Preventing antibodies to infliximab in patients with Crohn's disease: Optimize not immunize
2003; Elsevier BV; Volume: 124; Issue: 4 Linguagem: Inglês
10.1053/gast.2003.50182
ISSN1528-0012
Autores Tópico(s)Inflammatory Bowel Disease
ResumoSee article on page 917. Infliximab, an immunoglobulin (Ig) G1 mouse/human chimeric monoclonal antibody to tumor necrosis factor (TNF), is a major advance in the treatment of rheumatoid arthritis (RA) and Crohn's disease. Infliximab was approved for the treatment of RA in 1999 based on a phase 2 and a phase 3 trial. In the phase 2 trial, infliximab was administered to patients with RA as 5 infusions at 0, 2, 6, 10, and 14 weeks at doses of 1, 3, or 10 mg/kg, with and without methotrexate.1Maini RN Breedveld FC Kalden JR Smolen JS Davis D Macfarlane JD Antoni C Leeb B Elliott MJ Woody JN Schaible TF Feldmann M. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.Arthritis Rheum. 1998; 41: 1552-1563Crossref PubMed Scopus (1595) Google Scholar The best clinical responses occurred with infliximab 3 or 10 mg/kg in combination with methotrexate. The immunogenicity of infliximab was assessed using an assay developed by the manufacturer (Centocor, Malvern, PA) that was initially called human anti-chimeric antibody (HACA) and more recently antibody to infliximab (ATI). The ATI assay performed by Centocor measures anti-idiotype antibodies to epitopes on the murine variable region of infliximab as well as anti-allotype antibodies to the human IgG1 constant region (although anti-allotype antibodies were not found when competitive inhibition with the addition of human IgG1 was performed); the ATI assay does not measure nonspecific antibodies that cross-react with other chimeric antibodies.1Maini RN Breedveld FC Kalden JR Smolen JS Davis D Macfarlane JD Antoni C Leeb B Elliott MJ Woody JN Schaible TF Feldmann M. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.Arthritis Rheum. 1998; 41: 1552-1563Crossref PubMed Scopus (1595) Google Scholar, 2LoBuglio AF Wheeler RH Trang J Haynes A Rogers K Harvey EB Sun L Ghrayeb J Khazaeli MB. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response.Proc Natl Acad Sci U S A. 1989; 86: 4220-4224Crossref PubMed Scopus (506) Google Scholar Infliximab interferes with the ATI assay, and thus the presence of ATI can only be determined in serum samples in which infliximab is not detectable. It may be reasonable to consider samples that are indeterminate for ATI as negative because if ATIs are present, they are present in small amounts relative to the infliximab that is present in excess. The frequency of ATI was 53%, 21%, and 7% in patients receiving monotherapy with infliximab at doses of 1, 3, and 10 mg/kg, respectively; compared with 15%, 7%, and 0% in patients receiving combination therapy with methotrexate and infliximab at doses of 1, 3, and 10 mg/kg. In the phase 3 trial, infliximab was administered to patients with RA in combination with methotrexate as 3 induction infusions at 0, 2, and 6 weeks at doses of 3 and 10 mg/kg followed by regularly scheduled maintenance infusions every 4 or 8 weeks at the same doses. The optimal dose interval was every 8 weeks, and the difference between the 3 and 10 mg/kg doses was small. Because regular treatment with infliximab precluded assay for ATI in most patients, only 60 of 428 patients could be assessed, of whom 5 (8%) were positive (if indeterminate samples counted as negative, then 5 of 428 [1%]). Thus, the indicated dosing regimen for infliximab in RA at the time of regulatory approval (three 3 mg/kg induction doses at 0, 2, and 6 weeks followed by long-term treatment with regularly scheduled 3 mg/kg maintenance doses every 8 weeks in combination with methotrexate) was optimized to achieve a low rate of immunogenicity. The story for Crohn's disease is quite different. Infliximab was approved for the treatment of Crohn's disease in 1998 based on a phase 2 trial and a small phase 3 trial. In the phase 2 trial, infliximab was administered as a single induction infusion at doses of 5, 10, or 20 mg/kg.3Targan SR Hanauer SB van Deventer SJ Mayer L Present DH Braakman T DeWoody KL Schaible TF Rutgeerts PJ. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.N Engl J Med. 1997; 337: 1029-1035Crossref PubMed Scopus (3054) Google Scholar The best clinical response occurred with infliximab 5 mg/kg. The patients enrolled in this study were not homogenous with respect to the use of baseline concomitant medications, which included mesalamine, corticosteroids, and azathioprine or 6-mercaptopurine. Nonresponding patients received an open label dose of infliximab 10 mg/kg at week 4,3Targan SR Hanauer SB van Deventer SJ Mayer L Present DH Braakman T DeWoody KL Schaible TF Rutgeerts PJ. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.N Engl J Med. 1997; 337: 1029-1035Crossref PubMed Scopus (3054) Google Scholar and then all responding patients were re-randomized at week 12 into a 36-week retreatment study of infliximab 10 mg/kg every 8 weeks.4Rutgeerts P D'Haens G Targan S Vasiliauskas E Hanauer SB Present DH Mayer L Van Hogezand RA Braakman T DeWoody KL Schaible TF Van Deventer SJ. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.Gastroenterology. 1999; 117: 761-769Abstract Full Text Full Text PDF PubMed Scopus (1060) Google Scholar Thus, not all patients received just a single dose of infliximab. Because regular treatment with infliximab precluded assay for ATI in most patients, at week 12 of the induction study, only 43 of 102 patients who had received infliximab could be assessed, of whom 6 (14%) were positive (if indeterminate samples counted as negative, then 6 of 102 [6%]).3Targan SR Hanauer SB van Deventer SJ Mayer L Present DH Braakman T DeWoody KL Schaible TF Rutgeerts PJ. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.N Engl J Med. 1997; 337: 1029-1035Crossref PubMed Scopus (3054) Google Scholar At week 36 of the retreatment study, only 47 of 73 patients who entered the retreatment study could be assessed for ATI, of whom 7 (15%) were positive (if indeterminate samples counted as negative, then 7 of 73 [10%]); 3 patients (6%) were positive at the beginning of the retreatment study and 4 patients (9%) became positive during the retreatment study (if indeterminate samples counted as negative, then 3 of 73 [4%] and 4 of 73 [5%], respectively).4Rutgeerts P D'Haens G Targan S Vasiliauskas E Hanauer SB Present DH Mayer L Van Hogezand RA Braakman T DeWoody KL Schaible TF Van Deventer SJ. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.Gastroenterology. 1999; 117: 761-769Abstract Full Text Full Text PDF PubMed Scopus (1060) Google Scholar Throughout these 2 sequential studies, 60 of 102 patients who had received infliximab could be assessed for ATI, of whom 10 (16%) were positive (if indeterminate samples counted as negative, then 10 of 102 [10%]). In the placebo-controlled phase 3 trial, infliximab was administered as 3 induction infusions at 0, 2, and 6 weeks at doses of 5 or 10 mg/kg.5Present DH Rutgeerts P Targan S Hanauer SB Mayer L van Hogezand RA Podolsky DK Sands BE Braakman T DeWoody KL Schaible TF van Deventer SJ. Infliximab for the treatment of fistulas in patients with Crohn's disease.N Engl J Med. 1999; 340: 1398-1405Crossref PubMed Scopus (2427) Google Scholar The best clinical response occurred with infliximab 5 mg/kg. The patients enrolled in this study were not homogenous with respect to the use of baseline concomitant medications, which included mesalamine, antibiotics, corticosteroids, and azathioprine or 6-mercaptopurine. At week 18, 50 of 63 patients who had received infliximab could be assessed for ATI, of whom 3 (6%) were positive (if indeterminate samples counted as negative, then 3 of 63 [5%]). Combining all pilot studies and phase 2 and phase 3 trials for Crohn's disease, 134 of 199 patients who had received infliximab could be assessed for ATI, of whom 18 (13%) were positive (if indeterminate samples counted as negative, then 18 of 199 [9%]). Ninety-nine of these 134 patients were concomitantly treated with azathioprine, 6-mercaptopurine, or steroids, of whom 10 (10%) developed ATIs.6Remicade Infliximab for IV Injection. Prescribing information. Thomson PDR, Montvale, NJ1998Google Scholar In contrast, 35 of 134 patients were not receiving azathioprine, 6-mercaptopurine, or steroids, of whom 8 (23%) developed ATIs. Taken together, these data indicate that an increased rate of immunogenicity may occur when infliximab is administered as a single dose (ATI rate was 16% in the Targan trial3Targan SR Hanauer SB van Deventer SJ Mayer L Present DH Braakman T DeWoody KL Schaible TF Rutgeerts PJ. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.N Engl J Med. 1997; 337: 1029-1035Crossref PubMed Scopus (3054) Google Scholar; this likely underestimated the immunogenic effect because some patients actually received more than 1 dose in the subsequent retreatment trial) or when patients are not concomitantly receiving immunosuppressive therapy with azathioprine, 6-mercaptopurine, or steroids (ATI rate, 23%). These data were not incorporated into the initial indicated dosing regimen for infliximab in Crohn's disease section of the package insert that was approved for marketing in the United States, but rather in a separate section of the package insert devoted to immunogenicity. The initial indications for infliximab were a single 5 mg/kg induction dose in patients with moderately to severely active Crohn's disease unresponsive to conventional therapy, and three 5 mg/kg induction doses at 0, 2, and 6 weeks in patients with actively draining perianal and abdominal enterocutaneous fistulas. A precise definition of “conventional therapy” was not possible because the patients enrolled in these studies were not homogenous with respect to the use of baseline concomitant medications, and therefore no specific guidance was provided in the dosing section of the package insert regarding the need for concomitant immunosuppressive therapy to prevent immunogenicity. Physicians were cautioned that the safety and efficacy of infliximab beyond a single dose in patients with active disease and 3 doses in patients with fistulizing had not been established. Based on these instructions, clinicians frequently administered single doses of infliximab as induction therapy to patients with Crohn's disease failing to respond to mesalamine or antibiotics, without uniformly coadministering an immunosuppressive, and insurance carriers frequently declined to provide reimbursement for more than 1 dose of infliximab. Thus, in contrast to the situation in RA in which a uniform infliximab dosing regimen at the time of approval was optimized to achieve a low level of immunogenicity, the infliximab dosing regimen for Crohn's disease was not uniform and therefore not optimized at the time of approval. Instead the indicated dosing regimens for Crohn's disease included the option of giving the most immunogenic regimen (administering a single dose of infliximab without concomitant immunosuppressive therapy), which in essence could “immunize” patients to infliximab. Three recently published studies can potentially shed additional light on the clinical consequences of using this nonoptimized dosing regimen in patients with Crohn's disease. The first study is a phase 4 randomized controlled trial called ACCENT 1.7Hanauer SB Feagan BG Lichtenstein GR Mayer LF Schreiber S Colombel JF Rachmilewitz D Wolf DC Olson A Bao W Rutgeerts P. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3596) Google Scholar Five hundred seventy-three patients with moderately to severely active Crohn's disease were administered a single induction dose of infliximab 5 mg/kg. Patients responding at week 2 were then randomized to placebo or 2 additional induction doses of 5 mg/kg at weeks 2 and 6 followed by regularly scheduled maintenance doses every 8 weeks with infliximab 5 or 10 mg/kg for 54 weeks. Patients who responded and then lost the response, as well as patients who failed to respond, were crossed over to a higher dose after week 14. Maintenance treatment with placebo, with crossover to infliximab in the event of relapse, is referred to as episodic treatment. The optimal clinical benefit occurred with regularly scheduled maintenance infliximab doses every 8 weeks, and the difference between the 5 and 10 mg/kg doses was small. The patients enrolled in this study were not homogenous with respect to the use of baseline concomitant medications that included mesalamine, antibiotics, corticosteroids, and immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate. At week 54, only 233 of 442 patients who had received infliximab and either responded or crossed over could be assessed for ATI, of whom 64 (27%) were positive (if indeterminate samples counted as negative, then 64 of 442 [14%]). The frequency of ATI was 38%, 11%, and 8%, respectively, in patients receiving episodic infliximab, 5 mg/kg, or 10 mg/kg without concomitant immunosuppressive therapy (azathioprine, 6-mercaptopurine, methotrexate). This is compared with 16%, 7%, and 4% in patients receiving combination therapy with episodic infliximab, 5 mg/kg, or 10 mg/kg and an immunosuppressive agent (indeterminate samples counted as negative) (Thomas Schaible, Centocor, Malvern, PA, personal communication). These data indicate on the one hand that episodic infliximab treatment without concomitant immunosuppressive is a more immunogenic regimen than regimens that include concomitant immunosuppressive therapy and/or 3-dose induction followed by regularly scheduled maintenance therapy. Of these 2 potential dose optimization strategies, 3-dose induction followed by regularly scheduled maintenance therapy appears to give an overall better result, and the absolute benefit of adding immunosuppressive to 5 mg/kg maintenance dosing was only 4% (ATI rates of 11% vs. 7%). The second study is a prospective observational study reported by Baert et al.8Baert F Norman M Vermeire S Van Assche G D'Haens G Carbonez A Rutgeerts P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.N Engl J Med. 2003; 348: 601-608Crossref PubMed Scopus (1855) Google Scholar One hundred twenty-five patients with refractory luminal or fistulizing Crohn's disease were administered infliximab according to the approved indication as either a single 5 mg/kg induction dose (luminal disease) or three 5 mg/kg induction doses at 0, 2, and 6 weeks (fistulizing disease). If a patient had a response, then therapy was repeated on relapse of disease. None of the patients received regularly scheduled maintenance therapy as was used in the ACCENT 1 trial. The immunogenicity of infliximab was assessed using an assay developed by Prometheus Laboratories (San Diego, CA) that is referred to commercially as human anti-chimeric antibody (HACA), in the studies by Baert et al.8Baert F Norman M Vermeire S Van Assche G D'Haens G Carbonez A Rutgeerts P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease.N Engl J Med. 2003; 348: 601-608Crossref PubMed Scopus (1855) Google Scholar and Farrell et al.9Farrell RJ Alsahli M Jeen YTJ Falchuk KR Peppercorn MA Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial.Gastroenterology. 2003; 124: 917-924Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar as antibodies to infliximab, and subsequently in this article as ATI. It is not reported whether the ATI assay performed by Prometheus Laboratories measures anti-idiotype antibodies to epitopes on the murine variable region of infliximab, anti-allotype antibodies to the human IgG1 constant region, nonspecific antibodies that cross-react with other chimeric antibodies, or some combination of the above; infliximab interferes with the Prometheus ATI assay, and thus the presence of ATI can only be determined in serum samples in which infliximab is not detectable. No studies comparing the assay characteristics of the Centocor and Prometheus ATI assays have been reported. Over a 10-month period, a mean of 3.9 infliximab infusions per patient were administered. The patients in this study were not homogenous with respect to the use of baseline concomitant medications that included mesalamine, corticosteroids, and immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate. Antibodies against infliximab were detected in 61% of patients. The presence of ATI concentrations of 8.0 μg/mL or greater before an infusion (37% of all patients) predicted a shorter duration of response (35 days, as compared with 71 days among patients with ATI concentrations of less than 8.0 μg/mL) and a higher risk of infusion reactions (relative risk, 2.4). Concomitant immunosuppressive therapy was predictive of a lower frequency of ATI (42%) compared with patients not receiving immunosuppressives (75%). Three-dose induction therapy (without subsequent regularly scheduled maintenance therapy) was not protective against ATI formation. These data show that episodic infliximab treatment without concomitant immunosuppressive is an immunogenic regimen, and that concomitant immunosuppressive therapy significantly reduces the immunogenicity of infliximab. The third study is a prospective observational study reported by Farrell et al. in this issue of Gastroenterology.9Farrell RJ Alsahli M Jeen YTJ Falchuk KR Peppercorn MA Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial.Gastroenterology. 2003; 124: 917-924Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar Fifty-three patients with Crohn's disease were administered infliximab either as a single 5 mg/kg induction dose (luminal disease) or three 5 mg/kg induction doses at 0, 2, and 6 weeks (fistulizing disease). Patients with luminal disease who did not respond to the first infusion had a second infusion. Patients who relapsed were retreated on demand. None of the patients received regularly scheduled maintenance therapy as was used in the ACCENT 1 trial. The immunogenicity of infliximab was assessed using the ATI assay developed by Prometheus Laboratories (San Diego, CA) as described above. The patients in this study were not homogenous with respect to the use of baseline concomitant medications that included mesalamine, corticosteroids, and immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate. Thirty-six of 53 (68%) of patients initially responded to infliximab, of whom 15 of 36 (43%) subsequently lost the ability to respond to a 5 mg/kg infliximab dose. Antibodies against infliximab were detected in 19 of 53 (36%) patients during follow-up in whom the frequency of ATI was 0 of 21 (0%) in patients who continuously responded to infliximab and 11 of 15 (73%) in patients who responded and then lost the response. Seven of 53 patients experienced serious infusion reactions (defined as infusion reactions that required infliximab to be discontinued), of whom 7 of 7 (100%) were positive for ATI. Concomitant immunosuppressive therapy was predictive of a lower frequency of ATI (24%) compared with patients not receiving immunosuppressives (63%). Two- or 3-dose induction was independently protective for reducing the frequency of ATI formation. These data show that episodic infliximab treatment without concomitant immunosuppressive therapy is an immunogenic regimen, and that both concomitant immunosuppressive therapy and multi-dose induction therapy significantly reduce the immunogenicity of infliximab. Based on these observations, Farrell and colleagues then randomized 80 consecutive patients beginning infliximab to premedication with 200 mg intravenous hydrocortisone or placebo before each infliximab infusion. Patients were followed for the presence and concentration of ATI. At 16 weeks, 26% of hydrocortisone-treated patients were ATI positive compared with 42% of placebo patients (P = 0.06). Mean ATI concentrations at weeks 8 and 16 were 2.9 and 1.6 μg/mL in hydrocortisone-treated patients compared with 11.2 and 3.4 μg/mL in placebo patients (P = 0.002 at week 8 and P = 0.02 at week 16). It is clear from all of the studies reviewed above that administration of a single induction dose of infliximab 5 mg/kg without concomitant immunosuppressive therapy is an immunogenic regimen that frequently leads to the formation of ATIs, and that the presence of high concentrations of ATIs leads to adverse patient outcomes in the form of shortened duration of benefit or complete loss of response and infusion reactions. Thus, gastroenterologists should stop administering a single dose of infliximab to patients with Crohn's disease who are not receiving immunosuppressive therapy, because this dose regimen could immunize patients to infliximab. Instead, in the absence of data from randomized controlled trials to establish the optimal infliximab dosing regimen for minimizing ATI formation in patients with Crohn's disease, practitioners should use the best available evidence to create a dose optimization strategy for each patient that they treat, thereby attempting to reduce the risk of future loss of response and infusion reactions. One optimization strategy is immunosuppressive treatment for a clinically relevant period of time with azathioprine or 6-mercaptopurine (2-3 months) or methotrexate (1.5-2 months) prior to initiating infliximab and subsequent long-term continuation of the same immunosuppressive agent as concomitant therapy with infliximab. Although this approach is clearly protective against ATI formation, it may lead to greater rates of serious and opportunistic infections.10Colombel JF Loftus Jr, EV Tremaine WJ Egan LJ Harmsen WS Schleck CD Zinsmeister AR Sandborn WJ. The safety profile of infliximab for Crohn's disease in clinical practice: the Mayo Clinic experience in 500 patients.Gastroenterology. 2003; (abstr) (in press)Google Scholar Another optimization strategy is the use of 3-dose induction therapy at 0, 2, and 6 weeks followed by systematic (every 8 weeks) maintenance therapy. This strategy is attractive because it protects against ATI formation, it may not require concomitant immunosuppressive therapy, and it provides superior control of disease activity (superior short-term response and induction of remission rates, and lower relapse rates over 1 year4Rutgeerts P D'Haens G Targan S Vasiliauskas E Hanauer SB Present DH Mayer L Van Hogezand RA Braakman T DeWoody KL Schaible TF Van Deventer SJ. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease.Gastroenterology. 1999; 117: 761-769Abstract Full Text Full Text PDF PubMed Scopus (1060) Google Scholar, 7Hanauer SB Feagan BG Lichtenstein GR Mayer LF Schreiber S Colombel JF Rachmilewitz D Wolf DC Olson A Bao W Rutgeerts P. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3596) Google Scholar, 11Sands B Van Deventer S Bernstein C Kamm M Rachmilewicz D Chey W Lashner B Wolf D Blank M Wild G Fedorak R Feagan B Anderson F Marsters P Rutgeerts P. Long-term treatment of fistulizing Crohn's disease: response to infliximab in the ACCENT II trial through 54 weeks.Gastroenterology. 2002; 122 (abstr): A81Google Scholar). A final optimization strategy is to pretreat patients with 200 mg intravenous hydrocortisone before infusing infliximab. It is unclear from the available data whether this strategy is sufficiently protective against ATI formation to serve as the only dose optimization strategy. These infliximab dose optimization strategies, which are based on best available evidence from observational studies, are an interim solution. Ultimately, a randomized controlled trial is needed to compare the safety and efficacy of monotherapy with infliximab (3-dose induction followed by systematic maintenance) to combination therapy with azathioprine or methotrexate and infliximab in patients not currently treated with an immunosuppressive who require infliximab. Another randomized controlled trial is needed to compare the safety and efficacy of azathioprine withdrawal and monotherapy with infliximab (3-dose induction followed by systematic maintenance) to combination therapy with continued azathioprine and infliximab in azathioprine-treated patients who require infliximab. A theoretical alternative to dose regimen optimization of infliximab is to switch to another humanized or fully human therapeutic molecule that may be less immunogenic. Candidate agents include: etanercept (fully human p75 soluble tumor necrosis factor receptor: FC fusion protein12Sandborn WJ Hanauer SB Katz S Safdi M Wolf DG Baerg RD Tremaine WJ Johnson T Diehl NN Zinsmeister AR. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial.Gastroenterology. 2001; 121: 1088-1094Abstract Full Text Full Text PDF PubMed Scopus (817) Google Scholar); CDP571 (IgG4 monoclonal antibody to TNF13Sandborn WJ Feagan BG Hanauer SB Present DH Sutherland LR Kamm MA Wolf DC Baker JP Hawkey C Archambault A Bernstein CN Novak C Heath PK Targan SR. An engineered human antibody to TNF (CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial.Gastroenterology. 2001; 120: 1330-1338Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar); CDP870 (pegylated humanized FAB fragment to TNF14Schreiber S Rutgeerts P Fedorak R Khaliq-Kareemi M Kamm MA Patel J the CDP870 Crohn's Disease Study Group CDP870, a humanized anti-TNF antibody fragment, induces clinical response with remission in patients with active Crohn's disease (CD).Gastroenterology. 2003; (abstr) (in press)Google Scholar); onercept (recombinant fully human soluble p55 tumor necrosis factor receptor that binds TNF15Rutgeerts P Lemmens L Van Assche G Noman M Borghini-Fuhrer I Goedkoop R. Treatment of active Crohn's disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomized, open-label, pilot study.Aliment Pharmacol Ther. 2003; 17: 185-192Crossref PubMed Scopus (112) Google Scholar; adalimumab (D2E7) (fully human IgG1 monoclonal antibody to TNF16den Broeder A van de Putte L Rau R Schattenkirchner M Van Riel P Sander O Binder C Fenner H Bankmann Y Velagapudi R Kempeni J Kupper H. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis.J Rheumatol. 2002; 29: 2288-2298PubMed Google Scholar); and natalizumab (humanized IgG4 monoclonal antibody to α4 integrin17Ghosh S Goldin E Gordon FH Malchow HA Rask-Madsen J Rutgeerts P Vyhnalek P Zadorova Z Palmer T Donoghue S. Natalizumab for active Crohn's disease.N Engl J Med. 2003; 348: 24-32Crossref PubMed Scopus (768) Google Scholar). However, the safety and efficacy of each of these agents for the treatment of Crohn's disease remains to be fully clarified (2 of the agents, etanercept and CDP571, were not effective for this indication12Sandborn WJ Hanauer SB Katz S Safdi M Wolf DG Baerg RD Tremaine WJ Johnson T Diehl NN Zinsmeister AR. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial.Gastroenterology. 2001; 121: 1088-1094Abstract Full Text Full Text PDF PubMed Scopus (817) Google Scholar, 18Sandborn W Feagan B Radford-Smith G Kovacs A Enns R Patel J. A randomized, placebo-controlled trial of CDP571, a humanized monoclonal antibody to TNF-α, in patients with moderate to severe Crohn's disease.Gastroenterology. 2003; (abstr) (in press)Google Scholar). Furthermore, it is doubtful that any biologic therapies are completely without immunogenicity, but some may be relatively more or less immunogenic than others. Thus, in the future, we will be considering the relative safety, efficacy, and immunogenicity of various biologic therapies in the context of specific treatment regimens. In the mean time, gastroenterologists should once again follow the path of rheumatologists and “optimize not immunize” when they treat patients with infliximab.
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