Novel therapeutic options in the inflammatory bowel disease world

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doi:10.1016/j.dld.2007.07.169 Copyright © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.

Mini-Symposium

A. Noble1, a, R. Baldassano1, a and P. Mamula1, , a aDivision of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Received 23 July 2007; accepted 26 July 2007. Available online 7 November 2007.

Abstract

Advances in the understanding of the pathogenesis of inflammatory bowel disease have encouraged the development of many new therapies targeted at specific and non-specific mediators of the inflammatory bowel disease inflammatory pathway. The role of these therapies, including novel anti-tumour necrosis factor-α agents, anti-adhesion molecules, recombinant cytokines, myeloid growth factors, helminths, and probiotics, in the management of paediatric onset inflammatory bowel disease is promising and warrants further investigation.

Keywords: Biologics; Children; Crohn's disease; Helminthes; Inflammatory bowel disease; Leukocyte apheresis; Probiotics; Stem cell transplantation; Ulcerative colitis

Article Outline

1. Anti TNF-α agents

1.1. Adalimumab 1.2. CDP571 and certolizumab pegol (CDP870) 1.3. Etanercept and onercept

2. Adhesion molecule inhibitors

2.1. Natalizumab 2.2. MLN02 2.3. Alicaforsen

3. Targets of pro and anti-inflammatory cytokines

3.1. Anti-IL-2 receptor (CD25) 3.2. Anti-IL-12 and IL-23 3.3. Anti-INF-γ 3.4. Recombinant human IL-10

4. Other anti-inflammatory targets 5. Myeloid growth factors 6. Autologous hematopoietic stem cell transplantation 7. Leukocyte apheresis 8. Helminths 9. Probiotics 10. Conclusion Conflicts of interest statement References

1. Anti TNF-α agents

1.1. Adalimumab

Adalimumab is a subcutaneously administered fully humanized IgG1 monoclonal antibody to tumour necrosis factor-α (TNF-α). It binds soluble and membrane bound TNF-α and induces T-cell apoptosis. It has proven efficacy in the induction and maintenance of remission in adults with Crohn's disease. The CLASSIC-I trial, a randomized double blind dose ranging study of patients with moderate to severe Crohn's disease, demonstrated remission at 1 month in 24% and 36% of the adalimumab treated groups in comparison to 12% in the placebo group [1]. Responders to adalimumab from the CLASSIC-I trial were subsequently randomized to maintenance adalimumab therapy or placebo in the CLASSIC-II trial [2]. In this study, remission was maintained at 56 weeks in 79%, 83% and 44% of the patients receiving adalimumab every 2 weeks, every week and placebo, respectively. Also, steroid weaning was achieved in more adalimumab than placebo treated patients. These results were confirmed in a larger cohort of patients in the CHARM trial in which patients received a loading dose of adalimumab and then were randomized to adalimumab every 2 weeks, every week or placebo for 56 weeks [3]. Of the 854 enrolled patients, 499 responded to induction adalimumab therapy. In this subgroup, 36% and 41% of the patients in the adalimumab every 2 and 1 week groups were in remission at 56 weeks as compared to 12% in the placebo group. Corticosteroids were discontinued in 23% and 29% of the adalimumab treated groups versus 6% in the placebo group. And finally, the GAIN trial recently demonstrated the efficacy of adalimumab in persons with moderate to severe Crohn's disease intolerant or with loss of response to infliximab [4]. In this study, 21% of the adalimumab treated group attained remission at 1 month as compared to 7% of the placebo group. Subsequent to these clinical trials, adalimumab was approved by the Food and Drug Administration (FDA) in February 2007 for induction and maintenance of remission in adults with moderate to severe Crohn's disease, including those intolerant or with loss of response to infliximab. The recommended dose regimen for adults is 160 mg at week 0, 80 mg at week 2 and then 40 mg every 2 weeks for maintenance therapy. Fistulizing and perianal Crohn's disease was not specifically addressed in the CLASSIC, CHARM or GAIN trials as the numbers of patients with active fistulas or perianal disease enrolled in these trials did not allow for meaningful statistical comparisons between treatment groups. However, a trend of improvement in perianal disease and fistulas was noted in the adalimumab treated patients. Ten cases have been reported of children with Crohn's disease treated with adalimumab, all of whom were intolerant or had loss of response to infliximab [5] and [6]. In nine of the children, adalimumab 80–160 mg/1.73 m2 was administered at week 0 followed by 40–80 mg/1.73 m2 at week 2 [6]. At 1 month, four of these children achieved a complete response and maintenance of remission was documented in six at a median follow-up of 3.6 months. The tenth child, a 15-year-old, received adalimumab 40 mg at 0, 2 and 4 weeks [5]. Following these three doses, she achieved full remission off steroids. Side effects reported in these children included a flu-like illness in one patient following each injection, injection site pain and erythema in two patients, and pneumonia with pleural effusion in one patient. There is a similar paucity of data for adalimumab in ulcerative colitis. One open label study in 10 adults with ulcerative colitis intolerant or with loss of response to infliximab demonstrated clinical improvement in 3 and remission in 1 patient following two doses of adalimumab [7]. Prospective randomized clinical trials are currently enrolling patients to determine the efficacy and safety of adalimumab in paediatric onset Crohn's disease and ulcerative colitis (adults) (http://clinicaltrials.gov). The cumulative safety data from the placebo-controlled trials, including the open label arms, in adults with Crohn's disease demonstrate that adalimumab is generally well tolerated [1], [2], [3], [4] and [8]. The most frequently reported adverse event was injection site reactions in 10–38%. Most of these reactions consisted of localized erythema and pain at the injection site and did not result in discontinuation of the medication. The frequency of infections was similar in the adalimumab and placebo groups. However, 2% of adalimumab treated patients developed an opportunistic infection: oral candidiasis (22 cases), oesophageal candidiasis (4 cases), tuberculosis (3 cases) and one case each of nocardiosis and coccidioidomycosis. No malignancies attributed to adalimumab were noted in these studies. One study evaluated ANA and anti-dsDNA antibody conversion (CLASSIC-II); 19% of adalimumab treated patients converted from negative to positive antibody status but none developed a lupus like syndrome. However, three cases of lupus-like syndromes were reported in the total clinical trial population. Two cases of demyelinating disease and one case of congestive heart failure were also noted. Anti-adalimumab antibodies developed in 0–2.6% of the adalimumab treated patients; clinical sequelae of positive antibody status were not reported. 1.2. CDP571 and certolizumab pegol (CDP870)

CDP571 is a humanized IgG4 monoclonal antibody to TNF-α that is administered intravenously. Certolizumab pegol is, in a sense, a second generation CDP571 as it contains the Fab monoclonal antibody fragment of CDP571 linked to polyethelene glycol. It has the advantage of both intravenous and subcutaneous modes of administration. Both CDP571 and certolizumab neutralize soluble and membrane bound TNF-α but do not induce T-cell apoptosis. CDP571 has shown equivocal efficacy in the treatment of adults with Crohn's disease. Three randomized double-blind placebo controlled trials demonstrated a greater clinical response at 2 weeks in the CDP571 treated patients following a single infusion of 5–20 mg/kg in comparison to placebo [9], [10] and [11]. However, continued infusions every 8 weeks did not result in greater remission rates at 24 weeks; 11–30% in the CDP571 treated groups versus 4–24% in the placebo groups [10] and [11]. Two further randomized double-blind placebo controlled trials evaluated CDP571 in steroid dependent Crohn's disease in clinical remission [12] and [13]. The percentage of patients achieving steroid withdrawal without a disease flare was similar in the CDP571 and placebo treated patients. The results of clinical trials of certolizumab in Crohn's disease are more promising. Three randomized placebo controlled trials did not demonstrate efficacy in the induction of remission in certolizumab treated patients; however, the placebo response rates in these trials were high, ranging from 26 to 60% [14], [15] and [16]. A fourth randomized, double-blind, placebo controlled trial reported in abstract only found a 19% greater rate of remission at 26 weeks in initial responders to certolizumab who continued monthly injections versus placebo [17]. Prospective studies are currently recruiting patients to clarify the role of certolizumab in the treatment of Crohn's disease (http://clinicaltrials.gov). There is limited experience with CDP571 in paediatric onset Crohn's disease and in adults with ulcerative colitis. An open label study of 20 children with active Crohn's disease treated with a single dose of CDP571 10 mg/kg observed a reduction in the PCDAI by 10 points at 2 weeks post-infusion in 65%; 35% maintained a response to 7 weeks [18]. The safety profile was favourable: one patient experienced an infusion reaction that required treatment with anti-histamines and three patients experienced infections, one each of Rotavirus, Clostridium difficile, and Herpes zoster. Anti-CDP571 antibodies developed in six children (30%). In ulcerative colitis, an open label study enrolled 15 adults with mild to moderate disease activity to receive a single dose of CDP571 5 mg/kg [19]. Ten patients had a reduction of disease activity at 2 weeks; disease activity at later time points was not reported. There were no serious drug related adverse events noted. There is as of yet no published experience of certolizumab in ulcerative colitis or in paediatric onset IBD. The cumulative safety data from clinical trials with CDP571 and certolizumab indicate that their adverse event profiles are similar to those of the other anti-TNF-α agents [8], [9], [10], [11], [12], [13], [14], [15] and [17]. Infusion and injection site reactions were reported in 2–4% and 3–12% of CDP571 and certolizumab treated patients, respectively. Most of these reactions were mild in nature and did not result in the discontinuation of the medication. The frequency of infections in the treated and placebo groups were similar. However, serious infections were more common in the CDP571 and certolizumab groups including three cases of tuberculosis and one case each of pneumocystis carinii pneumonia, osteomyelitis, and pyelonephritis. Positive ANA antibodies were found in 2% of CDP571 treated patients in one study although no lupus-like syndromes were reported with this medication. In certolizumab treated patients, seroconversion of ANA and anti-dsDNA was found in 3–7% and 1.5–2.5%, respectively; one case each of lupus and sarcoidosis were reported. Both agents induced anti-idiotype antibodies. Anti-CDP571 antibodies developed in 6–33% and in one study, were associated with an increased risk of an infusion reaction [13]. Anti-certolizumab antibodies were found in 12.3% of those receiving higher doses of certolizumab in one trial [15]. There were no deaths or malignancies attributed to either medication reported in these clinical trials. 1.3. Etanercept and onercept

Etanercept and onercept are analogues of TNF-α receptors that are administered subcutaneously. Etanercept is a fully humanized fusion protein of the Fc domain of IgG1 and the extracellular binding portion of the p75 TNF-α receptor while onercept is a recombinant human soluble p55 TNF-α receptor. Both neutralize soluble TNF-α but do not induce T-cell apoptosis. One randomized, double-blind placebo controlled trial in adults with Crohn's disease has been completed for both etanercept [20] and onercept [21]. Neither demonstrated a benefit of the drug over placebo in clinical response or induction of remission. It is postulated that the equivocal results of these studies were secondary to inadequate dosing of these medications. The doses and dosing schedules in these two trials were based on experience in patients with rheumatoid arthritis whom have demonstrated clinical response to other anti-TNF-α agents at lower doses than required in Crohn's disease patients. Higher and/or more frequent doses of etanercept and onercept have not yet been evaluated in Crohn's disease. Both etanercept and onercept were well tolerated; the frequency of adverse events was similar between the placebo and active drug treated groups [20] and [21]. In the onercept trial, 7.9% of the drug treated group developed anti-onercept antibodies; clinical sequelae of positive antibody status were not reported [21]. 2. Adhesion molecule inhibitors

2.1. Natalizumab

Natalizumab is a humanized IgG4 monoclonal antibody to α4-integrin that is administered intravenously. Alpha-4-integrin is expressed on lymphocytes and mediates leukocyte migration into tissue via binding to the endothelial receptor, vascular cell adhesion molecule-1. Natalizumab binds α4-integrin thereby blocking leukocyte migration into inflamed tissues. Natalizumab has primarily been evaluated in adults with Crohn's disease. Four randomized, double-blind, placebo controlled trials demonstrated minimal efficacy of natalizumab over placebo in the induction of remission of moderate to severe Crohn's disease [22],[23], [24] and [25]. The greatest effect was found in patients with high C-reactive protein at baseline; remission at 12 weeks following three doses of the study medication was 26% in the natalizumab group versus 16% in the placebo group [25]. An advantage to natalizumab was however demonstrated in the maintenance of remission in one trial. The responders to natalizumab from the ENACT-1 clinical trial were randomized to natalizumab or placebo every 4 weeks (ENACT-2) [24]. The sustained remission at 36 weeks was 44% and 25%, respectively in the natalizumab and placebo treated groups. A further trial evaluated natalizumab in patients with active disease despite ongoing infliximab therapy [26]. No benefit of the addition of natalizumab to infliximab therapy was found in this small study of 79 patients; remission at 10 weeks was achieved in 37% and 30% of the natalizumab and placebo treated groups, respectively. In children with active Crohn's disease, an open label study of three doses of natalizumab 3 mg/kg at 4 week intervals demonstrated clinical remission at 10 weeks in 29% of the 38 enrolled patients [27]. Most of the serious adverse events reported during this trial were associated with Crohn's disease activity. Five (13%) reported an infusion reaction and two cases of Herpes zoster infection were noted. Anti-natalizumab antibodies were reported in 8% but were not associated with adverse events. An open label study in adults with ulcerative colitis similarly demonstrated safety of natalizumab in this population [28]. In the Crohn's disease clinical trials, natalizumab was generally well tolerated [22], [23], [24], [25] and [26]. Adverse events reported more frequently with natalizumab than placebo were hypersensitivity reactions, infections, and reversible lymphocytosis. Serious infections reported in the natalizumab treated group included varicella pneumonia (one case), CMV hepatitis (one case), and greater frequency of influenza (12% versus 5% in the placebo group). There was also one fatal case of progressive multifocal leukoencephalopathy (PML) secondary to a JC viral infection. Two further cases of natalizumab associated PML were reported in patients with multiple sclerosis. A review of the risk of PML in all persons exposed to natalizumab for any indication (IBD, multiple sclerosis, and rheumatoid arthritis) did not identify any other cases and estimated the risk of PML following natalizumab exposure to be 1/1000 [29]. Following the three cases of PML, natalizumab was temporarily withdrawn from the market (February 2006). It has since been approved for resumed marketing (June 2006) for patients with multiple sclerosis as monotherapy with close post-marketing surveillance (TOUCH program). Use of natalizumab as a monotherapy for Crohn's disease is under review. 2.2. MLN02

MLN02 is a fully humanized IgG1 monoclonal antibody to α4ß7-integrin that is administered intravenously. Similar to natalizumab, MLN02 interrupts leukocyte migration into tissues by blocking the binding of α4ß7-integrin to mucosal addressin-cell adhesion molecule-1. There is very little experience with MLN02 in IBD. A pilot study in adults with Crohn's disease did not show efficacy in the induction of remission [30]. In adults with ulcerative colitis, one randomized, double-blind placebo controlled trial demonstrated induction of remission at 6 weeks following two doses of study drug in 32% and 14% of MLN02 and placebo treated subjects, respectively [31]. There was also greater endoscopic improvement in the MLN02 group. The adverse event profile was favourable. One patient, positive for anti-MLN02 antibodies, experienced an infusion reaction. There were no differences in lymphocyte counts between placebo and MLN02 treated patients, in contrast to natalizumab. Anti-MLN02 antibodies were found in 44% and higher titers were associated with decreased clinical response [31]. 2.3. Alicaforsen

Alicaforsen is a phosphorothiate-modified antisense oligodeoxynucleotide that reduces intracellular adhesion molecule-1 (ICAM-1) mRNA expression resulting in decreased expression of ICAM-1 on the endothelial surface. The end result is an interruption of leukocyte migration into tissues. Alicaforsen is available for intravenous, subcutaneous and topical (enema) administration. It has been evaluated in both Crohn's disease and ulcerative colitis in adult populations. Four randomized double-blind placebo controlled trials in adults with Crohn's disease evaluated varying doses and dosing schedules of intravenously and subcutaneously administered alicaforsen. The smallest trial demonstrated a small benefit of intravenously administered alicaforsen for 13 doses over 1 month; 7 of 15 patients enrolled in the alicaforsen group attained remission at 4 weeks versus 1 of 5 patients in the placebo group [32]. These results were not reproduced in two larger cohorts [33] and [34]. Subcutaneous administration of alicaforsen similarly demonstrated minimal benefit over placebo in induction and maintenance of remission in patients with steroid dependent or refractory Crohn's disease [35]. In ulcerative colitis, alicaforsen enema preparations have been evaluated in three randomized double-blind placebo (or standard care) controlled trials [36], [37] and [38]. Decreases in the ulcerative colitis disease activity indices were more pronounced in alicaforsen than placebo treated subjects although this did not reach statistical significance. In the mesalamine (Rowasaâ„¢ 4 g) controlled study, the mean percent reduction of the disease activity index from baseline was 50% in the mesalamine group versus 41% in the alicaforsen group, suggesting but not proving similar efficacy of the two drugs [38]. Intravenous and subcutaneous alicaforsen was generally well tolerated [32], [33], [34] and [35]. Hypersensitivity reactions, nausea and vomiting, fever, asthenia, and flu-like symptoms were reported more frequently in the alicaforsen group. Also, a transient dose-related increase in the partial thromboplastin time (PTT) was observed without any adverse clinical sequelae. There were no differences in lymphocyte counts between the active and placebo treated groups. One patient in the alicaforsen group was diagnosed with non-Hodgkin's lymphoma during the clinical follow-up period. Anti-alicaforsen antibodies, only reported in one study, were only found in one of 91 patients. Adverse events with the topical alicaforsen preparation were similar to those reported in the placebo groups [36], [37] and [38]. 3. Targets of pro and anti-inflammatory cytokines

3.1. Anti-IL-2 receptor (CD25)

Daclizumab and basiliximab are respectively, humanized and chimeric IgG1 monoclonal antibodies to the α-chain of the interleukin-2 (IL-2) receptor (CD25) on activated T-cells. Both are administered intravenously. IL-2 binding to the IL-2 receptor promotes T-cell survival and proliferation. Blockage of the IL-2 receptor should therefore interfere with T-cell proliferation and down-regulate the inflammatory response. An open label trial in adults with moderately active ulcerative colitis refractive to medical therapy demonstrated an impressive clinical response after two doses of daclizumab [39]. Similar results were not found in a randomized double-blind placebo controlled trial; remission after two or four doses of daclizumab was 2–7% compared to 10% in the placebo group [40]. There was also no difference between the daclizumab and placebo treated patients in endoscopic and histologic improvement of disease. Two open label uncontrolled trials of basiliximab in ulcerative colitis have reported 50–90% clinical remission 2 months after treatment [41] and [42]. A randomized placebo controlled trial is required to confirm these results. Adverse events were similar for the two drugs and included fever, pneumonia (two cases), herpes zoster (two cases), and infusion related reactions. 3.2. Anti-IL-12 and IL-23

IL-12 and IL-23 are involved in the differentiation of naïve T-cells into Th1 and Th17 cells, respectively. Th1 and Th17 T-cells secrete pro-inflammatory cytokines including IL-6, IL-17, TNF-α, and interferon gamma (IFN-γ). IL-12 and IL-23 have a common p40 subunit. ABT-874 and CNTO 1275 are respectively, humanized and fully humanized IgG1 monoclonal antibodies to the IL-12/23 p40 subunit. Both are administered subcutaneously. A randomized double-blind placebo controlled trial of ABT-874 in adults with Crohn's disease demonstrated a benefit of ABT-874 in the induction of remission after 7 weekly injections [43]. Remission at week 7 and 18 was attained in 38% of the ABT-874 3 mg group versus 0–13% in the placebo and 1 mg ABT-874 groups. Increased adverse events reported in the ABT-874 treated group included injection site reactions, infections, vomiting, and abdominal pain; there were no opportunistic infections reported. Anti-ABT-874 antibodies were found in 5%; clinical sequelae of positive antibody status were not reported. 3.3. Anti-INF-γ

Fontolizumab is a humanized monoclonal antibody to IFN-γ that is administered intravenously. IFN-γ plays many roles in the immune response including activation of macrophages and up-regulation of HLA-2 expression on antigen presenting cells. Two randomized double-blind placebo controlled trials have evaluated fontolizumab for the induction of remission in adults with Crohn's disease. In the larger study (133 patients), induction of remission after two doses of fontolizumab was achieved in 53%, 41% and 27% in the 10 mg/kg, 4 mg/kg, and placebo groups, respectively [44]. The second smaller study (45 patients) failed to demonstrate a difference between the fontolizumab (4 mg/kg) and placebo treated patients; remission rates were 47% and 40%, respectively [45]. Adverse events reported more frequently in the fontolizumab treated patients included headache, chills, nausea and vomiting. One patient experienced Herpes zoster. Anti-fontolizumab antibodies developed in 8% but were not associated with adverse events. 3.4. Recombinant human IL-10

IL-10 is an anti-inflammatory cytokine that down-regulates HLA-2 expression on antigen presenting cells. Recombinant human IL-10 (rIL-10) can be administered intravenously, subcutaneously or orally. One randomized double-blind placebo controlled trial of rIL-10 for the induction of remission in active Crohn's disease demonstrated a benefit over placebo; remission of disease after subcutaneous administered drug was 15% and 0% in the rIL-10 and placebo groups, respectively [46]. Additional studies in steroid resistant or refractory patients did not demonstrate any benefit of the drug over placebo [47] and [48]. In these three trials, improvement in endoscopy (mucosal healing) was similar in the rIL-10 and placebo groups. A final study evaluated rIL-10 for the prevention of post-operative Crohn's disease [49]. In this small study (65 patients), there was no difference in mucosal inflammation three months post-operatively in the placebo (52%) and rIL-10 (46%) groups. The oral formulation of rIL-10 is provided through genetically modified Lactococcus lactis. Pilot studies of this novel approach to IL-10 therapy are in progress. Adverse events associated with IL-10 were headache, fever, back pain, and dizziness. Also, a dose dependent decrease in haemoglobin and platelets was observed. This was reversible on discontinuation of the rIL-10 and did not result in the need of blood products. However two patients in one study [46] discontinued the medication secondary to platelets less than 100,000 per microliter; there were no adverse clinical sequelae secondary to thrombocytopenia. No anti-rIL-10 antibodies were detected in the rIL-10 treated patients. 4. Other anti-inflammatory targets

Other anti-inflammatory agents of interest include altizumab, visiliumab, RDP58 and tetolimast. Altizumab, an intravenously administered humanized anti-IL-6 receptor monoclonal antibody, showed some efficacy in the induction of remission in a small trial of adults with Crohn's disease [50]. Visilizumab is a humanized IgG2 monoclonal antibody to the CD3 chain of T-cell receptors administered subcutaneously. It is being evaluated in severe ulcerative colitis [51] and [52]. RDP58 and tetolimast down regulate multiple pro-inflammatory cytokines and have the advantage of being administered orally. They have both shown some promise in the treatment of ulcerative colitis [53] and [54]. 5. Myeloid growth factors

It is hypothesized that Crohn's disease may be related to a defect in the innate immune system. Myeloid growth factors, by increasing neutrophil, macrophage, and dendritic functions, may normalize the innate immune response thus decreasing intestinal inflammation. Lending support to this hypothesis, inherited disorders of the innate immune system such as chronic granulomatous disease (CGD) and glycogen storage disease-Ib (GSD-Ib) are associated with a Crohn's like colitis [55] and [56]. In addition, there are case reports of the successful treatment of colitis in these immune disorders with granulocyte-colony stimulating factor (G-CSF) [56] and [57] and granulocyte macrophage-colony stimulating factor (GM-CSF) [58] and [59]. An open label trial of recombinant human G-CSF in adults with Crohn's disease demonstrated remission at 2 months in 4 of the 20 enrolled subjects [60]. Similar results were found in an open label trial of recombinant human GM-CSF [61]. A subsequent randomized double-blind placebo controlled trial in adults with moderate to severe Crohn's disease demonstrated efficacy in the remission of disease 2 months after daily 6 μg/kg subcutaneous injections; remission was attained in 40% and 19% of the GM-CSF and placebo treated subjects, respectively [62]. Injection site reactions and bone pain were reported more frequently in the GM-CSF treated subjects. Three serious adverse events were reported in the GM-CSF group; one migraine, one episode of anorexia, weakness and lethargy and one possible demyelination syndrome. An increase in neutrophils was expected and observed in the GM-CSF treated subjects. All white blood cell counts returned to baseline after treatment. Results of two additional randomized trials of GM-CSF in Crohn's disease are in press. 6. Autologous hematopoietic stem cell transplantation

Autologous hematopoietic stem cell transplantation (HSCT) was explored as a novel therapeutic option for IBD following the observation of long-term disease remission after bone marrow transplantation for other indications in patients with known IBD [63]. The suggested mechanism of action is of a resetting of the acquired immune response by repopulating the body's leukocytes. A pilot study to determine the safety and efficacy of HSCT was performed in 12 adults with moderate to severely active Crohn's disease despite aggressive medical therapy [64]. These patients were all significantly disabled by their disease. HSCT following cyclophosphamide and equine antithymocyte globulin was performed. At a median follow-up of 18.5 months, 11 of the 12 patients remained in remission off all medications. The remaining patient experienced a relapse at 15 months post HSCT and restarted prednisone and methotrexate. There was one accidental death (post discharge) that was not attributed to the study intervention. All other patients survived to the median follow-up of 18.5 months. Fever post HSCT was common but there were no cases of fungal infections or CMV reactivation. Post discharge, one case of central line associated bacteremia and another case of viral gastroenteritis were reported. Additionally, one patient required a small bowel resection secondary to a stricture. Two further case reports of successful HSCT for refractory Crohn's disease have been reported [65]. 7. Leukocyte apheresis

Multiple techniques of leukocyte apheresis have been explored in IBD, including leukocyte adsorption by polyester fibres (Cellsorba) or cellulose acetate beads (Adacolumn) and continuous flow cell separators (CS 3000 of COBE). Each apheresis treatment requires approximately 1 h and requires two venous access points. Treatments are generally once per week, except in severe disease where treatment is started at twice per week [66]. Its postulated mechanism of action is the removal of activated leukocytes involved in the IBD inflammatory cascade. Leukocyte apheresis has predominantly been evaluated in ulcerative colitis. In a non-blind randomized trial of Cellsorba in patients with moderate to fulminant ulcerative colitis, attainment of clinical remission and endoscopic improvement was similar in the Cellsorba and high dose corticosteroid treated groups, 23% and 16%, respectively [67]. A second randomized trial with Cellsorba in patients with moderate to severe ulcerative colitis who were unresponsive to two weeks of corticosteroids demonstrated no clinical benefit of the Cellsorba over the sham apheresis treatment [68]. There was however a trend for greater endoscopic improvement and steroid sparing in the Cellsorba treated subjects. Adacolumn was similarly evaluated in active steroid dependent ulcerative colitis. After 6 and 12 weeks, 52% and 83% of the Adacolumn treated subjects and 61% and 65% of the standard care treated subjects achieved clinical remission; there was no difference in the percent reduction of corticosteroids between the two groups [69]. In adults with Crohn's disease, a non-blind randomized trial of leukocyte apheresis by continuous flow cell separators was performed in 28 subjects in clinical remission after 3–7 weeks of corticosteroid therapy [70]. Steroid weaning and long term remission rates were not significantly different between the apheresis and placebo treatment groups. Adverse events reported with leukocyte apheresis included headache, fever, rash and flushing. None of the reported averse events were serious or interrupted treatment. 8. Helminths

Inflammatory bowel disease is more prevalent in developed countries. Some speculate that this may be secondary to differential exposure to intestinal parasites given that such infections are endemic in developing countries and now rare in developed countries. Also, parasitic intestinal infections stimulate a Th2 pattern immune response while the immune response in IBD is predominantly of a Th1 pattern [71]. Thus, it has been proposed that exposure to helminths in persons with IBD may induce a Th2 immune response and down-regulate the aberrant Th1 response involved in the IBD inflammatory cascade. Two open label studies have been done to determine the safety of the administration of Trichuris suis (T. suis) in adults with inflammatory bowel disease [72] and [73]. Ova from T. suis, a porcine whipworm not known to be pathogenic in humans, were isolated and purified to eliminate the risk of co-infection with bacterial or viral pathogens. Administration of 2500 live T. suis ova from 1 to 6 doses was well tolerated in 36 adults with IBD; no adverse effects secondary to the intervention were reported. Subsequently, a randomized double-blind placebo controlled trial in adults with active ulcerative colitis demonstrated a response following 12 weeks of therapy in 43.3% and 16.7% of the T. suis and placebo treated groups respectively [74]. However, only small numbers achieved disease remission, 10% in the T. suis group and 4% placebo. There were no adverse events attributed to T. suis. One subject in the T. suis treatment group developed pancreatitis that resolved after discontinuation of hydrochlorothiazide. No porcine whipworm or ova was identified in the stools. 9. Probiotics

The intestinal bacterial flora plays an important role in the pathogenesis of IBD. Animal models of colitis have shown that intestinal bacteria are necessary, although not sufficient, to trigger inflammation and that certain bacterial strains are more able to induce disease than others. Probiotics are viable bacteria that when ingested, are purported to modify the intestinal bacterial flora to decrease its pro-inflammatory potential [75]. There are many different preparations of probiotics of which Lactobacillus GG, Lactobacillus johnsonii LA1, Escherichia coli Nissle 197, and VSL#3 (a combination of Streptococcus thermophilus, Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. casei and L. bulgaricus) have been studied in IBD. Two randomized double-blind placebo controlled trials of VSL#3 in adult patients with ulcerative colitis post ileal pouch-anal anastomosis demonstrated a significant decrease in the incidence of pouchitis in the VSL#3 treated groups during a 1 year follow-up [76] and [77]. A maintenance of remission study of E. coli Nissle 197 versus mesalamine, standard care, in ulcerative colitis found equal rates of relapsed disease in the two groups at 1 year [78]. In children with Crohn's disease, a randomized trial of Lactobacillus GG did not show a clinical benefit when added to standard care [79]. Similarly in adults following resection for Crohn's disease, L. johnsonii LA1 did not demonstrate a benefit over placebo in the prevention of severe endoscopic relapse [80]. Probiotics were well tolerated. Adverse events reported in these clinical trials included abdominal pain, bloating, and diarrhoea; all were reversible on discontinuation of the medication. 10. Conclusion

Advances in the understanding of the pathogenesis of IBD have encouraged the development of many new therapies targeted at specific and non-specific mediators of the IBD inflammatory pathway. The results of clinical trials involving these agents are promising. However, their role in the management of paediatric onset IBD is yet to be elucidated as for most, there is a paucity of clinical experience in children. Clinical trials are therefore needed to confirm the efficacy and long-term safety of these agents in children before they can be confidently introduced into paediatric practice (Table 1).

Practice point

• Become familiar with some of the new therapeutic agents for IBD that target specific and non-specific mediators of the IBD inflammatory pathway.

Research agenda

• Improve our understanding of the mechanism of action of these novel therapies and their safety profile.

• Clinical trials of these new therapies are needed in pediatric onset inflammatory bowel disease.

Table 1. Novel therapies in IBD

Therapeutic agents

Target molecule

Specific immune-modulating agents

Anti-TNF-α

Adalimumab (Humira®)

Fully humanized IgG1 mAb

TNF-α

Certolizumab (Cimzia®)

Pegylated Fab fragment of humanized anti-TNF mAb

TNF-α

CDP571 (Humicade®)

Humanized IgG4 mAb

TNF-α

Etanercept (Enbrel®)

Fully humanized IgG1 Fc ab/p75 receptor fusion protein

TNF-α

Onercept

Recombinant human soluble p55 TNF receptor

TNF-α

Anti-adhesion molecules

Natalizumab (Tysabri®)

Humanized IgG4 mAb

α4-integrin

MLN02 (LDP-02)

Humanized IgG1 mAb

α4ß7-integrin

Alicaforsen (ISIS 2302)

Phophorothiate-modified antisense oligodeoxynucleotide

ICAM-1 mRNA

Recombinant cytokines

Basiliximab (Simulect®)

Chimeric IgG1 mAb

α-chain of IL-12 receptor

Daclizumab (Zenapax®)

Humanized IgG1 mAb

α-chain of IL-12 receptor

ABT-874

Humanized IgG1 mAb

IL-12/23 p40 subunit

CNTO 1275

Fully humanized IgG1 mAb

IL-12/23 p40 subunit

Fontolizumab (HuZAFâ„¢)

Humanized mAb

IFN-γ

IL-10 (Tenovil®)

Human recombinant IL-10

(Increases) IL-10

Visilizumab (Nuvion®)

Humanized IgG2 mAb

CD3

Atlizumab (Actemra®)

Humanized IgG1 mAb

IL-6 receptor

Tetomilast (OPC-6535)

Thiazole derivative

Phosphodiesterase-4

RDP58

Protease resistant decapeptide

MyD88/IRAK/TRAF6 protein complex

Non specific immune-modulating agents

Myeloid growth factors

Innate immune system

G-CSF (Filgrastim, Neupogen®)

GM-CSF (Sargramostim, Leukine®)

Autologous hematopoietic stem cell transplantation

Aberrant lymphocytes

Leukocyte apheresis

Aberrant lymphocytes

Helminths

Induce Th2 immune response

Probiotics

Colonic luminal flora

Chimeric (75% human, 25% murine); humanized (95% human, 5% murine); fully humanized (100% human); mAb monoclonal antibody; IL interleukin.

Conflicts of interest statement

None declared.

References

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Corresponding author at: Division of GI & Nutrition, The Children's Hospital of Philadelphia, 34th Street and Civic Boulevard, Philadelphia, PA 19104, USA. Tel.: +1 ; fax: +1 .1 These authors contributed equally to this work.

Digestive and Liver Disease Volume 40, Issue 1, January 2008, Pages 22-31