Ece A Mutlu
Assistant Professor of Medicine
MD FRCP(UK) FACP FACG
Professor of Medicine, Professor of Pharmacology and Molecular Biophysics & Physiology
Rush-Presbyterian-St-Luke’s Medical Center
IBD remains a cause of substantial morbidity worldwide. IBD is a result of uncontrolled and sustained dysregulated immunoinflammatory reactions to hostile luminal proinflammatory factors such as bacterial products and food antigens. It has been suggested that chronic gut inflammation is associated with an imbalance between pro- and anti-inflammatory cytokines. Thus manipulations that result in either decreasing proinflammatory cytokines or increasing anti-inflammatory ones can decrease inflammatory-induced mucosal damage and promote healing processes in IBD. There is an increasing body of experimental and clinical evidence to suggest that the final common pathway of immune injury in IBD is the result of enhanced production of reactive oxygen species (ROS).(1–4)
The ultimate treatment target would be achieved by simply eliminating the primary aetiological factors, but our restricted understanding of the pathogenesis of this disorder limits our identification of these factors. Therefore the therapeutic objective is to induce remission and to maintain it using treatment that controls immunoinflammatory processes, such as anti-inflammatory, immunosuppressive and immunomodulatory agents, and those agents that protect the epithelium from consequential damage, such as antioxidants.
Class I medicines
This group consists mostly of the the conventional medicines that are used in most gastroenterology clinics, and several clinical trials has approved their efficacy in inducing or maintaining remission in patients with IBD. In this review we will not cover this well-established group of medicines. However, there are emerging new medicines based on these conventional drugs that have the same mode of action and might be used in special circumstances.
Balsalazide is mesalazine attached to an inert carrier molecule, 4-aminobenzoyl-beta-alanine, via an -azo bond. This bond is cleaved by colonic bacteria via bacterial azo-reductase, releasing the locally active 5-aminosalicylic acid (5-ASA) moiety. Balsalazide is as effective as meselamine and sulfasalazine in both treatment and maintenance of remission of ulcerative colitis (UC), with a significantly better tolerability profile and shorter median time to relief.(5–7)
Budesonide is a newer steroid with higher topical anti-inflammatory activity and fewer systemic side-effects, such as adrenal suppression and bone disorders, compared with the conventional glucocorticoids. (8–11) The drug has a lower systemic bioavailability and an extensive first-pass metabolism in the liver.(12) Although a clear-cut role for budesonide in IBD therapy is yet to be defined, the drug seems most promising in the treatment of leftsided UC as an enema (especially when 5-ASA products are not well tolerated),(13) and also in patients with active Crohn’s disease (CD) who are finding it difficult to come off steroids rapidly and/or are experiencing systemic side-effects even with short-term use of steroids.(8,11,14,15) This drug has not been shown to be effective in maintenance of remission or in the prevention of recurrences in postoperative CD.(16)
Class II medicines
This group of medicines includes existing drugs that were introduced into IBD therapy recently. Most of these drugs are nonspecific immunosuppressants, and recent trials have shown their effectiveness in special subpopulations of patients with IBD.
Mycophenolate mofetil (MMF) primarily affects the T- and B-lymphocytes while sparing other immune cells such as neutrophils and macrophages. MMF may be a potential treatment for the prevention of stricture formation in CD.(17) Several open-label trials, case reports and randomised trials showed that this drug could be as effective as azathioprine. (18–20) Induction of remission was even faster, but maintenance of remission was less successful due to lack of tolerance. Thus MMF may be only an alternative for patients who do not respond or are intolerant to conventional treatments, for inducing or maintaining remission in the short term. This is largely because of the lack of long-term efficacy data, the expense of the drug, its teratogenicity and its side-effect profile compared with azathioprine.(21,22)
Thalidomide has proved beneficial in treating various immune-mediated diseases. Its mechanism of action has been attributed to the ability of thalidomide to inhibit tumour necrosis factor (TNF) and other inflammatory cytokines, to downregulate integrin, which is necessary for leukocyte migration, and to inhibit angiogenesis.(23) All of these effects may also be beneficial to modulate the inflammatory response in IBD. The results of several open-label trials showed a rapid initial response in 60–70% of subjects in 4–12 weeks.(24) The high side-effect profile of the drug, with peripheral neuropathy occurring in 20–25% of patients,(25) limits the use of thalidomide to patients who have failed all other treatments and who can be monitored closely for adverse effects.
Infliximab is a human/mouse chimeric monoclonal antibody origin (75% human and 25% mouse origin). It has been approved by the FDA for the treatment of CD after several randomised, double-blind, placebo-controlled studies demonstrated its effectiveness in inducing remission in patients with moderate-to-severe CD as well as in closing fistulae.(26) A detailed review of infliximab has recently been published.(27)
Etanercept is a genetically engineered, 100% human-soluble TNF-receptor blocker.(27) Although etanercept is an effective treatment for rheumatoid disorders, a recent randomised, double-blind, placebo- controlled study has not demonstrated any effectiveness in the treatment of moderately active CD.(28) Induction of monocyte apoptosis rather than simple blockade of TNF may be crucial in the therapeutic benefit of infliximab against CD.(29)
CDP571 is another human/mouse chimeric anti-TNF antibody (95% human and 5% mouse).(27) Unlike infliximab, it is of type IgG4, which does not activate complement or trigger cell-mediated cytotoxicity; therefore it is primarily expected to affect soluble rather than membrane-bound TNF. A handful of double-blind, placebo-controlled trials using the antibody have demonstrated favourable results.(30,31)
Class III medicines
This group includes new medicines for IBD therapy that are still under investigation. The efficacy of these drugs has not been evaluated completely, although many have undergone testing in animal models or limited clinical trials.
Heparin has recently been recruited for its anti-inflammatory properties in the treatment of IBD. Through its modulator effects on adhesion of leukocytes to the endothelium, it interferes with leukocyte recruitment from the vasculature.(32) In particular, it inhibits TNFa- induced leukocyte migration into gut tissue.(33) It also modulates the immune system through several other pathways and restores vascular permeability. Several case reports, case series and abstracts in the literature have shown promising effects of heparin in IBD treatment, particularly in UC.(34,35) However, the controlled studies available have given conflicting results.(36,37) Persistent rectal bleeding was one of the major side-effects of treatment, reported in up to 90% of cases, making it difficult to justify the use of this drug in acute flare-up. Similarly, low-molecular-weight heparin did not show efficacy in a multicentre, randomised, controlled trial.(38)
Enhancement of anti-inflammatory cytokine action
Interleukin-10 is a potent anti-inflammatory cytokine whose anti-inflammatory effects are mediated through its ability to reduce monocyte HLA class II expression and decrease the expression of various cytokines and proinflammatory mediators.(39,40) IL-10 may also stimulate electrolyte absorption and help maintain gastrointestinal (GI) tract barrier integrity. Animals deficient in IL-10 develop a model of colitis similar to CD, with severe granulomatous inflammation of the GI tract.(41) Although initial trials were promising,(42) subsequent large, multicentre trials showed poor efficacy.(43)
Interleukin-11 is a recombinant human cytokine that can maintain gut barrier function. It prevented enteric sepsis in an animal cancer model that received total body irradiation and chemotherapy.(44) Subcutaneous administration accelerated resolution of colitis in an animal model.(45) Part of its effect may be through downregulation of macrophage function via inhibition of nuclear factor kB and downregulation of T-cells via counterbalancing of other proinflammatory cytokines.(44) One pilot trial of IL-11 has been conducted in active CD,(46) and a larger phase II trial in patients with active CD is now underway.
Blocking inflammatory cytokine action
Interleukin-2 receptor antibody (daclizumab) is a humanised antibody against IL-2 receptor CD25. A recent pilot study showed its effectiveness in the treatment of acute UC.(47)
Disruption of immune cell trafficking
ICAM-1 antisense oligonucleotide (ISIS 2302) interferes with trafficking of immune cells to sites of inflammation. Intercellular adhesion molecule 1 (ICAM-1) is an inducible transmembrane glycoprotein that interacts with integrin on leukocytes, causing them to adhere and transmigrate.(48) Its expression on capillary and venule endothelium is upregulated or induced in response to proinflammatory cytokines and autacoids. This antisense oligonucleotide binds mRNA of human ICAM-1 and decreases intestinal mucosal ICAM-1 expression.(49) Although data from a pilot study were promising, a larger, multicentre, double-blind, placebo-controlled trial in patients with steroid-refractory CD was unsatisfactory.(50)
alpha4-integrin antibody (natalizumab) is a humanised monoclonal IgG4 antibody (95% human and 5% mouse) against alpha4-integrin. Integrin is a leukocyte glycoprotein receptor that mediates migration across the vascular endothelium via adhesion to ICAM on endothelial cells. Blockade of integrin with antibodies in an animal model resulted in remission of colitis.(51) In a recent double-blind, placebo-controlled trial, natalizumab increased the rates of clinical remission and response, improved the quality of life and C-reactive protein levels, and was well tolerated in patients with active CD.(52)
Antioxidant compounds are presumed to block the final common pathway of immune injury in IBD. In fact, part of the effects of conventional IBD medicine, such as 5-ASA compounds, has been attributed to their antioxidant properties.(53) Several compounds with antioxidant properties, such as vitamins A, C or E, rebamipide (OPC 12759), OPC 6535 and fish oil, are now being tested for the treatment of IBD.(54) Some, such as rebamipide and OPC 6535, inhibit the production or release of superoxide by neutrophils and scavenge the released ROS,(55) while others preserve intracellular supplies of glutathione and the activity of antioxidant enzymes, such as CuZn-superoxide dismutase.(56) Animal studies showed beneficial effects in the treatment of experimental colitis, and some of these drugs are under investigation in clinical studies in humans.
Probiotics are live microorganisms, given orally, that proliferate as part of the gut flora, typically lactobacilli, bifidobacteria and other nonpathogenic bacterial strains. Results with various probiotic therapies in experimental animal models of IBD have been very promising in preventing colitis or attenuating its severity, and even slowing the progression of inflammation to dysplasia and colon cancer.(57) Only a few controlled trials have evaluated the effect of probiotics in patients with IBD.(58,59) The results are promising and await verification. Genetically engineered Lactobacillus lactis that secretes IL-10 is one of the most interesting innovative advances in the probiotic area that is being tested in animal models of IBD.(60)
Prebiotics are food constituents, usually polysaccharides, that promote growth of certain types of bacteria of the intestinal flora. Currently studies are evaluating combined probiotic and prebiotic preparations, such as fructooligosaccharides in CD.
Intestinal helminths decrease the Th1-type lymphocyte response to common viral, bacterial or protozoan organisms while increasing Th2-type conditioning. This effect was first proposed by researchers at University of Iowa as the “hygiene hypothesis”.(61) This hypothesis may explain the higher rate of IBD in industrialised countries with an increasingly sanitary standard of living. Animal studies and limited open-label trials in humans with exposure to helminths (Schistosoma mansoni and Heligmosomoides polygyrus) have produced promising results.(62,63)
Alternative medicine and complementary therapies, including diet, acupuncture, behavioural therapies and herbal medicines, are being used commonly by up to 40% of IBD patients as indicated by several surveys.(64) None of these therapies has been scientifically tested in a randomised, double-blind clinical trial. However, the most promising complementary therapies appear to be stress reduction strategies and the use of herbs with antioxidant or immunomodulatory effects.
An enormous array of treatment modalities and novel therapies for IBD are under active experiment. Some of them, particularly immunosuppressive drugs and biological therapies, are likely to come into standard clinical care in the near future. As our understanding of IBD pathophysiology evolves, it is most likely that the treatment will be targeted towards specific immune abnormalities and move away from nonspecific immunosuppressants. Therapies that are now seen as eccentric and alternative, such as diet therapies, probiotics and prebiotics, and therapies directed at reducing stress or manipulating the brain-gut axis, could play a much larger role in the future, as more research is being carried out on these types of treatment.
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