent treatment. RESULTS: Incidence of adverse events (AEs) was similar in the treatment groups. AEs frequently reported in both groups were headache, CD exacerbation, nausea, and nasopharyngitis. No patient had a hypersensitivity-like reaction to natalizumab, whereas 4 patients (5%) experienced reactions to infliximab. Two patients (4%) developed anti-natalizumab antibodies; 10 patients (14%) developed anti-infliximab antibodies. The mean CDAI score decreased with natalizumab plus infliximab but was unchanged with infliximab alone (-37.7 versus +3.5; P = 0.084). Patients in both groups showed small increases in HRQoL (P = 0.811). No drug-drug interactions were noted. CONCLUSIONS: The combination of natalizumab plus infliximab was well tolerated. Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone

Leukocytapheresis has reemerged as a novel "nondrug" approach in the treatment of inflammatory bowel disease. The technique involves the extracorporeal passage of peripheral blood through a column of cellulose diacetate beads (Adacolumn) or a nonwoven polyester fiber filter (Cellsorba). The benefits accrued from the filtered extraction of granulocytes, monocytes (Adacolumn), and lymphocytes (Cellsorba) appear greater than the simple extraction of these cells. There appears to be an immunologic modulation of leukocytes and dendritic cells and a diminished response to proinflammatory cytokines. Unfortunately, blinded placebo-controlled trials are lacking. Nevertheless, the aggregate clinical experience detailed in this review suggests a relatively safe and attractive alternative to current inflammatory bowel disease therapies. Randomized, controlled sham trials are in progress.