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Journal of Digestive Diseases 2014; 15; 585–590
doi: 10.1111/1751-2980.12193
Leading article
Novel agents in the future: Therapy beyond anti-TNF agents in inflammatory bowel disease Jiang Chen PENG, Jun SHEN & Zhi Hua RAN State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai Inflammatory Bowel Disease Research Center, Shanghai, China
Anti-tumor necrosis factor (TNF)-α agents emerge as the hot spot in the last decade for treating patients with inflammatory bowel disease (IBD). The effect of anti-TNF-α agents is satisfactory; however, some patients fail to achieve clinical response. Fortunately, KEY WORDS:
in recent years, great efforts have been made and multiple novel therapies have been developed in the treatment for IBD. In this article, we aim to introduce anti-TNF-α drugs as well as other novel treatments currently undergoing clinical trials for IBD.
Crohn disease, inflammatory bowel diseases, tumor necrosis factor-alpha, ulcerative colitis.
INTRODUCTION Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a group of chronic inflammatory disorders of the gastrointestinal tract. The etiology of IBD remains unclear; however, it is strongly suggested that genetic susceptibility, environmental factors and immunological function may contribute to the development of inflammation.1 Tumor necrosis factor (TNF) that is
Correspondence to: Zhi Hua RAN, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai Inflammatory Bowel Disease Research Center, 145 Middle Shandong Road, Shanghai 200001, China. Email: [email protected] Conflict of interest: None. © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
secreted by immune cells plays a vital role in the pathogenesis of IBD.2 TNF regulates the expression of adhesion molecules to recruit immune cells, resulting in tissue inflammation and damage.3,4 Clinical application of anti-TNF-α has achieved a satisfactory result. It has been proved to induce clinical response and maintain remission. Infliximab is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody, which binds to TNF-α and inhibits its biological activity. At first, infliximab was mainly administered to treat patients with active CD. Recently, the application of infliximab has also been evaluated among UC patients. Several studies have shown that infliximab is effective in both UC and CD patients.5–8 However, some patients lack an initial response to infliximab, and others lose response gradually. To some extent, it is due to the fact that these patients produce antibodies to infliximab.9 So we can conclude that anti-TNF-α therapy is not a perfect way to treat IBD. Other alternative treatments are needed to be developed to obtain better results among IBD patients. In this article, we aim to introduce anti-TNF-α agents as well as other novel treatments currently undergoing clinical trials for IBD.
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Journal of Digestive Diseases 2014; 15; 585–590
ANTI-TNF-α AGENTS
and has been approved by FDA for treating CD.26 Sandborn et al.24 showed that at both weeks 6 and 26, the response rates were 23% in the certolizumab pegol group (400 mg, at weeks 0, 2, 4 and then every 4 weeks) and 16% in the placebo group (P = 0.02). Serious infections occurred in 2% of patients in the certolizumab pegol group.24 In another study, 425 patients who had a clinical response to certolizumab pegol at week 6 were assigned to continuous maintenance therapy and placebo therapy. The results showed that 63% in the certolizumab group (135/ 215) also had a response at week 26, as compared with 36% (76/210) in the placebo group (P < 0.001); while serious infections occurred in 3% of patients receiving certolizumab pegol.25 Etanercept and onercept are antagonists for TNF receptor (TNFR), both of which have failed to reach a beneficial result.23
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TNF is highly produced by active macrophages and T lymphocytes. After the binding of TNF with cognate membrane receptors (TNFR), p55TNFR (TNFR1) and p75TNFR (TNFR2), the complexes induce the activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways, leading to tissue damage and intestinal inflammation.3,4 Inhibiting TNF production can reduce the expression of inflammatory cytokines and alleviate intestinal inflammation. Infliximab binds with high affinity to TNF-α and inhibits its biological activity.10,11 After approved by the Food and Drug Administration (FDA) of USA, the clinical efficacy of infliximab has been well studied. In CD, infliximab has been used in patients with active disease and those who were resistant to corticosteroid therapy.5,7 Besides, it is also effective in treating patients with penetrating disease, which causes anal fistula.12,13 Several studies have shown that infliximab is an alternative treatment for the induction and maintenance of remission in patients with moderate to severe UC.14,15 Anti-TNF agents also include adalimumab, certolizumab pegol, golimumab, etanercept and onercept. Adalimumab is the first fully human IgG1 monoclonal antibody against TNF-α that has been approved by the United States and European countries16 in treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and CD. Adalimumab has been proven to be well tolerated and effective in inducing and maintaining mucosal healing in patients with active CD, including those fail to tolerate infliximab.17–21 However, the presence of antibodies against adalimumab is also associated with the loss of response to adalimumab therapy.18 Golimumab is another fully human TNF-α antibody. A phase III clinical trial showed that the clinical response rates at week 6 were 51.0% and 54.9% among active UC patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, compared with 30.3% among those given placebo (both, P ≤ 0.0001).22 It has been approved by FDA for the treatment of active UC.23 Certolizumab pegol is a pegylated humanized antigen-binding fragment (Fab) of the anti-TNF-α monoclonal antibody. Different from other monoclonal antibodies, certolizumab pegol lacks crystalizable fragment (Fc) portion. As a result, it does not induce the apoptosis of T cells or monocytes, which reduces potential side effects. It has also been proven to be effective in inducing and maintaining remission in patients with active CD24,25
NATALIZUMAB (ANTI-α4 MONOCLONAL ANTIBODY) Natalizumab is a humanized monoclonal IgG antibody to α4 integrin. α4β7 intergrin is responsible for migrating leukocytes from blood vessels to inflamed mucosa. By blocking this intergrin, natalizumab may be an alternative choice to reduce inflammation. A recent Cochrane analysis suggested that natalizumab could be a potential therapy to induce and maintain remission in patients with moderately to severely active CD.27 However, natalizumab features a fatal side effect, that is, progressive multifocal leukoencephalopathy (PML), which is a serious opportunistic infection in the central nervous system caused by activated JC virus. Natalizumab interferes the interaction between α4β1 and vascular cell adhesion molecule 1 (VCAM1), which is crucial for T cells to protect our brain against JC virus. As a result, the approval of natalizumab has been restricted in the United States and Europe.27–29 VEDOLIZUMAB (ANTI-α4β7 MONOCLONAL ANTIBODY) As mentioned above, due to the lack of α4-containing integrin specificity, natalizumab inhibits systemic immune function and causes severe side effects. Vedolizumab is a humanized antibody that specifically targets α4β7 integrin which is mainly expressed in gut-homing T lymphocytes. Clinical trials have been performed in active UC and CD patients. Feagan et al.30 reported that the clinical remission rates at week 6 were 33% and 32% for active UC patients receiving 0.5 mg/kg and 2.0 mg/kg of vedolizumab
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 585–590 intravenously on day 1 and day 29, while that in the placebo group was only 14% (both P = 0.02). In another study they also demonstrated that 37% of active CD patients receiving vedolizumab 2.0 mg/kg had significant clinical remission at day 57, as compared with 21% in the placebo group (P = 0.049).31 The drug is well tolerated in the absence of systemic effects.30,32 USTEKINUMAB (INTERLEUKIN [IL]-12/IL-23 MONOCLONAL ANTIBODY) IL-12 and IL-23 contribute to the development of CD.33,34 IL-12 promotes the differentiation of CD4+ T cells into T helper 1 (Th1) cells.35 IL-23 is involved in the differentiation of CD4+ T cells into Th17 cells.36,37 The pathogenesis of CD is associated with increasing inflammatory cytokines secreted by Th1 and Th17 cells.33,34 Interestingly, both IL-12 and IL-23 have a p40 subunit. Therefore, inhibiting the p40 subunit could be a promising therapeutic target.38 Ustekinumab is a fully human IgG monoclonal antibody against p40 subunit which is shared by IL-12/IL-23.38 Ustekinumab has been proven effective in psoriasis39,40 and multiple sclerosis41. Ustekinumab has also shown its efficacy in inducing and extending clinical remission in patients with CD. Sandborn et al.42 reported that the clinical response rate in CD patients receiving 6 mg/kg of ustekinumab was significantly higher than that in the placebo group at week 6 (39.7% vs 23.5%, P = 0.005). Besides, 55.6% (40/72) patients in ustekinumab group maintained clinical response compared with 32.9% (24/73) in the placebo group (P = 0.005). No opportunistic infection was reported in their study. TOFACITINIB (JAK INHIBITOR) The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways participate in the pathogenesis of several diseases including IBD. By inhibiting JAK, it is possible to inhibit the function of several cytokines simultaneously.43 Several JAK inhibitors are under development, and tofacitinib is the only one currently considered for IBD treatment. A phase II clinical trial has evaluated the efficacy of tofacitinib in moderately to severely active UC patients, in which 194 patients were randomly assigned to receive placebo (n = 48) and tofacitinib with a dose of 0.5 mg (n = 31), 3 mg (n = 33), 10 mg (n = 33) or 15 mg (n = 49) twice daily for 8 weeks. At week 8, 78% (38/ 49) patients receiving 15 mg of tofacitinib had a clinical response, which was significantly higher than 42%
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in the placebo group (P < 0.001). In addition, the clinical remission at 8 weeks occurred in 48% and 41% of patients receiving tofacitinib at a dose of 10 mg and 15 mg (both P < 0.001), respectively, as compared with 10% of patients receiving placebo. The major side effects were influenza and nasopharyngitis. Besides, tofacitinib could increase the level of lowdensity lipoprotein (LDL) and high-density lipoprotein (HDL). No death was reported in this trial.44 FONTOLIZUMAB (ANTI-IFN-γ MONOCLONAL ANTIBODY) IFN-γ is secreted by Th1 cells and natural killer (NK) cells, which contributes to the occurence of CD. IFN-γ can induce endothelial cells to express major histocompatibility complex (MHC) class II, causing the migration of leukocytes to the inflamed region. In addition, by inhibiting the function of Th2 cells, it could break the epithelial barrier.45 Therefore, strategies aiming at neutralising IFN-γ may be possible to be efficient for CD therapy. Fontolizumab is a humanised IgG monoclonal antibody against IFN-γ.46 A metaanalysis by Cui et al. included three clinical trials to evaluate the efficacy and safety of fontolizumab in CD patients. They concluded that fontolizumab could induce significant clinical remission at week 8 compared with placebo (RR 1.98, 95% CI 1.17–3.33).46–49 Fontolizumab was generally well tolerated with few serious adverse events. TOCILIZUMAB (ANTI-IL-6 RECEPTOR [IL-6R] ANTIBODY) IL-6 is a multifunctional cytokine that is involved in several biological activities. It plays a vital role in the immune system to prevent against bacterial and viral infections. However, overexpression of IL-6 will be pathologic and induces several autoimmune diseases. After binding with IL-6R, IL-6 is capable of activating intracellular pathways and producing biological reactions.50 Thus, agents that block the function of IL-6 could throw a new light on the treatment of CD. Tocilizumab is a humanized IgG1 antibody against IL-6R, which is approved by the European Union in treating rheumatoid arthritis.51 A pilot randomized trial from Japan investigated the efficacy and safety of tocilizumab in 36 active CD patients. At week 12, 80% patients in the tocilizumab group (8 mg/kg biweekly) had a clinical response compared with 31% in the placebo group (P = 0.019). In this study, tocilizumab was well-tolerated and three patients receiving ocilizumab developed paralytic ileus, gastrointestinal bleeding or abdominal pain.52
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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BASILIXIMAB AND DACLIZUMAB (ANTI-IL-2 RECEPTOR [IL-2R] α CHAIN) The expression of IL-2 is associated with the production of corticosteroid-resistant T lymphocytes.53 The complex of IL-2 binding to IL-2R activates several signaling pathways, including MAPK, extracellular signal–regulated kinase (ERK), p38 and c-Jun-Nterminal kinase (JNK).54 Each of them has been shown to inhibit the receptor of glucocorticoid.55–57 The α chain (CD25) of the IL-2R features high affinity to IL-2. Basiliximab is a chimeric monoclonal antibody against CD25. A pilot open-label study59 has shown that basiliximab could be effective in steroidresistant UC patients.58 In this study all 20 patients received a single dose of 40 mg basiliximab plus standard steroid therapy, as a result, 50% patients achieved clinical remission within 8 weeks and 65% patients were in clinical remission at weeks 24. However, another study showed that basiliximab did not increase the effect of corticosteroids in the induction of remission in patients with corticosteroid-resistant moderate to severe UC.58 In their study 149 patients were randomly assigned to three groups that were given 20 mg (n = 46) or 40 mg (n = 52) basiliximab or placebo (n = 51) at weeks 0, 2, and 4. The proportion of patients achieved clinical remission in the three groups was 26%, 29% and 28%, respectively (both P = 1.00 vs placebo).59 Daclizumab is a humanised anti-CD25 antibody. An initial pilot study suggested efficacy of daclizumab in active UC.60 In another study by van Assche et al.61 159 moderate UC patients were randomized to receive daclizumab 1 mg/kg at weeks 0 and 4, or 2 mg/kg at weeks 0, 2, 4 and 6, or placebo. However, neither 1 mg/kg (P = 0.11) nor 2 mg/kg (P = 0.73) daclizumab showed significant efficacy compared with placebo. Therefore, the therapeutic benefits of these agents need further investigation. RITUXIMAB (ANTI-CD20 MONOCLONAL ANTIBODY) Pathogenic antibodies produced by B cells might contribute to the development of multiple autoimmune diseases. Therefore, inhibiting the function of B cells could be another potential option to treat autoimmune diseases. Rituximab is an anti-CD20 monoclonal antibody aiming at B cells. It has been used to treat non-Hodgkin lymphoma and rheumatoid arthritis.62 Leiper et al.63 determined its efficacy in treating 24 moderate UC patients who were corticosteroid-
Journal of Digestive Diseases 2014; 15; 585–590 resistant or dependent. However, at week 4 only 1/8 placebo-treated patients and 3/16 rituximab-treated patients were in remission (P = 1.0). Their result did not show significant efficacy of rituximab in inducing clinical remission among these patients. TRANSGENIC PROBIOTICS Probiotics play an important role in various intestinal diseases.64,65 Live, genetically modified bacteria may provide new choice for the treatment of IBD. Lactococcus lactis (L. lactis) is transfected with the human IL-10 gene, which is an anti-inflammatory cytokine. In IL-10–deficient mice, the animals developed chronic intestinal inflammation that is similar to CD in human beings. This aberrant immune response was attributed to a lack of IL-10.66 A phase I clinical trial has been conducted to figure out whether L. lactis could improve symptoms in patients with CD.67 This study enrolled 10 patients with moderately to severely active CD, showing that L. lactis was safe and effective as maintenance therapy for chronic intestinal disease. The phase II clinical trial evaluating the efficacy of L. lactis among UC patients is being conducted.68 In conclusion, anti-TNF-α agents are still the main trend in treating IBD. The effect of anti-TNF-α agents is satisfactory, despite the fact that some patients fail to achieve response due to the presence of antibodies to these agents. As a result, biological medicines targeting different immune mediators are needed to improve the treatment for IBD. Fortunately, in recent years, great efforts have been made in the field of IBD. Multiple novel therapies have been developed and some of them are currently at the late stages of clinical trials. In this review, we have collected some clinical trials on the efficacy and safety of newly developed biological agents for treating IBD. Several promising candidates could be elegant therapeutic targets in the future, such as adalimumab, certolizumab pegol, golimumab, vedolizumab, ustekinumab, tofacitinib, fontolizumab and tocilizumab. What’s more, transgenic probiotics could also be potential therapy for IBD patients. There is no doubt that with further clinical trials, more and more biological therapies will be approved to be administered in the treatment for IBD. Patients suffering from IBD will certainly achieve a better result in the future. REFERENCES 1 Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448: 427–34.
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 585–590 2 Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 2000; 51: 289–98. 3 Apostolaki M, Armaka M, Victoratos P, Kollias G. Cellular mechanisms of TNF function in models of inflammation and autoimmunity. Curr Dir Autoimmun 2010; 11: 1–26. 4 Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011; 474: 307–17. 5 Targan SR, Hanauer SB, van Deventer SJ et al; Crohn’s Disease cA2 Study Group. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. N Engl J Med 1997; 337: 1029–35. 6 Present DH, Rutgeerts P, Targan S et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340: 1398–405. 7 Hanauer SB, Feagan BG, Lichtenstein GR et al; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–9. 8 Sands BE, Anderson FH, Bernstein CN et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004; 350: 876–85. 9 Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol 2013; 108: 40–7. 10 Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P. Autoimmunity and anti-TNF-α agents. Ann N Y Acad Sci 2005; 1051: 559–69. 11 Stokkers PC, Hommes DW. New cytokine therapeutics for inflammatory bowel disease. Cytokine 2004; 28: 167–73. 12 Desilva S, Kaplan G, Panaccione R. Sequential therapies for Crohn’s disease: optimizing conventional and biologic strategies. Rev Gastroenterol Disord 2008; 8: 109–16. 13 Taxonera C, Schwartz DA, García-Olmo D. Emerging treatments for complex perianal fistula in Crohn’s disease. World J Gastroenterol 2009; 15: 4263–72. 14 Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462–76. 15 Sandborn WJ, Rutgeerts P, Feagan BG et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology 2009; 137: 1250–60. 16 Cassinotti A, Ardizzone S, Porro GB. Adalimumab for the treatment of Crohn’s disease. Biologics 2008; 2: 763–77. 17 Hanauer SB, Sandborn WJ, Rutgeerts P et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006; 130: 323–33. 18 Sandborn WJ, Rutgeerts P, Enns R et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007; 146: 829–38. 19 Rutgeerts P, Van Assche G, Sandborn WJ et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology 2012; 142: 1102–11.e2. 20 Sandborn WJ, Hanauer SB, Rutgeerts P et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007; 56: 1232–9. 21 Colombel JF, Schwartz DA, Sandborn WJ et al. Adalimumab for the treatment of fistulas in patients with Crohn’s disease. Gut 2009; 58: 940–8. 22 Sandborn WJ, Feagan BG, Marano C et al.; PURSUIT-SC Study Group. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014; 146: 85–95.
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23 Mozaffari S, Nikfar S, Abdolghaffari AH, Abdollahi M. New biologic therapeutics for ulcerative colitis and Crohn’s disease. Expert Opin Biol Ther 2014; 14: 583–600. 24 Sandborn WJ, Feagan BG, Stoinov S et al.; PRECISE 1 Study Investigators. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007; 357: 228–38. 25 Schreiber S, Khaliq-Kareemi M, Lawrance IC et al.; PRECISE 2 Study Investigators. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007; 357: 239–50. 26 Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2008; (1): CD006893. 27 MacDonald JK, McDonald JW. Natalizumab for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2007; (1): CD006097. 28 Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005; 353: 375–81. 29 Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353: 369–74. 30 Feagan BG, Greenberg GR, Wild G et al. Treatment of ulcerative colitis with a humanized antibody to the α4β7 integrin. N Engl J Med 2005; 352: 2499–507. 31 Feagan BG, Greenberg GR, Wild G et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the α4β7 integrin. Clin Gastroenterol Hepatol 2008; 6: 1370–7. 32 Parikh A, Leach T, Wyant T et al. Vedolizumab for the treatment of active ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel Dis 2012; 18: 1470–9. 33 Peluso I, Pallone F, Monteleone G. Interleukin-12 and Th1 immune response in Crohn’s disease: pathogenetic relevance and therapeutic implication. World J Gastroenterol 2006; 12: 5606–10. 34 Neurath MF. IL-23: a master regulator in Crohn disease. Nat Med 2007; 13: 26–8. 35 Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003; 3: 133–46. 36 Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest 2006; 116: 1218–22. 37 Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 2007; 25: 221–42. 38 Sandborn WJ, Feagan BG, Fedorak RN et al.; Ustekinumab Crohn’s Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008; 135: 1130–41. 39 Leonardi CL, Kimball AB, Papp KA et al.; PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: 1665–74. 40 Papp KA, Langley RG, Lebwohl M et al.; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675–84.
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41 Kasper LH, Everitt D, Leist TP et al.; Multiple Sclerosis Investigators. A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis. Curr Med Res Opin 2006; 22: 1671–8. 42 Sandborn WJ, Gasink C, Gao LL et al.; CERTIFI Study Group. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012; 367: 1519–28. 43 Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res 2013; 76: 1–8. 44 Sandborn WJ, Ghosh S, Panes J et al.; Study A3921063 Investigators. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012; 367: 616–24. 45 Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-γ. Annu Rev Immunol 1997; 15: 749–95. 46 Hommes DW, Mikhajlova TL, Stoinov S et al. Fontolizumab, a humanised anti-interferon γ antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn’s disease. Gut 2006; 55: 1131–7. 47 Reinisch W, Hommes DW, Van Assche G et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe Crohn’s disease. Gut 2006; 55: 1138–44. 48 Reinisch W, de Villiers W, Bene L et al. Fontolizumab in moderate to severe Crohn’s disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 2010; 16: 233–42. 49 Cui D, Huang G, Yang D, Huang B, An B. Efficacy and safety of interferon-gamma-targeted therapy in Crohn’s disease: a systematic review and meta-analysis of randomized controlled trials. Clin Res Hepatol Gastroenterol 2013; 37: 507–13. 50 Tsuru T, Terao K, Murakami M et al. Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab. Mod Rheumatol 2014; 24: 511–6. 51 Scheinecker C, Smolen J, Yasothan U, Stoll J, Kirkpatrick P. Tocilizumab. Nat Rev Drug Discov 2009; 8: 273–4. 52 Ito H, Takazoe M, Fukuda Y et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 2004; 126: 989–96. 53 Kam JC, Szefler SJ, Surs W, Sher ER, Leung DY. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 1993; 151: 3460–6. 54 Ellery JM, Nicholls PJ. Alternate signalling pathways from the interleukin-2 receptor. Cytokine Growth Factor Rev 2002; 13: 27–40.
Journal of Digestive Diseases 2014; 15; 585–590 55 Jamieson CA, Yamamoto KR. Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling. Proc Natl Acad Sci U S A 2000; 97: 7319–24. 56 Rogatsky I, Logan SK, Garabedian MJ. Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase. Proc Natl Acad Sci U S A 1998; 95: 2050–5. 57 Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM. p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol 2002; 109: 649–57. 58 Creed TJ, Probert CS, Norman MN et al. Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease. Aliment Pharmacol Ther 2006; 23: 1435–42. 59 Sands BE, Sandborn WJ, Creed TJ et al. Basiliximab does not increase efficacy of corticosteroids in patients with steroid-refractory ulcerative colitis. Gastroenterology 2012; 143: 356–64.e1. 60 Van Assche G, Dalle I, Noman M et al. A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis. Am J Gastroenterol 2003; 98: 369–76. 61 Van Assche G, Sandborn WJ, Feagan BG et al. Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut 2006; 55: 1568–74. 62 Calderón-Gómez E, Panés J. Rituximab in active ulcerative colitis. Gastroenterology 2012; 142: 174–6. 63 Leiper K, Martin K, Ellis A et al. Randomised placebocontrolled trial of rituximab (anti-CD20) in active ulcerative colitis. Gut 2011; 60: 1520–6. 64 Whelan K, Quigley EM. Probiotics in the management of irritable bowel syndrome and inflammatory bowel disease. Curr Opin Gastroenterol 2013; 29: 184–9. 65 Sartor RB. Efficacy of probiotics for the management of inflammatory bowel disease. Gastroenterol Hepatol (N Y) 2011; 7: 606–8. 66 Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993; 75: 263–74. 67 Braat H, Rottiers P, Hommes DW et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin Gastroenterol Hepatol 2006; 4: 754–9. 68 Wells J. Mucosal vaccination and therapy with genetically modified lactic acid bacteria. Annu Rev Food Sci Technol 2011; 2: 423–45.
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 585–590
doi: 10.1111/1751-2980.12193
Leading article
Novel agents in the future: Therapy beyond anti-TNF agents in inflammatory bowel disease Jiang Chen PENG, Jun SHEN & Zhi Hua RAN State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai Inflammatory Bowel Disease Research Center, Shanghai, China
Anti-tumor necrosis factor (TNF)-α agents emerge as the hot spot in the last decade for treating patients with inflammatory bowel disease (IBD). The effect of anti-TNF-α agents is satisfactory; however, some patients fail to achieve clinical response. Fortunately, KEY WORDS:
in recent years, great efforts have been made and multiple novel therapies have been developed in the treatment for IBD. In this article, we aim to introduce anti-TNF-α drugs as well as other novel treatments currently undergoing clinical trials for IBD.
Crohn disease, inflammatory bowel diseases, tumor necrosis factor-alpha, ulcerative colitis.
INTRODUCTION Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a group of chronic inflammatory disorders of the gastrointestinal tract. The etiology of IBD remains unclear; however, it is strongly suggested that genetic susceptibility, environmental factors and immunological function may contribute to the development of inflammation.1 Tumor necrosis factor (TNF) that is
Correspondence to: Zhi Hua RAN, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai Inflammatory Bowel Disease Research Center, 145 Middle Shandong Road, Shanghai 200001, China. Email: [email protected] Conflict of interest: None. © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
secreted by immune cells plays a vital role in the pathogenesis of IBD.2 TNF regulates the expression of adhesion molecules to recruit immune cells, resulting in tissue inflammation and damage.3,4 Clinical application of anti-TNF-α has achieved a satisfactory result. It has been proved to induce clinical response and maintain remission. Infliximab is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody, which binds to TNF-α and inhibits its biological activity. At first, infliximab was mainly administered to treat patients with active CD. Recently, the application of infliximab has also been evaluated among UC patients. Several studies have shown that infliximab is effective in both UC and CD patients.5–8 However, some patients lack an initial response to infliximab, and others lose response gradually. To some extent, it is due to the fact that these patients produce antibodies to infliximab.9 So we can conclude that anti-TNF-α therapy is not a perfect way to treat IBD. Other alternative treatments are needed to be developed to obtain better results among IBD patients. In this article, we aim to introduce anti-TNF-α agents as well as other novel treatments currently undergoing clinical trials for IBD.
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ANTI-TNF-α AGENTS
and has been approved by FDA for treating CD.26 Sandborn et al.24 showed that at both weeks 6 and 26, the response rates were 23% in the certolizumab pegol group (400 mg, at weeks 0, 2, 4 and then every 4 weeks) and 16% in the placebo group (P = 0.02). Serious infections occurred in 2% of patients in the certolizumab pegol group.24 In another study, 425 patients who had a clinical response to certolizumab pegol at week 6 were assigned to continuous maintenance therapy and placebo therapy. The results showed that 63% in the certolizumab group (135/ 215) also had a response at week 26, as compared with 36% (76/210) in the placebo group (P < 0.001); while serious infections occurred in 3% of patients receiving certolizumab pegol.25 Etanercept and onercept are antagonists for TNF receptor (TNFR), both of which have failed to reach a beneficial result.23
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TNF is highly produced by active macrophages and T lymphocytes. After the binding of TNF with cognate membrane receptors (TNFR), p55TNFR (TNFR1) and p75TNFR (TNFR2), the complexes induce the activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways, leading to tissue damage and intestinal inflammation.3,4 Inhibiting TNF production can reduce the expression of inflammatory cytokines and alleviate intestinal inflammation. Infliximab binds with high affinity to TNF-α and inhibits its biological activity.10,11 After approved by the Food and Drug Administration (FDA) of USA, the clinical efficacy of infliximab has been well studied. In CD, infliximab has been used in patients with active disease and those who were resistant to corticosteroid therapy.5,7 Besides, it is also effective in treating patients with penetrating disease, which causes anal fistula.12,13 Several studies have shown that infliximab is an alternative treatment for the induction and maintenance of remission in patients with moderate to severe UC.14,15 Anti-TNF agents also include adalimumab, certolizumab pegol, golimumab, etanercept and onercept. Adalimumab is the first fully human IgG1 monoclonal antibody against TNF-α that has been approved by the United States and European countries16 in treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and CD. Adalimumab has been proven to be well tolerated and effective in inducing and maintaining mucosal healing in patients with active CD, including those fail to tolerate infliximab.17–21 However, the presence of antibodies against adalimumab is also associated with the loss of response to adalimumab therapy.18 Golimumab is another fully human TNF-α antibody. A phase III clinical trial showed that the clinical response rates at week 6 were 51.0% and 54.9% among active UC patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, compared with 30.3% among those given placebo (both, P ≤ 0.0001).22 It has been approved by FDA for the treatment of active UC.23 Certolizumab pegol is a pegylated humanized antigen-binding fragment (Fab) of the anti-TNF-α monoclonal antibody. Different from other monoclonal antibodies, certolizumab pegol lacks crystalizable fragment (Fc) portion. As a result, it does not induce the apoptosis of T cells or monocytes, which reduces potential side effects. It has also been proven to be effective in inducing and maintaining remission in patients with active CD24,25
NATALIZUMAB (ANTI-α4 MONOCLONAL ANTIBODY) Natalizumab is a humanized monoclonal IgG antibody to α4 integrin. α4β7 intergrin is responsible for migrating leukocytes from blood vessels to inflamed mucosa. By blocking this intergrin, natalizumab may be an alternative choice to reduce inflammation. A recent Cochrane analysis suggested that natalizumab could be a potential therapy to induce and maintain remission in patients with moderately to severely active CD.27 However, natalizumab features a fatal side effect, that is, progressive multifocal leukoencephalopathy (PML), which is a serious opportunistic infection in the central nervous system caused by activated JC virus. Natalizumab interferes the interaction between α4β1 and vascular cell adhesion molecule 1 (VCAM1), which is crucial for T cells to protect our brain against JC virus. As a result, the approval of natalizumab has been restricted in the United States and Europe.27–29 VEDOLIZUMAB (ANTI-α4β7 MONOCLONAL ANTIBODY) As mentioned above, due to the lack of α4-containing integrin specificity, natalizumab inhibits systemic immune function and causes severe side effects. Vedolizumab is a humanized antibody that specifically targets α4β7 integrin which is mainly expressed in gut-homing T lymphocytes. Clinical trials have been performed in active UC and CD patients. Feagan et al.30 reported that the clinical remission rates at week 6 were 33% and 32% for active UC patients receiving 0.5 mg/kg and 2.0 mg/kg of vedolizumab
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 585–590 intravenously on day 1 and day 29, while that in the placebo group was only 14% (both P = 0.02). In another study they also demonstrated that 37% of active CD patients receiving vedolizumab 2.0 mg/kg had significant clinical remission at day 57, as compared with 21% in the placebo group (P = 0.049).31 The drug is well tolerated in the absence of systemic effects.30,32 USTEKINUMAB (INTERLEUKIN [IL]-12/IL-23 MONOCLONAL ANTIBODY) IL-12 and IL-23 contribute to the development of CD.33,34 IL-12 promotes the differentiation of CD4+ T cells into T helper 1 (Th1) cells.35 IL-23 is involved in the differentiation of CD4+ T cells into Th17 cells.36,37 The pathogenesis of CD is associated with increasing inflammatory cytokines secreted by Th1 and Th17 cells.33,34 Interestingly, both IL-12 and IL-23 have a p40 subunit. Therefore, inhibiting the p40 subunit could be a promising therapeutic target.38 Ustekinumab is a fully human IgG monoclonal antibody against p40 subunit which is shared by IL-12/IL-23.38 Ustekinumab has been proven effective in psoriasis39,40 and multiple sclerosis41. Ustekinumab has also shown its efficacy in inducing and extending clinical remission in patients with CD. Sandborn et al.42 reported that the clinical response rate in CD patients receiving 6 mg/kg of ustekinumab was significantly higher than that in the placebo group at week 6 (39.7% vs 23.5%, P = 0.005). Besides, 55.6% (40/72) patients in ustekinumab group maintained clinical response compared with 32.9% (24/73) in the placebo group (P = 0.005). No opportunistic infection was reported in their study. TOFACITINIB (JAK INHIBITOR) The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways participate in the pathogenesis of several diseases including IBD. By inhibiting JAK, it is possible to inhibit the function of several cytokines simultaneously.43 Several JAK inhibitors are under development, and tofacitinib is the only one currently considered for IBD treatment. A phase II clinical trial has evaluated the efficacy of tofacitinib in moderately to severely active UC patients, in which 194 patients were randomly assigned to receive placebo (n = 48) and tofacitinib with a dose of 0.5 mg (n = 31), 3 mg (n = 33), 10 mg (n = 33) or 15 mg (n = 49) twice daily for 8 weeks. At week 8, 78% (38/ 49) patients receiving 15 mg of tofacitinib had a clinical response, which was significantly higher than 42%
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in the placebo group (P < 0.001). In addition, the clinical remission at 8 weeks occurred in 48% and 41% of patients receiving tofacitinib at a dose of 10 mg and 15 mg (both P < 0.001), respectively, as compared with 10% of patients receiving placebo. The major side effects were influenza and nasopharyngitis. Besides, tofacitinib could increase the level of lowdensity lipoprotein (LDL) and high-density lipoprotein (HDL). No death was reported in this trial.44 FONTOLIZUMAB (ANTI-IFN-γ MONOCLONAL ANTIBODY) IFN-γ is secreted by Th1 cells and natural killer (NK) cells, which contributes to the occurence of CD. IFN-γ can induce endothelial cells to express major histocompatibility complex (MHC) class II, causing the migration of leukocytes to the inflamed region. In addition, by inhibiting the function of Th2 cells, it could break the epithelial barrier.45 Therefore, strategies aiming at neutralising IFN-γ may be possible to be efficient for CD therapy. Fontolizumab is a humanised IgG monoclonal antibody against IFN-γ.46 A metaanalysis by Cui et al. included three clinical trials to evaluate the efficacy and safety of fontolizumab in CD patients. They concluded that fontolizumab could induce significant clinical remission at week 8 compared with placebo (RR 1.98, 95% CI 1.17–3.33).46–49 Fontolizumab was generally well tolerated with few serious adverse events. TOCILIZUMAB (ANTI-IL-6 RECEPTOR [IL-6R] ANTIBODY) IL-6 is a multifunctional cytokine that is involved in several biological activities. It plays a vital role in the immune system to prevent against bacterial and viral infections. However, overexpression of IL-6 will be pathologic and induces several autoimmune diseases. After binding with IL-6R, IL-6 is capable of activating intracellular pathways and producing biological reactions.50 Thus, agents that block the function of IL-6 could throw a new light on the treatment of CD. Tocilizumab is a humanized IgG1 antibody against IL-6R, which is approved by the European Union in treating rheumatoid arthritis.51 A pilot randomized trial from Japan investigated the efficacy and safety of tocilizumab in 36 active CD patients. At week 12, 80% patients in the tocilizumab group (8 mg/kg biweekly) had a clinical response compared with 31% in the placebo group (P = 0.019). In this study, tocilizumab was well-tolerated and three patients receiving ocilizumab developed paralytic ileus, gastrointestinal bleeding or abdominal pain.52
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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BASILIXIMAB AND DACLIZUMAB (ANTI-IL-2 RECEPTOR [IL-2R] α CHAIN) The expression of IL-2 is associated with the production of corticosteroid-resistant T lymphocytes.53 The complex of IL-2 binding to IL-2R activates several signaling pathways, including MAPK, extracellular signal–regulated kinase (ERK), p38 and c-Jun-Nterminal kinase (JNK).54 Each of them has been shown to inhibit the receptor of glucocorticoid.55–57 The α chain (CD25) of the IL-2R features high affinity to IL-2. Basiliximab is a chimeric monoclonal antibody against CD25. A pilot open-label study59 has shown that basiliximab could be effective in steroidresistant UC patients.58 In this study all 20 patients received a single dose of 40 mg basiliximab plus standard steroid therapy, as a result, 50% patients achieved clinical remission within 8 weeks and 65% patients were in clinical remission at weeks 24. However, another study showed that basiliximab did not increase the effect of corticosteroids in the induction of remission in patients with corticosteroid-resistant moderate to severe UC.58 In their study 149 patients were randomly assigned to three groups that were given 20 mg (n = 46) or 40 mg (n = 52) basiliximab or placebo (n = 51) at weeks 0, 2, and 4. The proportion of patients achieved clinical remission in the three groups was 26%, 29% and 28%, respectively (both P = 1.00 vs placebo).59 Daclizumab is a humanised anti-CD25 antibody. An initial pilot study suggested efficacy of daclizumab in active UC.60 In another study by van Assche et al.61 159 moderate UC patients were randomized to receive daclizumab 1 mg/kg at weeks 0 and 4, or 2 mg/kg at weeks 0, 2, 4 and 6, or placebo. However, neither 1 mg/kg (P = 0.11) nor 2 mg/kg (P = 0.73) daclizumab showed significant efficacy compared with placebo. Therefore, the therapeutic benefits of these agents need further investigation. RITUXIMAB (ANTI-CD20 MONOCLONAL ANTIBODY) Pathogenic antibodies produced by B cells might contribute to the development of multiple autoimmune diseases. Therefore, inhibiting the function of B cells could be another potential option to treat autoimmune diseases. Rituximab is an anti-CD20 monoclonal antibody aiming at B cells. It has been used to treat non-Hodgkin lymphoma and rheumatoid arthritis.62 Leiper et al.63 determined its efficacy in treating 24 moderate UC patients who were corticosteroid-
Journal of Digestive Diseases 2014; 15; 585–590 resistant or dependent. However, at week 4 only 1/8 placebo-treated patients and 3/16 rituximab-treated patients were in remission (P = 1.0). Their result did not show significant efficacy of rituximab in inducing clinical remission among these patients. TRANSGENIC PROBIOTICS Probiotics play an important role in various intestinal diseases.64,65 Live, genetically modified bacteria may provide new choice for the treatment of IBD. Lactococcus lactis (L. lactis) is transfected with the human IL-10 gene, which is an anti-inflammatory cytokine. In IL-10–deficient mice, the animals developed chronic intestinal inflammation that is similar to CD in human beings. This aberrant immune response was attributed to a lack of IL-10.66 A phase I clinical trial has been conducted to figure out whether L. lactis could improve symptoms in patients with CD.67 This study enrolled 10 patients with moderately to severely active CD, showing that L. lactis was safe and effective as maintenance therapy for chronic intestinal disease. The phase II clinical trial evaluating the efficacy of L. lactis among UC patients is being conducted.68 In conclusion, anti-TNF-α agents are still the main trend in treating IBD. The effect of anti-TNF-α agents is satisfactory, despite the fact that some patients fail to achieve response due to the presence of antibodies to these agents. As a result, biological medicines targeting different immune mediators are needed to improve the treatment for IBD. Fortunately, in recent years, great efforts have been made in the field of IBD. Multiple novel therapies have been developed and some of them are currently at the late stages of clinical trials. In this review, we have collected some clinical trials on the efficacy and safety of newly developed biological agents for treating IBD. Several promising candidates could be elegant therapeutic targets in the future, such as adalimumab, certolizumab pegol, golimumab, vedolizumab, ustekinumab, tofacitinib, fontolizumab and tocilizumab. What’s more, transgenic probiotics could also be potential therapy for IBD patients. There is no doubt that with further clinical trials, more and more biological therapies will be approved to be administered in the treatment for IBD. Patients suffering from IBD will certainly achieve a better result in the future. REFERENCES 1 Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448: 427–34.
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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