To review the literature on novel immunomodulators such as tumor necrosis factor alpha (TNF-α)- and interleukin (IL)-related agents, 6-thioguanine (6-TG), tacrolimus, and leflunomide, and antibiotics such as ornidazole, rifaximin, and ciprofloxacin for the treatment of Crohn's disease.
Data Sources:
Literature was accessed through MEDLINE (1966–January 2006) using the terms Crohn's disease, novel therapies, immunomodulators, and antibiotics. Article references were hand-searched for additional relevant articles and abstracts.
Study Selection and Data Extraction:
All articles in English identified from the data sources were evaluated. Studies including greater than 5 patients with primarly adult populations were included in the review.
Data Synthesis:
There are a number of new TNF-α and IL-related agents that may be useful for management of Crohn's disease. They include CDP 571, CDP 870, etanercept, onercept, thalidomide, IL-10, and IL-11. Several studies have shown that CDP 571 decreases the Crohn's Disease Activity Index score and is promising, especially in patients with refractory disease. 6-TG, tacrolimus, and leflunomide are among other immunomodulators that appear to have a role in refractory/severe disease. Finally, ornidazole, rifaximin, and ciprofloxacin are antimicrobials that may be used in patients who have failed other therapies or as adjunctive therapies.
Conclusions:
A number of new treatment modalities are being investigated for Crohn's disease. Many of them are promising, and some of these agents may be considered in treatment-refractory patients in the future. However, some of the agents reviewed here are not available in the US. Future studies need to be double-blinded and placebo- or other treatment-controlled in a more homogeneous patient population.
WallGC, HeynemanC, PfannerTP. Medical options for treating Crohn's disease in adults: focus on antitumor necrosis factor-alpha chimeric monoclonal antibody. Pharmacotherapy1999; 19: 1138–52.
2.
HanauerSB, SandbornW.Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults. Am J Gastroenterol2001; 96: 635–43.
3.
HumeG, Radford-SmithGL. The pathogenesis of Crohn's disease in the 21st century. Pathology2002; 34: 561–7.
4.
HibiT, InoueN, OgataH, NaganumaM.Introduction and overview: recent advances in the immunotherapy of inflammatory bowel disease. J Gastroenterol2003; 38(suppl 15):36–42.
5.
RoglerG, AndusT.Cytokines in inflammatory bowel disease. World J Surg1998; 22: 382–9.
6.
BamiasG, NyceMR, De La RueSA, CominelliF.New concepts in the pathophysiology of inflammatory bowel disease. Ann Intern Med2005; 143: 895–904.
7.
DuX, WilliamsDA. Interleukin-11: review of molecular, cell biology, and clinical use. Blood1997; 89: 3897–908.
8.
Van DeventerSJH. Tumor necrosis factor and Crohn's disease. Gut1997; 40: 443–8.
GuslandiM.Antibiotics for inflammatory bowel disease: do they work?Eur J Gastroenterol Hepatol2005; 17: 145–7.
12.
SandbornWJ, FeaganBG, HanauerSBAn engineered human antibody to TNF (CDP 571) for active Crohn's disease: a randomized double-blind placebo-controlled trial. Gastroenterology2001; 120: 1330–8.
13.
SandbornWJ, FeaganBG, Radford-SmithGCDP 571, a humanized monoclonal antibody to tumor necrosis factor γ for moderate to severe Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gut2004; 53: 1485–93.
14.
FeaganBG, SandbornWJ, BakerJPA randomized, double-blind, placebo-controlled trial of CDP 571, a humanized monoclonal antibody to tumor necrosis factor γ, in patients with corticosteroid-dependent Crohn's disease. Aliment Pharmacol Ther2005; 21: 373–84.
15.
SchreiberS, RutgeertsP, FedorakRNA randomized, placebo-controlled trial of certolizumab pegol (CDP 870) for treatment of Crohn's disease. Gastroenterology2005; 129: 807–18.
16.
SandbornWJ, HanauerSB, KatzSEtanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology2001; 121: 1088–94.
17.
RutgeertsP, LemmensL, Van AsscheG, NomanM, Borghini-FuhrerI, GoedkoopR.Treatment of active Crohn's disease with onercept (recombinant human soluble p55 tumor necrosis factor receptor): results of a randomized, open-label, pilot study. Aliment Pharmacol Ther2003; 17: 185–92.
18.
EhrenpreisED, KaneSV, CohenLB, CohenRD, HanauerSB. Thalidomide therapy for patients with refractory Crohn's disease: an open-label trial. Gastroenterology1999; 117: 1271–7.
19.
FedorakRN, GanglA, ElsonCORecombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. Gastroenterology2000; 119: 1473–82.
20.
SchreiberS, FedorakRN, NielsenOHSafety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Gastroenterology2000; 119: 1461–72.
21.
SandsBE, BankS, SninskyCAPreliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease. Gastroenterology1999; 117:58–64.
22.
D'HaensG, NomanM, LemmensL, GeboesK, RutgeertsP.Etanercept (TNF receptor fusion protein, Enbrel) is effective and well-tolerated in active refractory Crohn's disease: results of a single center pilot study (abstract). Gastroenterology2000; 118:A656.
23.
SrinivasanR, LichtensteinGR. Recent developments in the pharmacologic treatment of Crohn's disease. Expert Opin Investig Drugs2004; 13: 373–91.
24.
DubinskyMC, HassardPV, SeidmanEGAn open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis2001; 7: 181–9.
25.
DubinskyMC, FeldmanEJ, AbreuMT, TarganSR, VisiliauskasEA. Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine. Am J Gastroenterol2003; 98: 1058–63.
26.
BonazB, BoitardJ, MarteauPTioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine. Aliment Pharmacol Ther2003; 18: 401–8.
27.
DerijksLJJ, de JongDJ, GilissenLPL6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment. Eur J Gastroenterol Hepatol2003; 15: 63–7.
28.
HerrlingerKR, KreiselW, SchwabM6-Thioguanine—efficacy and safety in chronic active Crohn's disease. Aliment Pharmacol Ther2003; 17: 503–8.
29.
FellermannK, HerrlingerKR, HormannN, LudwigD, StangeEF. Tacrolimus: a new immunosuppressant for steroid refractory inflammatory bowel disease. Transplant Proc2001; 33: 2247–8.
30.
IerardiE, FrancavillaR, PisaniA, RendinaM, PanellaC, FrancavillaA.Long-term tacrolimus: a promising therapeutic approach for Crohn's disease. Transplant Proc2001; 33: 2107–9.
31.
Gonzalez-LamaY, AbreuL, VeraMILong-term oral tacrolimus therapy in refractory to infliximab fistulizing Crohn's disease: a pilot study. Inflamm Bowel Dis2005; 11: 8–15.
32.
SandbornWJ, PresentDH, IsaacsKLTacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized, placebo-controlled trial. Gastroenterology2003; 125: 380–8.
33.
PrajapatiDN, KnoxJF, EmmonsJ, SaeianK, CsukaME, BinionDG. Leflunomide treatment of Crohn's disease patients intolerant to standard immunomodulator therapy. J Clin Gastroenterol2003; 37: 125–8.
34.
NurmohamedMT, DijkmansBA. Efficacy, tolerability and cost effectiveness of disease-modifying antirheumatic drugs and biologic agents in rheumatoid arthritis. Drugs2005; 65: 661–94.
35.
RutgeertsP, Van AsscheG, VermeireSOrnidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology2005; 128: 856–61.
36.
ShafranI, JohnsonLK. An open-label evaluation of rifaximin in the treatment of active Crohn's disease. Curr Med Res Opin2005; 21: 1165–70.
37.
PranteraC, KohnA, ZannoniF, SpimpoloN, BonfaM.Metronidazole plus ciprofloxacin in the treatment of active, refractory Crohn's disease: results of an open study. J Clin Gastroenterol1994; 19: 79–80.
38.
GreenbloomSL, SteinhartAH, GreenbergGR. Ciprofloxacin and metronidazole: combination antibiotic therapy for ileocolonic Crohn's disease (abstract). Gastroenterology1995; 108(suppl):A827.
39.
PranteraC, ZannoniF, ScribanoMLAn antibiotic regimen for the treatment of active Crohn's disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Clin Gastroenterol1996; 91: 328–32.
40.
ColombelJF, LemannM, CassagnouMA controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Am J Gastroenterol1999; 94: 674–8.
41.
ArnoldGL, BeavesMR, PryjdunVO, MookWJ. Preliminary study of ciprofloxacin in active Crohn's disease. Inflamm Bowel Dis2002; 8: 10–5.
42.
RutgeertsP, HieleM, GeboesKControlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection. Gastroenterology1995; 108: 1617–21.
43.
WolfJL. Ciprofloxacin may be useful in Crohn's disease (abstract). Gastroenterology1990; 98(part 2 suppl):A212.
44.
PeppercornMA. Is there a role for antibiotics as primary therapy in Crohn's ileitis?J Clin Gastroenterol1993; 17: 235–7.
45.
TurunenU, FarkkilaM, ValtonenVLong-term outcome of ciprofloxacin treatment in severe perianal or fistulous Crohn's disease (abstract). Gastroenterology1993; 104(suppl):A793.
