Therapy of Inflammatory Bowel Disease: What to Expect in the Next Decade

David A. Leiman; Gary R. Lichtenstein

Disclosures

Curr Opin Gastroenterol 

In This Article

Long-range Options

There are several therapeutic options at early stages of study, but still they have shown promise in both the Crohn's disease and the ulcerative colitis.

Antiinterleukin-6/Tocilizumab

IL-6 is a cytokine secreted by a variety of immune and nonimmune cells that functions to stimulate the immune response and is involved in the acute-phase response. Tocilizumab is a humanized monoclonal antibody that blocks both membrane-bound and soluble IL-6 receptor.[33] A small randomized controlled pilot trial of 36 patients with active Crohn's disease treated with tocilizumab showed encouraging results.[34] Patients received biweekly infusions of either drug or placebo at 8 mg/kg and after 12 weeks there was a statistically significant difference in clinical response (80 versus 31%; P = 0.019). These findings need to be confirmed in a larger clinical trial. Other drugs in this class that will continue to be tested include BMS-945429 and PF-04236921, which are fully human antibodies to IL-6.[35,36]

Laquinimod

Laquinimod is a novel orally administered synthetic agent that has been studied for use in multiple sclerosis and explored as a potential agent in Crohn's disease. It acts as an immunomodulator but does not seem to lead to immunosuppression, primarily acting to direct T cells into an antiinflammatory phenotype[37] and downregulating proinflammatory cytokines. In a phase IIa multicenter, sequential cohort randomized controlled exploratory trial of 180 patients with moderately-to-severely active Crohn's disease, clinical remission, clinical response, and intestinal inflammation (based on fecal calprotectin levels) were assessed. Patients were given doses of 0.5, 1, 1.5, or 2 mg/day of laquinimod for 8 weeks or placebo. In this study, patients on the lowest dosage of laquinimod have the greatest benefit in clinical remission (48.3 versus 15.9% with placebo, no P-value reported), clinical response (55.2 versus 31.7% with placebo, no P-value reported), and more than 50% reduction in fecal calprotectin (38.9 versus 13.6% with placebo, no P-value reported). These data represent early findings and warrant further investigation.[38]

HMPL-004

HMPL-004 (Andrographis paniculata extract) is a plant derivative that has been shown to have several antiinflammatory properties that work by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells, TNF-α, and IL-1β.[39] It has known efficacy in murine colitis models and, therefore, has been evaluated in patients with ulcerative colitis.[40] A double-blind, randomized placebo-controlled trial was conducted over 8 weeks to evaluate its efficacy in 224 patients with mild-to-moderate ulcerative colitis at daily doses of 1.2 g, 1.8 g, or placebo. There was a statistically significant response seen in patients treated at high dose of A. paniculata, with 60% of patients achieving clinical response compared with 40% receiving placebo (P = 0.018). However, it has not yet been tested in patients with more severe disease and, therefore, may represent an alternative to traditional mesalamine compounds in the future, with unclear utility in patients with refractory disease.

Stem Cell Therapy

Case reports suggesting that IBD could be cured through stem cell transplants raised hopes for a paradigm-shifting therapy.[41,42] This led to the investigation of both hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) as therapeutic options in Crohn's disease.

The use of HSC has been reserved for the most refractory Crohn's disease cases and has shown some degree of success. It is believed that HSC exert effects through 'resetting' the immune system, although this requires a cytotoxic conditioning regimen prior to transplant.[41] Two case series of patients treated with autologous HSC transplant had success rates of 80 and 91%, with cohorts of 10 and 24 patients, respectively.[43,44] In the only randomized controlled trial investigating autologous stem cell transplant, 45 patients with severe Crohn's disease were randomized to receive either cytotoxic conditioning followed by autologous cell infusion or conditioning alone.[45] Early results demonstrated a greater reduction in CDAI in the transplanted patients (324 to 161) compared with conditioning alone (351 to 272), but no P-value was reported. While these findings highlight some of the potential benefits, there are substantial risks. Separating the potential benefit of HSC transplant versus the risk of the conditioning cytotoxic regimen alone is crucial but still an unresolved issue.

It is believed that MSC, which can be derived from both bone marrow and adipose tissue, work through two mechanisms to be both immunosuppressive and antiinflammatory.[41] In patients with IBD, MSC therapy has been tested for treatment of fistulizing disease and luminal disease. Early phase I and phase II studies of feasibility described fistula closure with local injection of MSC along with fibrin glue.[46,47] These successes were followed by investigations of injecting peripherally expanded MSC into a fistulous tract.[48] In the study of 10 patients, seven had complete sustained closure (P < 0.01) on magnetic resonance imaging and reduction in Crohn's disease and perianal disease activity indices (P < 0.01 for both).

Treating luminal Crohn's disease with MSC seems promising based on recent data. A phase II open-label, multicenter, nonrandomized study of 16 refractory Australian patients with Crohn's disease who had failed anti-TNF therapy investigated the benefit of sequential MSC infusions, which were given 1 week apart over 4 weeks.[49] The primary outcome of clinical response was evaluated at day 42 and showed success in 80% (P < 0.0001) of the patients, with improvement in secondary outcomes of clinical remission and endoscopic score in 53 and 47%, respectively.

The use of stem cell therapy offers great promise, including a potential cure for patients with IBD. However, it comes with significant potential risk and with scant data for use in the setting of ulcerative colitis. These early reports of success will continue to prompt deeper investigation into the utility of both HSC and MSC.

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