Higher Intra-Abdominal Visceral Adipose Tissue Mass Is Associated With Lower Rates of Clinical and Endoscopic Remission in Patients With Inflammatory Bowel Diseases Initiating Biologic Therapy: Results of the Constellation Study.

BACKGROUND & AIMS: We sought to assess the association between intra-abdominal visceral adipose tissue (IA-VAT) and response to 3 different biologic drugs in patients with inflammatory bowel disease (IBD) and to investigate its effects on inflammatory cytokine expression, pharmacokinetics, and intestinal microbiota. METHODS: We prospectively enrolled subjects with active IBD initiating infliximab, vedolizumab, or ustekinumab and a healthy control group. Baseline body composition (including IA-VAT as percent of total body mass [IA-VAT%]) was measured using GE iDXA scan. Primary outcome was corticosteroid- free deep remission at weeks 14-16, defined as Harvey Bradshaw Index <5 for Crohn's disease and partial Mayo score <2 for ulcerative colitis, with a normal C-reactive protein and fecal calprotectin. Secondary outcomes were corticosteroid-free deep remission and endoscopic remission (Endoscopic Mayo Score ≤1 in ulcerative colitis or Simple Endoscopic Score for Crohn's disease ≤2) at weeks 30-46. RESULTS: A total of 141 patients with IBD and 51 healthy controls were included. No differences in body composition parameters were seen between the IBD and healthy control cohorts. Patients with higher IA-VAT% were less likely to achieve corticosteroid-free deep remission (P < .001) or endoscopic remission (P = .02) vs those with lower IA-VAT%. Furthermore, nonresponders with high IA-VAT% had significantly higher serum interleukin-6 and tumor necrosis factor at baseline compared with responders and patients with low IA-VAT%. Drug pharmacokinetic properties and microbiota diversity were similar when comparing high and low IA-VAT% groups. CONCLUSIONS: Higher IA-VAT% was independently associated with worse outcomes. This association could be driven at least partially by discrete differences in inflammatory cytokine expression.

HMPL-004 (Andrographis paniculata extract) prevents development of murine colitis by inhibiting T-cell proliferation and TH1/TH17 responses.

BACKGROUND: Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double-blind, placebo-controlled trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate ulcerative colitis (UC). We aimed to determine if HMPL-004 could prevent the development of T-cell-dependent murine colitis and to define its in vivo mechanism(s) of action. METHODS: CD(+)4CD45RB(high) T cells were transferred into Rag1(-/-) mice and gavaged daily with HMPL-004 or methyl cellulose (MC). Severity of colitis was evaluated by weight loss, histology, and cytokine expression. RESULTS: Mice treated with MC developed colitis within 4-7 weeks, as evaluated by weight loss, and severe intestinal inflammation. HMPL-004-treated mice did not lose weight and displayed only very mild intestinal inflammation. Tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, interferon-gamma (IFN-γ), and IL-22 expression were significantly decreased in HMPL-004-treated mice. We observed higher percentages of naïve CD4(+) T cells in the lamina propria of HMPL-004-treated mice. At early timepoints HMPL-004-treated mice have significantly reduced splenic cell counts, reduced CD4(+), and IL-17(+), and IFN-γ T(+) cells. Furthermore, HMPL-004 inhibited the proliferation of CD4 T cells and differentiation into TH1/TH17 cells in vitro. CONCLUSIONS: HMPL-004 inhibits the development of chronic colitis by affecting early T-cell proliferation, differentiation, and TH(1)/TH(17) responses in a T-cell-driven model of colitis, presenting a unique mechanism of action. Our data suggest that HMPL-004 could be an attractive herbal therapeutic for inflammatory bowel disease.

Andrographis paniculata extract (HMPL-004) for active ulcerative colitis.

OBJECTIVES: Andrographis paniculata has in vitro inhibitory activity against TNF-α, IL-1ß and NF-κB. A pilot study of A. paniculata extract (HMPL-004) suggested similar efficacy to mesalamine for ulcerative colitis. METHODS: A randomized, double-blind, placebo-controlled trial evaluated the efficacy of A. paniculata extract (HMPL-004) in 224 adults with mild-to-moderate ulcerative colitis. Patients were randomized to A. paniculata extract (HMPL-004) 1,200 mg or 1,800 mg daily or placebo for 8 weeks. RESULTS: In total, 45 and 60% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical response at week 8, compared with 40% of those who received placebo (P=0.5924 for 1,200 mg vs. placebo and P=0.0183 for 1,800 mg vs. placebo). In all, 34 and 38% of patients receiving A. paniculata 1,200 mg and 1,800 mg daily, respectively, were in clinical remission at week 8, compared with 25% of those who received placebo (P=0.2582 for 1,200 mg vs. placebo and P=0.1011 for 1,800 mg vs. placebo). Adverse events developed in 60 and 53% of patients in the A. paniculata 1,200 mg and 1,800 mg daily groups, respectively, and 60% in the placebo group. CONCLUSIONS: Patients with mildly to moderately active ulcerative colitis treated with A. paniculata extract (HMPL-004) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo.

Future biologic targets for IBD: potentials and pitfalls.

The treatment of patients with IBD has evolved towards biologic therapy, which seeks to target specific immune and biochemical abnormalities at the molecular and cellular level. Multiple genes have been associated with susceptibility to IBD, and many of these can be linked to alterations in immune pathways. These immune pathways provide avenues for understanding the pathogenesis of IBD and suggest future drug targets, such as the IL-12-IL-23 pathway. In addition, failed therapeutic drug trials can provide valuable information about pitfalls in study design, drug delivery and disease activity assessment. Future biologic drug development will benefit from the early identification of subsets of patients who are most likely to respond to therapy by use of biological markers of genetic susceptibility or immunologic susceptibility.

Ex vivo induction of mRNA in human whole blood as a new platform of drug and dietary supplement development.

PURPOSE: We introduced a new concept of ex vivo gene expression analysis (Mitsuhashi, Clin Chem 53:148-149, 2007), where drug action was simulated under physiological conditions. This model system was applied to study various fields of drug development. MATERIALS AND METHODS: Heparinized human whole blood was incubated with drugs for less than 4h. The changes of specific mRNA were then quantified using the method we developed (Mitsuhashi, Tomozawa, Endo, and Shinagawa, Clin Chem 52:634-642, 2006). RESULTS: The mRNA quantitation method was used as a model system to study the following areas: (1) identification of respondents and non-respondents, (2) ex vivo compound screening, (3) determination of individually optimized doses, (4) drug-to-drug comparison, (5) assessment of leukocyte toxicity, (6) discovery of molecular targets, (7) assessment of the action of dietary supplements, and (8) characterization of respondents and non-respondents for various dietary supplements. CONCLUSION: Since ex vivo assays are safe, a large number of healthy donors and disease patients can be recruited to identify individual-to-individual variations, which is not available from current preclinical study models. Although each system should be validated using a large number of samples, the ex vivo analysis will be a new tool for the development of drugs and dietary supplements in future.

Biologic therapy of inflammatory bowel disease.

Advancing knowledge regarding the biology of chronic inflammation has led to the development of specific biologic therapies that mechanistically target individual inflammatory pathways. Many biologic therapies are being evaluated for the treatment of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis. Biologic compounds proven to be effective for Crohn's disease include monoclonal antibodies to tumor necrosis factor (infliximab and CDP571) and to the leukocyte adhesion molecule alpha4 integrin (natalizumab). Other biologic compounds for which there is insufficient evidence to judge efficacy for inflammatory bowel disease include: p55 tumor necrosis factor binding protein (onercept); interferon alpha; interferon beta-1a; anti-interferon gamma antibody; anti-interleukin 12 antibody; p65 anti-sense oligonucleotide (blocks NF-kappaB); granulocyte colony stimulating factor, and granulocyte macrophage colony stimulating factor; anti-interleukin 2 receptor antibody; epidermal growth factor; keratinocyte growth factor 2 (repifermin); human growth hormone; anti-CD4 antibody; and anti-alpha4beta7 antibody. Biologic therapies that have been proven ineffective for inflammatory bowel disease include: interleukin 10; interleukin 11; anti-sense intercellular adhesion molecule-1; and the tumor necrosis factor receptor fusion protein etanercept. Based on the early successes of infliximab, CDP571 and natalizumab, it seems certain that biologic therapy will play an important role in the future treatment of inflammatory bowel disease.