Faculty Bibliography

GOALS: Two uncontrolled, multicenter feasibility studies evaluated safety and pilot efficacy of selective granulocyte and monocyte adsorption apheresis (GMA) with the Adacolumn Apheresis System for treatment of moderate-to-severe ulcerative colitis (UC) and Crohn disease (CD) patients refractory/intolerant to conventional pharmacologic therapy. BACKGROUND: Patients with UC and CD, characterized by elevations in peripheral blood granulocytes, monocytes/macrophages, and proinflammatory mediators, may benefit from reductions in activated granulocytes and monocytes by selective apheresis. METHODS: Patients underwent weekly Adacolumn sessions for 5 weeks. Pilot efficacy assessments used disease activity index (DAI) for UC (0-12) or CD activity index (CDAI; 0-600) for CD. RESULTS: Eleven of 15 UC patients completed all 5 treatments. Mean DAI scores fell from 8.4+/-1.3 (baseline) to 5.2+/-2.9 (week 7). Five patients had DAI reductions of > or = 3 points at week 7. Fourteen of 15 CD patients completed all 5 treatments. Mean CDAI scores fell from 308.0+/-76.5 (baseline) to 200.6+/-117.4 (week 7). Nine CD patients responded (CDAI reductions > or = 70 points) at week 7. Remission (CDAI score < or = 150 at week 7) was observed in 6 patients. There were no device-related serious adverse effects. CONCLUSIONS: Treatment with Adacolumn may be feasible and effective in patients with moderate-to-severe refractory inflammatory bowel disease. Larger sham-controlled studies are ongoing

Patients with inflammatory bowel disease (IBD) are at increased risk for osteoporotic fracture. Bone density testing and osteoporosis management are recommended for IBD patients at greater risk for fracture (ie, postmenopausal women, men aged . 60 years, and those with low body mass indices, glucocorticoid use, family history of osteoporosis, and malabsorption). Patient management includes modification of osteoporosis risk factors, such as calcium and vitamin D supplementation, hormone deficiency correction, and smoking cessation. When indicated, bisphosphonates, such as risedronate and alendronate, have been shown to increase bone mass and reduce fracture risk in patients with glucocorticoid-induced osteoporosis. Infliximab, an anti-tumor necrosis factor a antibody, increases bone mineral density, but this effect has not as yet translated into reduced fracture risk

Curcumin, a natural compound used as a food additive, has been shown to have anti-inflammatory and antioxidant properties in cell culture and animal studies. A pure curcumin preparation was administered in an open label study to five patients with ulcerative proctitis and five with Crohn's disease. All proctitis patients improved, with reductions in concomitant medications in four, and four of five Crohn's disease patients had lowered CDAI scores and sedimentation rates. This encouraging pilot study suggests the need for double-blind placebo-controlled follow-up studies

The principal investigator is responsible for everything involved in the conduct of a clinical research study. Prior to the initiation of any clinical trial, an investigator must become acquainted with the material requirements, personnel needs, and best practices involved in the conduct of the trial. Commitment to a clinical trial should not be taken lightly because even a simple study may require a major investment of staff, space, and time. Standard operating procedures help to standardize staff training and improve regulatory compliance. Reasons for participation in clinical research may differ between community and academic gastroenterologists, but responsibility for patient care, regulatory requirements, and assumption of accountability are identical. Careful attention to the details of site organization, administrative requirements, and patient recruitment and retention all contribute to the successful performance of clinical research

BACKGROUND AND AIMS: Preliminary data have shown that delayed release oral mesalamine (Asacol) dosed at 4.8 g/day provided additional efficacy benefit compared to 1.6 g/day in patients with mildly to moderately active ulcerative colitis. Additionally, Asacol dosed at 2.4 g/day has been proved to be more effective than 1.6 g/day. Whether 4.8 g/day of mesalamine (dosed with an investigational 800 mg tablet) is more effective than Asacol 2.4 g/day (dosed with a 400 mg tablet) in patients with moderately active ulcerative colitis is unknown. METHODS: A randomized, double-blind, controlled trial (ASCEND II) was conducted to evaluate the efficacy of 4.8 g/day of mesalamine in adults with active ulcerative colitis. Three hundred eighty-six patients with mild to moderate ulcerative colitis were randomized for treatment with mesalamine 2.4 g/day (400 mg tablet) or 4.8 g/day (800 mg tablet) for 6 wk. The primary efficacy population was 268 patients with moderately active ulcerative colitis treated with 2.4 g/day (n = 139) or 4.8 g/day (n = 129). The primary endpoint was the proportion of patients in each treatment group that achieved overall improvement ('treatment success,' defined as either complete remission or a clinical response to therapy) from baseline at week 6. RESULTS: Seventy-two percent of patients receiving 4.8 g/day of mesalamine for moderate ulcerative colitis (89/124 patients) achieved treatment success at week 6, compared with 59% of those who received 2.4 g/day (77/130 patients) (p= 0.036). Both regimens were well tolerated. Adverse events and clinically significant changes in laboratory results were similar in both treatment groups. CONCLUSIONS: Patients with moderately active ulcerative colitis treated with 4.8 g/day of mesalamine (800 mg tablet) are significantly more likely to achieve overall improvement at 6 wk compared to patients treated with 2.4 g/day

Recent advances in the pathogenesis of ulcerative colitis recognize the interface of genetic susceptibility, environmental factors (eg, gut microflora), and an altered host's immune response. The meteoric evolution of new therapies designed to address these pathogenetic factors may lead to confusing and often confounding treatment programs. This review is designed to assist the practitioner when incorporating new or novel therapies into a treatment program. These decisions are based on new clinical trial data and the experience of seasoned gastroenterologists with established remedies

OBJECTIVES: Infliximab, an anti-tumor necrosis factor (TNF) monoclonal antibody, might exert some of its long-term therapeutic effects in Crohn's disease (CD) by interacting directly with cells of the immune system such as monocytes and T lymphocytes via membrane TNF and by inducing apoptosis. Accordingly, the effects of inflix-imab on monocyte apoptosis and down-regulation of proinflammatory cytokines (reverse signaling) were assessed. METHODS: To assess apoptosis, monocytes from healthy individuals (controls) and CD patients were incubated in the presence or absence of infliximab or the apoptotic agent gliotoxin for 24 hours. Annexin V staining and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-FITC nick end labeling assay were used to measure early and late apoptosis. To measure the effects of infliximab on reverse signaling, monocytes from healthy individuals pretreated in vitro with infliximab were stimulated with lipopolysaccharide or staphylococcal enterotoxin A, and the induction of the proinflammatory cytokines, TNF-alpha, interleukin (IL)-1beta, IL-6, and IL-8 was measured by reverse transcription polymerase chain reaction. The effect of in vivo infliximab treatment of monocytes was similarly determined by comparing the responses of monocytes from CD patients before and immediately after infliximab infusion. RESULTS: Infliximab did not induce apoptosis of monocytes from either healthy individuals or CD patients but rather stabilized them. However, monocytes from healthy individuals treated with infliximab in vitro, or from CD patients infused with infliximab, produced significantly less TNF and other proinflammatory cytokines when stimulated with the bacterial products lipopolysaccharide and staphylococcal enterotoxin A. CONCLUSIONS: Apoptosis of monocytes is not responsible for the therapeutic effects of infliximab. However, some of the therapeutic effects of infliximab may be caused by its ability to down-regulate proinflammatory cytokines production by monocytes exposed to bacterial antigens