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Episodic retreatment versus scheduled maintenance therapy of Crohn’s disease with infliximab: Not so far apart

2004; Elsevier BV; Volume: 126; Issue: 2 Linguagem: Inglês

10.1053/j.gastro.2003.12.019

1528-0012

R. Balfour Sartor,

Autoimmune and Inflammatory Disorders

Infliximab, the first Food and Drug Administration (FDA)-approved biologic therapy for Crohn’s disease, has substantially improved management of this idiopathic disorder by providing an alternative means to induce remission of active disease, including many patients unresponsive to corticosteroids, 5-ASA compounds, or antibiotics. Multicenter randomized, placebo-controlled clinical trials have documented improvement in 65% and remission in 35% of patients with active luminal Crohn’s disease who received a single infusion of infliximab1Targan S.R. Hanauer S.B. van Deventer S.J. Mayer L. Present D.H. Braakman T. DeWoody K.L. Schaible T.F. Rutgeerts P.J. 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 (3048) Google Scholar and improvement in 68% and at least transient closure in 55% of patients with fistulae.2Present D.H. Rutgeerts P. Targan S. Hanauer S.B. Mayer L. Van Hogezand R.A. Podolsky D.K. Sands B.E. Braakman T. DeWoody K.L. Schaible T.F. van Deventer S.J. Infliximab for the treatment of fistulas in patients with Crohn’s disease.N Engl J Med. 1999; 340: 1398-1405Crossref PubMed Scopus (2421) Google Scholar However, only a minority of patients maintains the clinical improvement achieved by a single infliximab infusion without concomitant immunosuppressive therapy, leading to continued infusions in some patients. Considerable uncertainty exists regarding choice of maintenance strategies in patients with recurrent disease and whether to use a single versus a series of 3 infliximab treatments as inductive therapy for nonfistulizing luminal disease. A recent large multicenter trial (ACCENT 1) was designed to address the use of regularly scheduled infusions of infliximab (5 mg/kg or 10 mg/kg) every 8 weeks for 1 year versus placebo.3Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. 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 (3580) Google Scholar However, this otherwise well performed but complex study was complicated by 2 different inductive regimens (i.e., a single 5-mg/kg infusion in the group subsequently receiving placebo versus a series of 3 infusions of 5 mg/kg infliximab at 0, 2, and 6 weeks in those patients receiving scheduled maintenance with 2 doses of infliximab) and by randomizing only those patients who responded to the first infliximab infusion by 2 weeks.Thus, publication of a derivative study of the ACCENT 1 trial by Rutgeerts et al.4Rutgeerts P. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. Olson A. Bao W. Hanauer S. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar in this issue of Gastroenterology fills some information gaps and provides data more directly applicable to clinical practice. This report describes the outcome of all patients who received the initial infliximab treatment in the ACCENT 1 study (rapid responders, delayed responders and nonresponders) and includes both regularly scheduled (every 8 weeks) maintenance and episodic (after relapse of symptoms) infusion protocols used in practice. In this complicated study design, 573 patients initially infused with a single 5-mg/kg infusion of infliximab were stratified by response status at 2 weeks and then randomized to receive either 5 mg/kg infliximab at 2 and 6 weeks, and then either 5 mg/kg or 10 mg/kg infliximab infusions every 8 weeks for 46 weeks (8 infusions), or placebo on the same schedule. In addition, patients who lost efficacy after a response at any time to infliximab were eligible to receive “rescue” therapy with either 5 mg/kg for patients in the placebo group, 10 mg/kg for those failing 5 mg/kg scheduled infliximab infusions, or 15 mg/kg for patients breaking through 10 mg/kg scheduled infusions. These “rescue” infliximab treatments for loss of response were administered every 8 weeks, and subjects remained in their original group for analysis. These 3 groups were designated episodic, 5-mg/kg scheduled, and 10-mg/kg scheduled treatment strategies. With the important exceptions that patients were not allowed access to “rescue” therapy until week 14 of the trial and the interval between infusions was fixed at 8 weeks, this study design more closely replicates clinical treatment strategies of “on-demand” versus regularly scheduled infliximab treatments. However, an important confounding variable is that the episodic group had only 1 inductive treatment versus 3 infusions for the scheduled treatment groups.One should consider efficacy, toxicity, cost, and compliance (adherence) when comparing various treatment options. The authors stress the clinical superiority of the combined scheduled treatment groups (combining both 5 mg/kg and 10 mg/kg doses) over the episodic strategy, with significant advantages in remission and response rates, quality of life, mucosal healing, Crohn’s disease-related hospitalizations, and intra-abdominal surgery. However, regularly scheduled administration of the FDA-approved dose of 5 mg/kg infliximab was significantly better than episodic infusion in only 2 of these parameters (hospitalization, 23% vs. 38%; P = 0.047; intra-abdominal surgeries, 3% vs. 7%; P = 0.04). Moreover, even the 10 mg/kg scheduled infusion dose was significantly better than the episodic group at only 2 of the 8 evaluated time points after 2 weeks of remission (Crohn’s Disease Activity Index [CDAI] < 150) and at 3 time points for clinical response (≥ 70-point CDAI decrease) despite approximately 200 patients per group, which should provide adequate power to detect clinically significant results in each group independently. Remission and response are the most widely accepted outcome measurements for Crohn’s disease clinical trials.5Sandborn W.J. Targan S.R. Biologic therapy of inflammatory bowel disease.Gastroenterology. 2002; 122: 1592-1608Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Finally, only a minority of patients (44%) in the 5-mg/kg regularly scheduled group completed the study as designed; 26% discontinued treatment without crossover and 30% were crossed over to 10 mg/kg “rescue” therapy. Therefore, an alternative interpretation of these results is that on-demand retreatment with 5 mg/kg after a single inductive infusion of infliximab is comparable to the more expensive strategy of 3 inductive infusions followed by scheduled treatments every 8 weeks.Toxicity was similar between groups and was identical to that previously reported for the parent ACCENT 1 study.3Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. 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 (3580) Google Scholar Serious infections occurred in 3%–4% of all groups. The single tuberculosis case occurred in a woman in the 10 mg/kg maintenance group 4 weeks after she received her first 15 mg/kg (rescue dose). Similarly, the 6 malignancies (1% overall) were randomly distributed between treatment groups. Although not mentioned in this report, 3 deaths occurred, 1 of which (sepsis in the 5 mg/kg maintenance group), may have been in response to infliximab. Although relatively rare, mortality is an outcome that must be considered in light of the report of a 1% mortality rate attributed to infliximab in a recent retrospective analysis of 500 patients treated with this agent at the Mayo Clinic.6Colombel J.F. Loftus Jr, E.V. Tremaine W.J. Egan L.J. Harmsen W.S. Schleck C. Zinsmeister A.R. Sandborn W.J. The safety profile of infliximab in patients with Crohn’s disease the Mayo Clinic experience in 500 patients.Gastroenterology. 2004; 126: 19-31Abstract Full Text Full Text PDF PubMed Scopus (837) Google Scholar Antinuclear antibodies (ANA) and antibodies to double stranded DNA (dsDNA) were most frequent in the combined scheduled treatment groups (56% ANA and 34% dsDNA vs. 35% ANA and 11% dsDNA in the episodic group), although only 1 patient (in the 10 mg/kg scheduled treatment group) had a clinically apparent lupus syndrome that responded to corticosteroid therapy. These data are consistent with a report from an independent, intermittently treated patient population in Belgium that had 57% positive ANA and 11% dsDNA antibody rates.7Vermeire S. Noman M. Van Assche G. Baert F. Van Steen K. Esters N. Joossens S. Bossuyt X. Rutgeerts P. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn’s disease a prospective cohort study.Gastroenterology. 2003; 125: 32-39Abstract Full Text Full Text PDF PubMed Scopus (309) Google ScholarDecreased production of antibodies to infliximab has been proposed as a reason to initially treat patients with a series of 3 infusions rather than a single treatment and to treat regularly rather than episodically. Unfortunately, this study does not provide results of anti-infliximab antibody tests at 72 weeks, as described in the methods, but merely refers the reader to the previously published results of the ACCENT 1 study that measured antibodies at 0, 14, 22, and 54 weeks.3Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. 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 (3580) Google Scholar Although anti-infliximab antibodies in 24% of the episodic treatment group versus 9% in the 5 mg/kg group and 6% in the 10 mg/kg scheduled infusion groups appear to support this claim, 46% of the study population had inconclusive results because of detectible serum infliximab, which prevents detection of antibodies because of in vivo complexing with antibodies. Thus, these results almost certainly understate the true incidence of antibodies to infliximab, which can be only measured after circulating infliximab has cleared. In an independent cohort, 61% of patients receiving multiple infliximab infusions developed antibodies to infliximab.8Baert F. Noman 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 (1844) Google Scholar The risk of developing antibodies was higher in patients with fistulizing disease who received 3 initial infusions of infliximab compared with those receiving a single initial infusion for luminal disease (2.4 vs. 2.85 relative risk).8Baert F. Noman 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 (1844) Google Scholar In the current ACCENT 1 study, infusion reactions were more frequent in the regularly scheduled groups, being highest (23%; 2% serious) in the 5-mg/kg scheduled group and lowest (9%; 0.5% serious) in the episodically treated group, further supporting the contention that the frequency of antibodies to infliximab were understated and that 3 initial infusions followed by regularly scheduled infusions does not prevent anti-infliximab antibodies. Although it is true that the number of infusions was higher in the regularly scheduled group, infusion reactions complicated 6% of each regularly scheduled 5 mg/kg infusion versus 3% of each episodic infusion. Two recent studies unequivocally correlate infusion reactions with the presence of antibodies to infliximab.8Baert F. Noman 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 (1844) Google Scholar, 9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 Likewise, serum sickness-like reactions, which are associated with high anti-infliximab antibody titers,10Sandborn W.J. Hanauer S.B. Infliximab in the treatment of Crohn’s disease a user’s guide for clinicians.Am J Gastroenterol. 2002; 97: 2962-2972Crossref PubMed Google Scholar were equal in all groups (2% episodic vs. 3% of scheduled groups). Finally, loss of efficacy, also associated with antibodies to infliximab,9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 did not appear to be different in each group, because discontinuation of treatment because of lack of efficacy was 17% in the episodic group and 16% in the 5-mg/kg scheduled group. It is likely that a substantial portion of the 58 of 192 patients in the 5-mg/kg scheduled group and the 51 of 193 patients in the 10-mg/kg group who were crossed over to higher-dose rescue treatment after not maintaining their initial response had antibodies to infliximab. Farrell et al.9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 found antibodies in 71% of patients who lost response to infliximab treatment versus 0% of those with good long-term responses. The increased frequency of infusion reactions in patients receiving increased doses of infliximab in the crossover group (8% episodic, 10% scheduled) supports the presence of antibodies leading to loss of efficacy. Unfortunately, only 27%–35% of patients in the present study by Rutgeerts et al. were taking concomitant immunosuppressive agents, such as 6 mercaptopurine, azathioprine, or methotrexate, that inhibit anti-infliximab antibody formation.8Baert F. Noman 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 (1844) Google Scholar, 9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 ScholarCosts must be considered when planning a treatment approach. The ACCENT 1 protocol of 8 scheduled infliximab infusions with 5 mg/kg (the FDA-approved dose), consisting of 3 initial infusions and maintenance every 8 weeks through 46 weeks, costs an 80-kg individual $45,944, based on a representative charge of 2 times average wholesale pharmacy costs for infliximab plus $175 infusion fees. Because 30% (58 of 192) of the patients in the 5 mg/kg scheduled group required an increased dose (10 mg/kg) to maintain clinical response, the average yearly costs would be higher. Representative costs per 10 mg/kg infusion are $11,311 per infusion for a 70-kg patient. Obviously, the costs for patients receiving the most effective schedule protocol, 10 mg/kg with rescue by 15 mg/kg, are 2–3 times baseline 5 mg/kg expenses. Although the authors correctly point out that increased hospitalization rates and loss of work must be factored into a cost analysis, the 1992 cost modeling exercise quoted by the authors used a baseline drug cost far lower than that of infliximab treatment.11Hay J.W. Hay A.R. Inflammatory bowel disease costs-of-illness.J Clin Gastroenterol. 1992; 14: 309-317Crossref PubMed Scopus (214) Google Scholar Each care provider must decide if the statistically nonsignificant improvement in remission and response rates and decreased hospitalization rates of 23% versus 38% justifies the extra expense of administering 8 scheduled infliximab infusions versus a mean of 2.2 treatments in the on-demand protocol.Despite its complicated experimental design and relatively large number of patients, this study did not compare outcome data on patients on immunosuppressant drugs versus those not on 6-mercaptopurine (6MP), azathioprine, or methotrexate. Between 27% and 35% of patients in the various groups received concomitant 6MP, azathioprine, or methotrexate. Unfortunately, this study and most inflammatory bowel disease trials prohibit addition of new immunosuppressive agents within 3 months of study initiation, avoid changing doses during the trial, and include only those patients who have failed doses of immunosuppressant therapy used for the duration of the study. Whether the addition or dose optimization of 6MP, azathioprine, and methotrexate at the time of initial infliximab injection will sustain responses is a key question because this approach would be the most cost-effective strategy for using infliximab, if effective. Immunosuppressive agents reproducibly decrease the rate of anti-infliximab antibodies, in theory prolonging efficacy and minimizing infusion reactions.3Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. 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 (3580) Google Scholar, 8Baert F. Noman 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 (1844) Google Scholar, 9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 Previous studies and extensive clinical experience have shown that approximately two thirds of patients with Crohn’s disease beginning 6MP or azathioprine12Present D.H. Korelitz B.I. Wisch N. Glass J.L. Sachar D.B. Pasternack B.S. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study.N Engl J Med. 1980; 302: 981-987Crossref PubMed Scopus (972) Google Scholar or 39% of those beginning methotrexate13Feagan B.G. Rochon J. Fedorak R.N. Irvine E.J. Wild G. Sutherland L. Steinhart A.H. Greenberg G.R. Gillies R. Hopkins M. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators.N Engl J Med. 1995; 332: 292-297Crossref PubMed Scopus (870) Google Scholar will clinically respond. It is likely that similar response rates will occur after induction of remission or initial improvement by using infliximab after the initiation of immunosuppressants in patients not previously treated with these agents.In summary, the study by Rutgeerts et al.4Rutgeerts P. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. Olson A. Bao W. Hanauer S. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar provides important clinically relevant data comparing episodic use of infliximab on an as-needed basis versus regularly scheduled infliximab maintenance therapy. Although the experimental design does not answer all questions regarding this issue, it provides physicians with enough information to help them decide whether the slightly increased efficacy of the regularly scheduled maintenance approach justifies the substantially increased expense of this strategy. Toxicity is not substantially enhanced and infusion reactions are not decreased by regularly scheduled infusions. The majority of patients who lose response to repeated doses of infliximab can at least be temporarily “rescued” by escalating the dose, although the duration of improved response is not clear. However, only a minority of patients in each group remained in remission for 1 year when treated with 1 of the 3 randomized strategies, although approximately two thirds of patients in all groups maintained a clinical response if allowed to escalate infliximab dose when responses waned. During this trial, 49% of single dose infliximab, 30% of 5-mg/kg scheduled, and 26% of 10 mg/kg scheduled patients escalated their dose because of decreased efficacy. A substantial number of patients eventually failed treatment with higher doses of infliximab; 37% (34 of 92) episodically treated, 38% (22 of 58) 5 mg/kg scheduled patients who eventually received 10 mg/kg, and 31% (18 of 57) patients in the 10 mg/kg scheduled group who were crossed over to the 15 mg/kg infusions every 8 weeks eventually dropped out of the study for various reasons. The investigative community needs to determine whether institution of 6MP, azathioprine, or methotrexate begun at the time of initial infliximab infusion will provide an equally efficacious and more cost-effective approach to maintaining remission after induction with infliximab. In lieu of these data, this study shows that either episodic or scheduled maintenance therapy can be performed with escalation of doses if necessary. The decision to use either strategy must be based on careful consideration of efficacy, associated costs, and demonstrated toxicities, including rare mortality. In my view, a patient with luminal Crohn’s disease who requires infliximab treatment and who is not yet on immunosuppressant drugs should be induced with a single infliximab infusion after beginning maintenance 6MP, azathioprine, or methotrexate, thereby reserving regularly scheduled infliximab infusions for those patients failing optimal immunosuppressant maintenance treatment. Infliximab, the first Food and Drug Administration (FDA)-approved biologic therapy for Crohn’s disease, has substantially improved management of this idiopathic disorder by providing an alternative means to induce remission of active disease, including many patients unresponsive to corticosteroids, 5-ASA compounds, or antibiotics. Multicenter randomized, placebo-controlled clinical trials have documented improvement in 65% and remission in 35% of patients with active luminal Crohn’s disease who received a single infusion of infliximab1Targan S.R. Hanauer S.B. van Deventer S.J. Mayer L. Present D.H. Braakman T. DeWoody K.L. Schaible T.F. Rutgeerts P.J. 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 (3048) Google Scholar and improvement in 68% and at least transient closure in 55% of patients with fistulae.2Present D.H. Rutgeerts P. Targan S. Hanauer S.B. Mayer L. Van Hogezand R.A. Podolsky D.K. Sands B.E. Braakman T. DeWoody K.L. Schaible T.F. van Deventer S.J. Infliximab for the treatment of fistulas in patients with Crohn’s disease.N Engl J Med. 1999; 340: 1398-1405Crossref PubMed Scopus (2421) Google Scholar However, only a minority of patients maintains the clinical improvement achieved by a single infliximab infusion without concomitant immunosuppressive therapy, leading to continued infusions in some patients. Considerable uncertainty exists regarding choice of maintenance strategies in patients with recurrent disease and whether to use a single versus a series of 3 infliximab treatments as inductive therapy for nonfistulizing luminal disease. A recent large multicenter trial (ACCENT 1) was designed to address the use of regularly scheduled infusions of infliximab (5 mg/kg or 10 mg/kg) every 8 weeks for 1 year versus placebo.3Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. 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 (3580) Google Scholar However, this otherwise well performed but complex study was complicated by 2 different inductive regimens (i.e., a single 5-mg/kg infusion in the group subsequently receiving placebo versus a series of 3 infusions of 5 mg/kg infliximab at 0, 2, and 6 weeks in those patients receiving scheduled maintenance with 2 doses of infliximab) and by randomizing only those patients who responded to the first infliximab infusion by 2 weeks. Thus, publication of a derivative study of the ACCENT 1 trial by Rutgeerts et al.4Rutgeerts P. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. Olson A. Bao W. Hanauer S. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar in this issue of Gastroenterology fills some information gaps and provides data more directly applicable to clinical practice. This report describes the outcome of all patients who received the initial infliximab treatment in the ACCENT 1 study (rapid responders, delayed responders and nonresponders) and includes both regularly scheduled (every 8 weeks) maintenance and episodic (after relapse of symptoms) infusion protocols used in practice. In this complicated study design, 573 patients initially infused with a single 5-mg/kg infusion of infliximab were stratified by response status at 2 weeks and then randomized to receive either 5 mg/kg infliximab at 2 and 6 weeks, and then either 5 mg/kg or 10 mg/kg infliximab infusions every 8 weeks for 46 weeks (8 infusions), or placebo on the same schedule. In addition, patients who lost efficacy after a response at any time to infliximab were eligible to receive “rescue” therapy with either 5 mg/kg for patients in the placebo group, 10 mg/kg for those failing 5 mg/kg scheduled infliximab infusions, or 15 mg/kg for patients breaking through 10 mg/kg scheduled infusions. These “rescue” infliximab treatments for loss of response were administered every 8 weeks, and subjects remained in their original group for analysis. These 3 groups were designated episodic, 5-mg/kg scheduled, and 10-mg/kg scheduled treatment strategies. With the important exceptions that patients were not allowed access to “rescue” therapy until week 14 of the trial and the interval between infusions was fixed at 8 weeks, this study design more closely replicates clinical treatment strategies of “on-demand” versus regularly scheduled infliximab treatments. However, an important confounding variable is that the episodic group had only 1 inductive treatment versus 3 infusions for the scheduled treatment groups. One should consider efficacy, toxicity, cost, and compliance (adherence) when comparing various treatment options. The authors stress the clinical superiority of the combined scheduled treatment groups (combining both 5 mg/kg and 10 mg/kg doses) over the episodic strategy, with significant advantages in remission and response rates, quality of life, mucosal healing, Crohn’s disease-related hospitalizations, and intra-abdominal surgery. However, regularly scheduled administration of the FDA-approved dose of 5 mg/kg infliximab was significantly better than episodic infusion in only 2 of these parameters (hospitalization, 23% vs. 38%; P = 0.047; intra-abdominal surgeries, 3% vs. 7%; P = 0.04). Moreover, even the 10 mg/kg scheduled infusion dose was significantly better than the episodic group at only 2 of the 8 evaluated time points after 2 weeks of remission (Crohn’s Disease Activity Index [CDAI] < 150) and at 3 time points for clinical response (≥ 70-point CDAI decrease) despite approximately 200 patients per group, which should provide adequate power to detect clinically significant results in each group independently. Remission and response are the most widely accepted outcome measurements for Crohn’s disease clinical trials.5Sandborn W.J. Targan S.R. Biologic therapy of inflammatory bowel disease.Gastroenterology. 2002; 122: 1592-1608Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Finally, only a minority of patients (44%) in the 5-mg/kg regularly scheduled group completed the study as designed; 26% discontinued treatment without crossover and 30% were crossed over to 10 mg/kg “rescue” therapy. Therefore, an alternative interpretation of these results is that on-demand retreatment with 5 mg/kg after a single inductive infusion of infliximab is comparable to the more expensive strategy of 3 inductive infusions followed by scheduled treatments every 8 weeks. Toxicity was similar between groups and was identical to that previously reported for the parent ACCENT 1 study.3Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. 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 (3580) Google Scholar Serious infections occurred in 3%–4% of all groups. The single tuberculosis case occurred in a woman in the 10 mg/kg maintenance group 4 weeks after she received her first 15 mg/kg (rescue dose). Similarly, the 6 malignancies (1% overall) were randomly distributed between treatment groups. Although not mentioned in this report, 3 deaths occurred, 1 of which (sepsis in the 5 mg/kg maintenance group), may have been in response to infliximab. Although relatively rare, mortality is an outcome that must be considered in light of the report of a 1% mortality rate attributed to infliximab in a recent retrospective analysis of 500 patients treated with this agent at the Mayo Clinic.6Colombel J.F. Loftus Jr, E.V. Tremaine W.J. Egan L.J. Harmsen W.S. Schleck C. Zinsmeister A.R. Sandborn W.J. The safety profile of infliximab in patients with Crohn’s disease the Mayo Clinic experience in 500 patients.Gastroenterology. 2004; 126: 19-31Abstract Full Text Full Text PDF PubMed Scopus (837) Google Scholar Antinuclear antibodies (ANA) and antibodies to double stranded DNA (dsDNA) were most frequent in the combined scheduled treatment groups (56% ANA and 34% dsDNA vs. 35% ANA and 11% dsDNA in the episodic group), although only 1 patient (in the 10 mg/kg scheduled treatment group) had a clinically apparent lupus syndrome that responded to corticosteroid therapy. These data are consistent with a report from an independent, intermittently treated patient population in Belgium that had 57% positive ANA and 11% dsDNA antibody rates.7Vermeire S. Noman M. Van Assche G. Baert F. Van Steen K. Esters N. Joossens S. Bossuyt X. Rutgeerts P. Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn’s disease a prospective cohort study.Gastroenterology. 2003; 125: 32-39Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar Decreased production of antibodies to infliximab has been proposed as a reason to initially treat patients with a series of 3 infusions rather than a single treatment and to treat regularly rather than episodically. Unfortunately, this study does not provide results of anti-infliximab antibody tests at 72 weeks, as described in the methods, but merely refers the reader to the previously published results of the ACCENT 1 study that measured antibodies at 0, 14, 22, and 54 weeks.3Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. 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 (3580) Google Scholar Although anti-infliximab antibodies in 24% of the episodic treatment group versus 9% in the 5 mg/kg group and 6% in the 10 mg/kg scheduled infusion groups appear to support this claim, 46% of the study population had inconclusive results because of detectible serum infliximab, which prevents detection of antibodies because of in vivo complexing with antibodies. Thus, these results almost certainly understate the true incidence of antibodies to infliximab, which can be only measured after circulating infliximab has cleared. In an independent cohort, 61% of patients receiving multiple infliximab infusions developed antibodies to infliximab.8Baert F. Noman 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 (1844) Google Scholar The risk of developing antibodies was higher in patients with fistulizing disease who received 3 initial infusions of infliximab compared with those receiving a single initial infusion for luminal disease (2.4 vs. 2.85 relative risk).8Baert F. Noman 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 (1844) Google Scholar In the current ACCENT 1 study, infusion reactions were more frequent in the regularly scheduled groups, being highest (23%; 2% serious) in the 5-mg/kg scheduled group and lowest (9%; 0.5% serious) in the episodically treated group, further supporting the contention that the frequency of antibodies to infliximab were understated and that 3 initial infusions followed by regularly scheduled infusions does not prevent anti-infliximab antibodies. Although it is true that the number of infusions was higher in the regularly scheduled group, infusion reactions complicated 6% of each regularly scheduled 5 mg/kg infusion versus 3% of each episodic infusion. Two recent studies unequivocally correlate infusion reactions with the presence of antibodies to infliximab.8Baert F. Noman 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 (1844) Google Scholar, 9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 Likewise, serum sickness-like reactions, which are associated with high anti-infliximab antibody titers,10Sandborn W.J. Hanauer S.B. Infliximab in the treatment of Crohn’s disease a user’s guide for clinicians.Am J Gastroenterol. 2002; 97: 2962-2972Crossref PubMed Google Scholar were equal in all groups (2% episodic vs. 3% of scheduled groups). Finally, loss of efficacy, also associated with antibodies to infliximab,9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 did not appear to be different in each group, because discontinuation of treatment because of lack of efficacy was 17% in the episodic group and 16% in the 5-mg/kg scheduled group. It is likely that a substantial portion of the 58 of 192 patients in the 5-mg/kg scheduled group and the 51 of 193 patients in the 10-mg/kg group who were crossed over to higher-dose rescue treatment after not maintaining their initial response had antibodies to infliximab. Farrell et al.9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 found antibodies in 71% of patients who lost response to infliximab treatment versus 0% of those with good long-term responses. The increased frequency of infusion reactions in patients receiving increased doses of infliximab in the crossover group (8% episodic, 10% scheduled) supports the presence of antibodies leading to loss of efficacy. Unfortunately, only 27%–35% of patients in the present study by Rutgeerts et al. were taking concomitant immunosuppressive agents, such as 6 mercaptopurine, azathioprine, or methotrexate, that inhibit anti-infliximab antibody formation.8Baert F. Noman 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 (1844) Google Scholar, 9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 Costs must be considered when planning a treatment approach. The ACCENT 1 protocol of 8 scheduled infliximab infusions with 5 mg/kg (the FDA-approved dose), consisting of 3 initial infusions and maintenance every 8 weeks through 46 weeks, costs an 80-kg individual $45,944, based on a representative charge of 2 times average wholesale pharmacy costs for infliximab plus $175 infusion fees. Because 30% (58 of 192) of the patients in the 5 mg/kg scheduled group required an increased dose (10 mg/kg) to maintain clinical response, the average yearly costs would be higher. Representative costs per 10 mg/kg infusion are $11,311 per infusion for a 70-kg patient. Obviously, the costs for patients receiving the most effective schedule protocol, 10 mg/kg with rescue by 15 mg/kg, are 2–3 times baseline 5 mg/kg expenses. Although the authors correctly point out that increased hospitalization rates and loss of work must be factored into a cost analysis, the 1992 cost modeling exercise quoted by the authors used a baseline drug cost far lower than that of infliximab treatment.11Hay J.W. Hay A.R. Inflammatory bowel disease costs-of-illness.J Clin Gastroenterol. 1992; 14: 309-317Crossref PubMed Scopus (214) Google Scholar Each care provider must decide if the statistically nonsignificant improvement in remission and response rates and decreased hospitalization rates of 23% versus 38% justifies the extra expense of administering 8 scheduled infliximab infusions versus a mean of 2.2 treatments in the on-demand protocol. Despite its complicated experimental design and relatively large number of patients, this study did not compare outcome data on patients on immunosuppressant drugs versus those not on 6-mercaptopurine (6MP), azathioprine, or methotrexate. Between 27% and 35% of patients in the various groups received concomitant 6MP, azathioprine, or methotrexate. Unfortunately, this study and most inflammatory bowel disease trials prohibit addition of new immunosuppressive agents within 3 months of study initiation, avoid changing doses during the trial, and include only those patients who have failed doses of immunosuppressant therapy used for the duration of the study. Whether the addition or dose optimization of 6MP, azathioprine, and methotrexate at the time of initial infliximab injection will sustain responses is a key question because this approach would be the most cost-effective strategy for using infliximab, if effective. Immunosuppressive agents reproducibly decrease the rate of anti-infliximab antibodies, in theory prolonging efficacy and minimizing infusion reactions.3Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. 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 (3580) Google Scholar, 8Baert F. Noman 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 (1844) Google Scholar, 9Farrell R.J. Alsahli M. Jeen Y.T. Falchuk K.R. Peppercorn M.A. 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 Previous studies and extensive clinical experience have shown that approximately two thirds of patients with Crohn’s disease beginning 6MP or azathioprine12Present D.H. Korelitz B.I. Wisch N. Glass J.L. Sachar D.B. Pasternack B.S. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study.N Engl J Med. 1980; 302: 981-987Crossref PubMed Scopus (972) Google Scholar or 39% of those beginning methotrexate13Feagan B.G. Rochon J. Fedorak R.N. Irvine E.J. Wild G. Sutherland L. Steinhart A.H. Greenberg G.R. Gillies R. Hopkins M. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators.N Engl J Med. 1995; 332: 292-297Crossref PubMed Scopus (870) Google Scholar will clinically respond. It is likely that similar response rates will occur after induction of remission or initial improvement by using infliximab after the initiation of immunosuppressants in patients not previously treated with these agents. In summary, the study by Rutgeerts et al.4Rutgeerts P. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. Olson A. Bao W. Hanauer S. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar provides important clinically relevant data comparing episodic use of infliximab on an as-needed basis versus regularly scheduled infliximab maintenance therapy. Although the experimental design does not answer all questions regarding this issue, it provides physicians with enough information to help them decide whether the slightly increased efficacy of the regularly scheduled maintenance approach justifies the substantially increased expense of this strategy. Toxicity is not substantially enhanced and infusion reactions are not decreased by regularly scheduled infusions. The majority of patients who lose response to repeated doses of infliximab can at least be temporarily “rescued” by escalating the dose, although the duration of improved response is not clear. However, only a minority of patients in each group remained in remission for 1 year when treated with 1 of the 3 randomized strategies, although approximately two thirds of patients in all groups maintained a clinical response if allowed to escalate infliximab dose when responses waned. During this trial, 49% of single dose infliximab, 30% of 5-mg/kg scheduled, and 26% of 10 mg/kg scheduled patients escalated their dose because of decreased efficacy. A substantial number of patients eventually failed treatment with higher doses of infliximab; 37% (34 of 92) episodically treated, 38% (22 of 58) 5 mg/kg scheduled patients who eventually received 10 mg/kg, and 31% (18 of 57) patients in the 10 mg/kg scheduled group who were crossed over to the 15 mg/kg infusions every 8 weeks eventually dropped out of the study for various reasons. The investigative community needs to determine whether institution of 6MP, azathioprine, or methotrexate begun at the time of initial infliximab infusion will provide an equally efficacious and more cost-effective approach to maintaining remission after induction with infliximab. In lieu of these data, this study shows that either episodic or scheduled maintenance therapy can be performed with escalation of doses if necessary. The decision to use either strategy must be based on careful consideration of efficacy, associated costs, and demonstrated toxicities, including rare mortality. In my view, a patient with luminal Crohn’s disease who requires infliximab treatment and who is not yet on immunosuppressant drugs should be induced with a single infliximab infusion after beginning maintenance 6MP, azathioprine, or methotrexate, thereby reserving regularly scheduled infliximab infusions for those patients failing optimal immunosuppressant maintenance treatment.