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Biological Therapies for Inflammatory Bowel Diseases

2009; Elsevier BV; Volume: 136; Issue: 4 Linguagem: Inglês

10.1053/j.gastro.2009.02.001

1528-0012

Paul Rutgeerts, Séverine Vermeire, Gert Van Assche,

Microscopic Colitis

Crohn's disease and ulcerative colitis are chronic disabling inflammatory bowel diseases (IBDs). Although the causes of IBD are unknown, defects in innate and adaptive immune pathways have been identified and biological therapies that target key molecules have been designed. Infliximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody to tumor necrosis factor, dramatically improved treatment of patients with Crohn's disease and ulcerative colitis. Infliximab has achieved treatment goals such as mucosal healing and decreasing the need for hospitalizations and surgeries. Although several anti–tumor necrosis factor therapies have been developed, there is a great need for drugs that target other pathways. Natalizumab, an antibody against the integrin α4 subunit, blocks leukocyte adhesion and has reached the clinic in the United States but has not been approved in the European Union; other anti-adhesion molecules currently are under development. Additional approaches under clinical development include therapeutics that target cytokines, such as interleukin-12/23, as well as those that block T-cell signaling. The use of recombinant human proteins, including immunoregulatory cytokines and growth factors, has not been successful so far. The efficacy of each therapy must be shown in carefully designed clinical programs. Biological therapies carry a definite safety risk, so their place in treatment algorithms must be defined carefully. Crohn's disease and ulcerative colitis are chronic disabling inflammatory bowel diseases (IBDs). Although the causes of IBD are unknown, defects in innate and adaptive immune pathways have been identified and biological therapies that target key molecules have been designed. Infliximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody to tumor necrosis factor, dramatically improved treatment of patients with Crohn's disease and ulcerative colitis. Infliximab has achieved treatment goals such as mucosal healing and decreasing the need for hospitalizations and surgeries. Although several anti–tumor necrosis factor therapies have been developed, there is a great need for drugs that target other pathways. Natalizumab, an antibody against the integrin α4 subunit, blocks leukocyte adhesion and has reached the clinic in the United States but has not been approved in the European Union; other anti-adhesion molecules currently are under development. Additional approaches under clinical development include therapeutics that target cytokines, such as interleukin-12/23, as well as those that block T-cell signaling. The use of recombinant human proteins, including immunoregulatory cytokines and growth factors, has not been successful so far. The efficacy of each therapy must be shown in carefully designed clinical programs. Biological therapies carry a definite safety risk, so their place in treatment algorithms must be defined carefully. Inflammatory bowel diseases (IBDs) are a group of chronic systemic diseases involving inflammation of the gastrointestinal tract. IBDs include ulcerative colitis, which affects only the large bowel; Crohn's disease, which can affect the entire gastrointestinal tract; and indeterminate colitis, which consists of large-bowel inflammation that shows features of both Crohn's disease, ulcerative colitis, and microscopic colitis. The pathogenesis of IBDs is not well understood. No single infectious microorganism has been identified that causes these diseases, and the genetic factors that permit predisposition to IBDs are being unraveled. The current premise is that defects in the innate immune system allow bacteria to invade the mucosa of the gut, resulting in an exaggerated adaptive immune response, which leads to extensive bowel damage. It is not clear why in ulcerative colitis the inflammation is confined to the mucosal layer of the colon and spread diffusely, whereas in Crohn's disease the inflammation is transmural and has a segmental distribution that can affect the entire gastrointestinal tract. The ideal therapeutic strategies for patients with Crohn's disease and ulcerative colitis would induce remission and maintain long-term remission without steroid exposure and with minimal surgeries.1Baumgart D.C. Sandborn W.J. Inflammatory bowel disease: clinical aspects and established and evolving therapies.Lancet. 2007; 12: 1641-1657Google Scholar Corticosteroids have been used in the treatment of active IBD for many decades and are effective in inducing clinical remission of Crohn's disease and ulcerative colitis. However, corticosteroids are not effective for maintenance of remission and their long-term use is associated with sometimes severe and irreversible side effects. Topically acting steroids have fewer side effects than systemic steroids but also are not effective in maintaining remission. Within 1 year from the start of steroid therapy, most patients relapse or develop corticosteroid dependency.2Faubion Jr, W.A. Loftus Jr, E.V. Harmsen W.S. et al.The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.Gastroenterology. 2001; 121: 255-260Google Scholar, 3Munkholm P. Langholz E. Davidsen M. et al.Frequency of glucocorticoid resistance and dependency in Crohn's disease.Gut. 1994; 35: 360-362Google Scholar Other patients are refractory or become refractory to corticosteroids, not responding to even high doses. The thiopurine immunosuppressive agents azathioprine and 6-mercaptopurine are effective steroid-sparing drugs that maintain remission in patients with Crohn's disease.1Baumgart D.C. Sandborn W.J. Inflammatory bowel disease: clinical aspects and established and evolving therapies.Lancet. 2007; 12: 1641-1657Google Scholar Their full effect is not reached until 12–16 weeks after initiation of dosing, although steady-state 6-TG thioguanine levels are observed by 2 weeks.4Sandborn W.J. Tremaine W.J. Wolf D.C. et al.North American Azathioprine Study GroupLack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease.Gastroenterology. 1999; 117: 527-535Google Scholar The efficacy of azathioprine in ulcerative colitis is less well established. Ardizzone et al5Ardizzone S. Maconi G. Russo A. et al.Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis.Gut. 2006; 55: 47-53Google Scholar showed that azathioprine is more effective than mesalamine in inducing steroid-free clinical and endoscopic remission at 6 months (53% vs 19%; P = .006; odds ratio, 4.78) in patients with steroid-dependent ulcerative colitis. Methotrexate is effective in inducing and maintaining remission in patients with Crohn's disease,6Feagan B.G. Rochon J. Fedorak R.N. et al.The North American Crohn's Study Group InvestigatorsMethotrexate for the treatment of Crohn's disease.N Engl J Med. 1995; 332: 292-297Google Scholar, 7Feagan B.G. Fedorak R.N. Irvine E.J. et al.North American Crohn's Study Group InvestigatorsA comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease.N Engl J Med. 2000; 342: 1627-1632Google Scholar but its use in patients with ulcerative colitis has not been investigated thoroughly. In patients with severe ulcerative colitis, intravenous doses of cyclosporine A (4 mg/kg) are an effective rescue therapy that allows patients to avoid surgery8Lichtiger S. Present D.H. Kornbluth A. et al.Cyclosporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med. 1994; 330: 1841-1845Google Scholar (a dose of 2 mg/kg is equivalent in efficacy to 4 mg/kg and carries a lower incidence of overall side effects).9Van Assche G. D'Haens G. Noman M. et al.Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis.Gastroenterology. 2003; 125: 1025-1031Google Scholar This strategy is only valuable in patients in whom remission can be maintained with azathioprine. However, even with this strategy the majority of patients eventually need colectomies.10Moskovitz D.N. Van Assche G. Maenhout B. et al.Incidence of colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis.Clin Gastroenterol Hepatol. 2006; 4: 760-765Google Scholar The introduction of biologics such as infliximab has changed the treatment of refractory IBD dramatically; many of these are either approved or are likely to enter the market. What pivotal studies have shown the efficacy of these agents? Biological therapies help to correct the imbalance of the gut immune system causing the diseases. Although the cause of IBD is unknown, many molecules that are involved in the disease process have been identified and can be targets of biological therapies. We first will review the biological agents that have proven successful and are routinely used in the clinic, then discuss promising agents for which definitive proof of efficacy has not been established, and, finally, discuss biological approaches that have failed. Tumor necrosis factor (TNF) (also known as TNF-α) is a proinflammatory cytokine that induces cell proliferation and differentiation; its signaling pathways regulate gene expression and up-regulate adhesion molecules. TNF promotes the inflammatory response in various diseases including rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and ulcerative colitis, and psoriasis. Symptoms of these disorders improve upon therapy with TNF inhibitors. Three anti-TNF molecules are used currently to treat IBD: infliximab, adalimumab, and certolizumab pegol. Etanercept, which links human soluble TNF receptor 2 to the Fc component of human immunoglobulin (Ig)G1 and onercept, a recombinant, soluble human p55 receptor to TNF-α have not been shown to be effective in treating Crohn's disease.11Sandborn W.J. Hanauer S.B. Katz S. et al.Etanercept for active Crohn's disease: Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial.Gastroenterology. 2001; 121: 1088-1094Google Scholar, 12Rutgeerts P. Sandborn W.J. Fedorak R.N. et al.Onercept for moderate-to-severe Crohn's disease: a randomized, double-blind, placebo-controlled trial.Clin Gastroenterol Hepatol. 2006; 4: 888-893Google Scholar Infliximab is a chimeric monoclonal IgG1 against TNF that has proven to be a highly efficacious induction and maintenance agent in patients with refractory luminal and fistulizing Crohn's disease.13Targan S.R. Hanauer S.B. van Deventer S.J. et al.Crohn's Disease cA2 Study GroupA short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease.N Engl J Med. 1997; 337: 1029-1035Google Scholar, 14Present D.H. Rutgeerts P. Targan S. et al.Infliximab for the treatment of fistulas in patients with Crohn's disease.N Engl J Med. 1999; 340: 1398-1405Google Scholar, 15Rutgeerts P. D'Haens G. Targan S. et al.Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.Gastroenterology. 1999; 117: 761-769Google Scholar, 16Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Google Scholar, 17Sands B.E. Anderson F.H. Bernstein C.N. et al.Infliximab maintenance therapy for fistulizing Crohn's disease.N Engl J Med. 2004; 350: 876-885Google Scholar, 18Rutgeerts P. Feagan B.G. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.Gastroenterology. 2004; 126: 402-413Google Scholar The ACCENT I16Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Google Scholar and the ACCENT II17Sands B.E. Anderson F.H. Bernstein C.N. et al.Infliximab maintenance therapy for fistulizing Crohn's disease.N Engl J Med. 2004; 350: 876-885Google Scholar studies have shown that scheduled maintenance therapy with infliximab is superior to episodic therapy to maintain response and remission both in luminal and in fistulizing Crohn's disease. Infliximab also induces rapid and profound endoscopic healing, improves quality of life, and allows patients to avoid hospitalization and surgery.18Rutgeerts P. Feagan B.G. Lichtenstein G.R. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.Gastroenterology. 2004; 126: 402-413Google Scholar, 19Lichtenstein G.R. Yan S. Bala M. et al.Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease.Gastroenterology. 2005; 128: 862-869Abstract Full Text Full Text PDF Scopus (512) Google Scholar Therapy with infliximab also has proven highly effective in children with refractory Crohn's disease.20Hyams J. Crandall W. Kugathasan S. et al.Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children.Gastroenterology. 2007; 132: 863-873Abstract Full Text Full Text PDF Scopus (705) Google Scholar The optimal treatment schedule is the same as in adults and successful therapy with this anti-TNF agent induces weight gain, restores growth, and improves bone formation in children21Borrelli O. Bascietto C. Viola F. et al.Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn's disease.Dig Liver Dis. 2004; 36: 342-347Google Scholar, 22Thayu M. Leonard M.B. Hyams J.S. et al.Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn's disease: results of the REACH study.Clin Gastroenterol Hepatol. 2008; 6: 1378-1384Google Scholar Infliximab is administered as an intravenous infusion at a dose of 5 mg/kg body weight at weeks 0, 2, and 6, followed by 5-mg/kg infusions every 8 weeks for maintenance. The combination of infliximab and azathioprine is more effective than infliximab alone to induce steroid-free remission and mucosal healing of the bowel in luminal Crohn's disease when given for up to 24 weeks to patients who were not treated previously with azathioprine.23Sandborn W.J. Rutgeerts P. Reinisch W. et al.SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn's disease naive to immunomodulators and biologic therapy.Am J Gastroenterology. 2008; (Abstract ACG)Google Scholar The Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC)23Sandborn W.J. Rutgeerts P. Reinisch W. et al.SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathioprine to azathioprine in patients with Crohn's disease naive to immunomodulators and biologic therapy.Am J Gastroenterology. 2008; (Abstract ACG)Google Scholar also showed that infliximab monotherapy is significantly better for inducing steroid-free remission and mucosal healing than azathioprine alone in azathioprine-naive patients. In contrast, there seems to be no synergism between methotrexate and infliximab for the induction and maintenance of steroid-free remission in luminal Crohn's disease.24Feagan B. McDonald J.W.D. Panaccione R. et al.A randomized, placebo-controlled study to evaluate the efficacy of infliximab in combination with methotrexate for the long-term treatment of Crohn's disease.Gastroenterology. 2008; 135 (Abstract): 294Abstract Full Text Full Text PDF Google Scholar It is less clear whether it is beneficial to use the infliximab-azathioprine combination in patients who previously failed therapy with azathioprine. In that setting the combination of infliximab and azathioprine has not been observed to be more effective than only infliximab when given beyond 6 months25Van Assche G. Magdelaine-Beuzelin C. D'Haens G. et al.Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial.Gastroenterology. 2008; 134: 1861-1868Abstract Full Text Full Text PDF Scopus (441) Google Scholar and because of the increased safety risk of combination therapy we recommend that azathioprine therapy be discontinued after 6 months of combination treatment. A large, open cohort study of patients with Crohn's disease who were given infliximab for many years showed a sustained benefit if the dose was adjusted when the treatment effects decreased.26Schnitzler F. Fidder H. Ferrante M. et al.Long-term outcome of treatment with infliximab in 614 Crohn's disease patients: results from a single centre cohort.Gut. 2008; (November (Epub ahead of print))Google Scholar Surprisingly, infliximab also has proven to be effective in the treatment of refractory ulcerative colitis27Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Google Scholar and for rescue from cortisone-resistant presurgical ulcerative colitis.28Jarnerot G. Hertervig E. Friis-Liby I. et al.Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study.Gastroenterology. 2005; 128: 1805-1811Abstract Full Text Full Text PDF Scopus (930) Google Scholar The Active Ulcerative Colitis (ACT) trials showed that induction with intravenous infliximab 5 mg/kg at weeks 0, 2, and 6 followed by scheduled maintenance therapy every 8 weeks is effective in refractory moderate-to-severe ulcerative colitis to improve the disease, to induce remission, to heal the mucosa, and to decrease the need for steroids over 54 weeks.27Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Google Scholar In patients with acute severe ulcerative colitis resistant to high doses of glucocorticosteroids a single infusion of infliximab 5 mg/kg reduced the need for colectomy at 3 months from 67% with placebo to 29% (P = .017).28Jarnerot G. Hertervig E. Friis-Liby I. et al.Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study.Gastroenterology. 2005; 128: 1805-1811Abstract Full Text Full Text PDF Scopus (930) Google Scholar The indications for infliximab therapy are summarized in Table 1. The main problem with infliximab is that an important proportion of patients develop antibodies to infliximab, formerly called human antichimeric antibodies, because of the presence of foreign sequences in the variable, complementarity-determining regions of the antibody. These antibodies to infliximab predispose to acute infusion reactions and delayed serum sickness-like reactions and secondary loss of response.29Baert F. Noman M. Vermeire S. et al.Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.N Engl J Med. 2003; 348: 601-608Google Scholar, 30Maser E.A. Villela R. Silverberg M.S. et al.Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease.Clin Gastroenterol Hepatol. 2006; 4: 1248-1254Google Scholar, 31Vermeire S. Noman M. Van Assche G. et al.Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease.Gut. 2007; 56: 1226-1231Google Scholar Several treatment strategies, including scheduled maintenance therapy, concomitant immunosuppression, and prophylactic systemic steroids, have been proposed to decrease the incidence and the impact of antibodies to infliximab. Nevertheless, at least 10% of patients each year have to stop therapy because of intolerance and/or loss of response, even on scheduled maintenance therapy.26Schnitzler F. Fidder H. Ferrante M. et al.Long-term outcome of treatment with infliximab in 614 Crohn's disease patients: results from a single centre cohort.Gut. 2008; (November (Epub ahead of print))Google Scholar, 32Wu E.Q. Mulani P.M. Yu A.P. et al.Loss of treatment response to infliximab maintenance therapy in Crohn's disease: a payor perspective.Value Health. 2008; (May (Epub ahead of print))Google ScholarTable 1Indications and Contraindications for Infliximab Therapy in IBDIndicationsContraindicationsRefractory luminal (including upper gastrointestinal) CDSteroid-dependent CDRefractory fistulizing CDChronic refractory UCAcute, severe UCSystemic manifestations of IBDAnkylosing spondylitis and sacroiliitisPyoderma gangrenosumChronic uveitisMetastatic CDFirst-line therapyaPotential indications.Postoperative prophylaxisaPotential indications.Indeterminate colitisaPotential indications.Refractory pouchitisaPotential indications.Active abscessSuspected active tuberculosisIntestinal obstructionMultiple sclerosis or optical neuritisClass III/IV congestive heart failurePrevious lymphomaCD, Crohn's diseasea Potential indications. Open table in a new tab CD, Crohn's disease Hence, there was and there still is an important need to develop other anti-TNF agents including other monoclonal antibodies to TNF. In parallel with infliximab, 2 more humanized anti-TNF agents were developed (Figure 1 and Table 2). Adalimumab (Humira; Abbott) is a fully human recombinant human IgG1 monoclonal antibody against TNF approved for use in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and to treat luminal Crohn's disease. Unlike infliximab, adalimumab is administered by subcutaneous injection and easily can be self-administered every 2 weeks. The pivotal trials are the Clinical Assessment of Adalimumab Safety and Efficacy Studied as an Induction Therapy in Crohn's disease I (CLASSIC I) and CLASSIC II, Crohn's trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM), and Gauging Adalimumab Effectiveness in Infliximab Nonresponders (GAIN) studies. The CLASSIC-I was a dose-finding induction study33Hanauer S.B. Sandborn W.J. Rutgeerts P. et al.Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.Gastroenterology. 2006; 130: 323-333Google Scholar with remission at week 4 as the primary end point (Crohn's disease activity index [CDAI] score, <150). There was a clear dose-response effect. Remission was achieved in 18%, 24%, and 36% of patients in the adalimumab 40/20 mg, 80/40 mg, and 160/80 mg groups, respectively, compared with 12% in the group that was given placebo (P = .001 for the 160/80 mg group vs placebo). The efficacy of maintenance therapy with adalimumab 40 mg subcutaneously (sc) every 2 weeks through 56 weeks was shown in the CLASSIC II trial.34Sandborn W.J. Hanauer S.B. Rutgeerts P. et al.Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial.Gut. 2007; 56: 1232-1239Google ScholarTable 2Monoclonal Antibodies and Constructs in the Treatment of IBDTargetCompoundManufacturerStage of developmentDiseaseGovernment approval US/EUTNFInfliximabCentocorCD, UCCD, UC/CD, UCAdalimumabAbbottCD, UCCD/CDCertolizumab pegolUCBCDCD/–GolimumabCentocorPhase IIICD, UCEtanerceptWyeth-AmgenStoppedOnerceptSeronoStoppedα4-integrinNatalizumabElanCD, UCCD/–α4β7-integrinVedolizumab (MLN0002)MillenniumPhase IIICD, UCβ7-integrinrhuMab β7GenentechPhase IUCMadcam-1PF-00547659PfizerPhase IIUCIL 12/23ABT-874AbbottPhase IICDUstekinumabCentocorPhase IICDIFN γFontolizumabPDLHaltedCDIL-6 receptorTocilizumabRochePhase IICDIL-2 receptorDaclizumabRocheStoppedUCBasiliximabCerimonPhase IIIUCCD4cm-t412CentocorStoppedCDCD3VisilizumabPDLStoppedUCN1-0401-01NovImmunePhase I/IIaCDCD40Ch5D12TanoxPhase ICDCTLA-4AbataceptBMSPhase IIICD, UCCD20RituximabRochePhase IIICD, UCIL-17AIN457NovartisPhase IICDCXCL10MDX-1100 (IP-10)MedarexPhase IUCNOTE. Data from http://www.clinicaltrials.gov/ct2/results?term=inflammatory+bowel=disease&pg=1. Accessed: December 30, 2008. Open table in a new tab NOTE. Data from http://www.clinicaltrials.gov/ct2/results?term=inflammatory+bowel=disease&pg=1. Accessed: December 30, 2008. In the phase III Crohn's trial of the Fully Human Antibody Adalimumab for Remission Maintenance.35Colombel J.F. Sandborn W.J. Rutgeerts P. et al.Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.Gastroenterology. 2007; 132: 52-65Google Scholar patients with moderate to severely active Crohn's disease received open-label induction therapy with subcutaneous adalimumab (80 mg) at weeks 0 and 40 mg at week 2 and then were assigned randomly to groups that were given adalimumab 40 mg every week, 40 mg every 2 weeks, or placebo. Fifty-eight percent of the patients displayed a clinical response. Both dosing regimens of adalimumab maintenance therapy were associated with significantly greater clinical remission rates (CDAI, <150) at week 26 (47% and 40%, respectively) and week 56 (41% and 36%, respectively) compared with placebo (17% and 12%, respectively; P < .001). At week 56, 23% of patients receiving weekly adalimumab and 29% of patients receiving adalimumab every 2 weeks were able to discontinue steroids while maintaining remission, compared with 6% in the placebo group (P ≤ .001). A key question is whether adalimumab is able to rescue patients who lost response or are intolerant to other anti-TNFs (such as infliximab). The study Gauging Adalimumab Effectiveness in Infliximab Nonresponders36Sandborn W.J. Rutgeerts P. Enns R. et al.Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.Ann Intern Med. 2007; 146: 829-838Google Scholar was a randomized, double-blind, placebo-controlled analysis of 325 patients with moderate to severe Crohn's disease who had lost previous response or were intolerant to infliximab. At week 4, 21% of the patients who had received adalimumab 160 mg at week 0, followed by adalimumab 80 mg at week 2 achieved remission, compared with 7% on placebo (P < .001). The rates of response and remission in the Gauging Adalimumab Effectiveness in Infliximab Nonresponders study (patients who already had been exposed to infliximab) clearly were lower than the rates observed in the CLASSIC trial and the Crohn's trial of the Fully Human Antibody Adalimumab for Remission Maintenance, in patients who had not previously received anti-TNF therapies. Hence, it seems that a proportion of patients is developing genuine resistance to anti-TNF strategies overall and not only to a single agent. Controlled studies of the use of infliximab or certolizumab pegol in patients who have lost response to or have become intolerant to adalimumab have not yet been performed. Certolizumab pegol or CDP-870 (Cimzia; Celltech/UCB, Slough, UK) is a pegylated humanized fragment antigen binding (Fab) that binds TNF; it is administered sc and has been approved in the United States for treatment of Crohn's disease. After 2 phase II clinical studies produced equivocal results, 2 large placebo-controlled phase III studies were performed. Pegylated Antibody Fragment Evaluation in Crohn's Disease: Safety and Efficacy (PRECISE)-137Sandborn W.J. Feagan B.G. Stoinov S. et al.Certolizumab pegol for the treatment of Crohn's disease.N Engl J Med. 2007; 357: 228-238Google Scholar and PRECISE-238Schreiber S. Khaliq-Kareemi M. Lawrance I.C. et al.Maintenance therapy with certolizumab pegol for Crohn's disease.N Engl J Med. 2007; 357: 239-250Google Scholar were designed to evaluate the efficacy of certolizumab pegol in inducing and maintaining a response in patients with Crohn's disease. In the PRECISE-1 study, 662 patients with moderately to severely active luminal Crohn's disease (CDAI, 220–450) were assigned randomly to groups that were given certolizumab pegol 400 mg or placebo at weeks 0, 2, and 4, and then every 4 weeks through week 24. The primary end points were clinical response (decrease in CDAI, ≥100) at weeks 6 and 26 in patients with baseline C-reactive protein (CRP) levels of 10 mg/L or higher. At week 6, 26% of the placebo and 37% of the certolizumab pegol–treated patients had a clinical response (P < .05); at weeks 6 and 26, the rates were 12% and 22%, respectively (P = .05). In the PRECISE-2 study, 668 adult patients with Crohn's disease (CDAI, 220–450) received open-label induction therapy with certolizumab pegol, 400 mg, at weeks 0, 2, and 4. At week 6, the 428 of 668 patients with Crohn's disease (64%) who responded to therapy were assigned randomly to groups that were given maintenance therapy with certolizumab pegol 400 mg (n = 216) or placebo (n = 212) every 4 weeks through week 24. The primary end point was maintenance of clinical response at week 26 in a subgroup of patients with baseline CRP levels of 10 mg/L or higher (112 certolizumab pegol patients and 101 placebo patients). The clinical response rates at week 26 were 61.6% and 33.7% for certolizumab pegol and placebo, respectively (P < .001) in the CRP of 10 mg/L or greater group. In the overall intent-to-treat analysis, at week 26 the clinical response rates were 62.8% and 36.2% for certolizumab pegol and placebo, respectively (P < .001) A post hoc analysis of 278 (42%) patients with remission at week 6 showed that significantly more patients maintained remission throughout week 26 in the group given certolizumab pegol compared with placebo (61% vs 34%; P < .001). Although there are no comparative trials available for the 3 different anti-TNF agents, it seems that infliximab, adalimumab, and certolizumab pegol have comparable efficacy, especially for maintenance of remission. In patients naive to anti-TNF therapy, higher doses of these agents has not been shown to be more effective than the standard doses and only if there is loss of response may higher doses be needed to maintain response. Immunogenicity is more of a problem with infliximab than with the other drugs, but none should be administered