INTRODUCTION

Crohn's disease is a chronic inflammatory disorder with a prevalence of 50 per 100,000 and an incidence of 5 per 100,000 newly diagnosed cases each year in the United States (¹). Its course varies widely, with periods of remission, and exacerbation including abdominal pain, diarrhea, and fatigue. Within 2 yr of establishing medical remission, an estimated 35–80% of patients relapse (²). Medical treatments ameliorate symptoms but despite improved understanding of the etiology and pathogenesis of the disease (³), a cure remains elusive.

The primary goals of pharmacological intervention in Crohn's disease are to improve the patient's quality of life, reduce the risk of Crohn's disease-related complications, and avoid surgical intervention (⁴). Corticosteroids have been the mainstay of therapy, used to halt progression and to induce remission. However, in addition to well-documented side effects (⁵), the usefulness of corticosteroid treatment is limited by an inability to (1) modify the course of the disease, (2) maintain remission, and (3) induce mucosal healing.

An alternative therapy targets the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-), and provides important steroid-sparing effects (⁶). TNF- is significantly elevated in Crohn's disease (⁵) and is believed to play a key role in its initiation and propagation (^7,8). Clinical trials have found infliximab, a chimeric monoclonal Ig-G1 antibody that binds and neutralizes soluble and membrane-bound TNF-, to be effective in inducing and maintaining the remission of Crohn's disease (^{4,9,10,11,12,13}).

An early double-blind placebo-controlled trial by Targan et al. revealed that a single infusion of infliximab was often sufficient to induce remission in patients with resistant Crohn's disease (¹³), while a study by Present et al. (¹⁰) showed that infliximab was clinically effective in promoting the closure of fistulas. Hanauer et al. (⁸) found that in patients responsive to infliximab treatment, maintenance infusions (q 8 wk) were significantly better than placebo in maintaining remission over 1 yr. This study also demonstrated improved short-term healing of fistulas, increased mucosal healing, and reduced corticosteroid requirements.

However, consensus on episodic retreatment versus maintenance therapy as the preferred regimen for long-term treatment of Crohn's disease is still lacking (¹⁴). Two important studies have addressed this question. The ACCENT I trial (^8,15), a multicenter, randomized, double-blind study, investigated maintenance (5 or 10 mg/kg q 8 wk) and episodic (5 mg/kg) treatment strategies with infliximab for long-term (54 wk) efficacy (clinical response, clinical remission) and safety, as well as for effects on quality of life and overall cost. The ACCENT II trial (¹⁶) evaluated the effectiveness of placebo versus maintenance (5 mg/kg q 8 wk) dosing strategies with infliximab in sustaining fistula closure in patients suffering from single or multiple fistulas.

APPROPRIATENESS OF MAINTENANCE THERAPY

I believe that lifetime use of infliximab for maintenance is justified in Crohn's disease because of five key issues:

1.  Outcomes at 1 Yr

The ACCENT I trial demonstrated consistently superior clinical response and remission rates with maintenance infliximab therapy (10 mg/kg) compared with episodic treatment (p < 0.05) (^8,15). Though diminishing group sizes reduced the statistical power of the study by week 54 for 5 mg/kg maintenance therapy, differences at many earlier time points were significant (p < 0.05) (¹⁵). Regular maintenance therapy has proven to be more effective than episodic dosing in permitting mucosal healing at 54 wk in which 44% of combined patient groups (5 mg/kg and 10 mg/kg infliximab maintenance treatment) experienced healing compared to 18% of episodic patients (p= 0.041) (¹⁵). In addition, significantly fewer Crohn's disease-related hospitalizations and intraabdominal surgical procedures occurred in patients with a scheduled infliximab strategy. Only 24% of the combined scheduled strategy patients were hospitalized compared to 38% for episodic strategy patients (p= 0.014) and 2.9% of maintenance patients needed surgery compared to 7.4% of episodic strategy patients (p= 0.01) (¹⁵). Furthermore, approximately three times or 29% of schedule-treated patients discontinued corticosteroids while in clinical remission compared to 9% in the episodic-treated patients (p= 0.004) (¹⁵).

The ACCENT II trial (¹⁶) demonstrated that patients treated with maintenance infliximab maintained their remission for 40 wk compared to 14 wk in placebo-treated patients (p < 0.001). In addition, at 54 wk the effectiveness of infliximab maintenance therapy in maintaining complete absence of draining fistulas was 36% in patients on infliximab maintenance versus 19% of patients in the placebo maintenance group (p= 0.009). Furthermore, 46% of maintenance patients versus 23% placebo patients exhibited a clinical response (p= 0.0001). In this study the comparison to an episodic treatment strategy was not done; however, placebo patients initially responsive to infliximab were permitted to cross over to infliximab maintenance if they did not maintain remission; 61% of these patients did reestablish a response to infliximab but were subjected to a temporary increase in disease activity and decreased quality of life, therefore, further supporting the use of maintenance therapy.

2.  Immunogenicity

The presence of antibodies to infliximab is associated with decreased clinical responsiveness and an increased risk of infusion reactions, albeit with low (36%) positive predictive value. Maintenance therapy is less immunogenic than episodic therapy, as demonstrated by results from the ACCENT I trial (¹⁷). In this analysis, immunogenicity was evaluated at week 72 in order to decrease the interference of serum infliximab in the detection of antibodies. Antibodies to infliximab were detected at significantly higher rates (30%) in the episodic-treated patients compared with 8% in the combined 5 and 10 mg/kg maintenance-treated patients (p < 0.0001). In addition, the range of antibody titers differed between the two treatment strategies with <1% of patients in the maintenance arm with an antibody titer greater than 1:40 compared to 9% in the episodic-treated patient group. Overall, the presence of antibodies to infliximab did not appear to affect clinical response or clinical remission. However, in the episodic treatment group, development of antibodies at week 14 was associated with decreased serum infliximab concentrations, decreased duration of response (7 wk vs 11 wk), and a lower clinical response.

Although concurrent immunomodulator therapy reduces the risk of immunogenicity and infusion-site reactions in episodic-treated patients to levels similar to scheduled therapy, the use of immunomodulators with episodic treatment strategies must be balanced by the increased potential of toxicity due to combination therapy (¹⁷).

3.  Safety

The rate of reasonably related serious adverse events in the ACCENT I trial (⁸) was similar for all three groups, 7% for episodic and 8% and 6% for 5 mg/kg, and 10 mg/kg scheduled therapy, respectively. The rate of infusion reactions when assessed on a per infliximab infusion basis was similar for maintenance-treated patients (7% and 5% for 5 and 10 mg/kg, respectively) versus 7% for episodic-treated patients (¹⁷). Although a greater number of patients in the maintenance-strategy group developed anti-dsDNA and ANA than in the episodic-treatment group, only one patient showed clinical symptoms (arthralgia and lupus-like syndrome).

To compare single treatment versus multiple treatments, safety was evaluated at week 14, and there was no difference in single-dose infliximab infusion (12%) versus multiple-dose infusion (10%), p= 0.561. Nor was there a difference in the infection rate (13% for single infusion versus 13% for multiple infusion, p= 1.00) (⁸).

4.  Health Economic Outcomes

Indirect costs associated with relapse, such as hospitalization, surgery, and days lost from work, reveal that maintenance therapy is substantially more cost effective. Feagan et al. (^12,18) have demonstrated that hospitalization accounts for 56% of the health-care costs in the care of patients with Crohn's disease. Cohen et al. (¹⁹) have shown that the mean length of stay for hospitalizations is 9 days and the mean reimbursement per hospitalization is $22,000. Therefore, if hospitalizations can be decreased or eliminated due to scheduled maintenance treatment strategies, patients, employers, and insurance companies responsible for reimbursements will all benefit greatly. The institutional cost savings and increased productivity of the patient certainly offset any increased drug acquisition costs.

The Inflammatory Bowel Disease Questionnaire (IBDQ) is a widely used questionnaire to evaluate health-related quality of life. Within the ACCENT I trial (¹⁵), significantly more patients treated with 10 mg/kg scheduled therapy group had IBDQ scores over 170 (indicting remission) than in the episodic strategy group from week 14 through week 54 (p < 0.05). Although the 5 mg/kg scheduled-treatment strategy group did not reach statistical significance, the combined group (5 and 10 mg/kg) had IBDQ scores indicative of remission at weeks 14 (p= 0.028), 22 (p= 0.012), and 46 (p= 0.049) compared to the episodic-treatment group.

5.  Should Infliximab Be Used as a Bridge to Long-Term Immunomodulator Therapy?

Though efficacy may vary, multiple clinical strategies are available for both inducing and maintaining remission (³). Although immunomodulator therapy has been successfully used to prolong remission (²⁰), there is no evidence that infliximab-induced improvement of Crohn's disease is a bridge to long-term immunomodulator therapy. Tuvlin et al. (Tuvlin JA, Schaefer KG, Sane NP, Cohen RD, Hanauer SB. Infliximab Is Not a Bridge to Immunomodulators in Crohn's Disease. Gastroenterology. 2003: A-518 [Abstract T 1360]) showed in their infliximab maintenance immunosupression discontinuation (IMID) trial in luminal Crohn's disease that the likelihood of maintaining infliximab-induced response without subsequent infusions is low (fewer than 2%) and is not improved by the use of concomitant immunomodulators. This would argue against using infliximab-induced improvement of Crohn's disease as a bridge to long-term immunomodulator therapy.

CONCLUSIONS

A plethora of available data demonstrates the superiority of maintenance therapy to episodic therapy. The advantages include improved clinical response and remission rates, better quality of life for patients, significantly fewer hospitalizations and surgeries, significantly greater mucosal healing, faster steroid weaning, and less antibody formation. Recurrence of Crohn's disease-related symptoms increases the risk of ulcer formation, fibrosis, scarring, and subsequent obstruction. Nonetheless, episodic therapy provides adequate but less optimal outcomes, and is available as a potential treatment modality for patients unwilling or unable to undergo maintenance infusions for a variety of reasons, including pregnancy.

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