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Refining the Role for TNF Antagonists for Crohn’s Disease

Special Issue Based on a CME Satellite Symposium held on October 22^nd, 2006 in Las Vegas, Nevada

This educational symposium focused on evidence-based review of the clinical value of early use of anti-TNF therapy, the long-term efficacy and safety of anti-TNF therapy in Crohn’s disease, and the future of biologics in the treatment of Crohn’s disease.

Evidence-based review of biologic therapy in Crohn’s disease (CD): Edward V. Loftus, MD. In the U.S., infliximab, an intravenously administered chimeric antibody to tumor necrosis factor (TNF), has been commercially available for the treatment of CD for 8 years. Infliximab is currently approved for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderate to severe CD with inadequate response to standard therapy. Infliximab is also indicated for reducing the number of draining perianal and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD. In the ACCENT I trial, infliximab administered every 8 weeks was superior to single dose induction and episodic treatment in maintenance of clinical remission at week 54.  Adalimumab, a fully humanized subcutaneously administered antibody to TNF, is in advanced clinical development for treatment of Crohn’s disease. The CLASSIC I phase III trial demonstrated that a loading dose of 160 mg followed 2 weeks later by 80 mg was significantly better than placebo at inducing remission (CDAI < 150) in active CD at week 4 (36% vs 12%).  Additionally, the CLASSIC I study showed there was no difference in remission rates observed at week 4 in patients administered concomitant immunosuppressants versus patients administered adalimumab monotherapy. Patients completing the CLASSIC I trial were enrolled in the CLASSIC II trial of adalimumab for maintenance of remission. Subjects were stratified into 2 groups: those already in remission at week 0 and those with active CD at week 0. For those patients who were on active drug and in remission at weeks 0 and 4, there was a significantly higher incidence of maintenance of remission than for the placebo group at weeks 24 and 56. Patients not in remission at weeks 0 and 4 were dosed at 40 mg every other week or 40 mg weekly if they flared. Investigators noted that remission rates tended to increase over time, which suggests that this subgroup may have been received a subtherapeutic loading dose of adalimumab in the CLASSIC I trial.  The CHARM study evaluated the efficacy of 2 dosing regimens of adalimumab in maintaining remission in 854 patients responding to open-label 2-dose induction (80 mg at week 0, 40 mg at week 2). In patients receiving 40 mg weekly, clinical remission was noted in 47% of patients at week 26 and 41% at week 56, thus demonstrating a persistency of effect over time. Further, no differences in remission rates were noted between patients on concomitant immunosuppressants and those on adalimumab monotherapy. ¨ Certolizumab pegol is a subcutaneously administered pegylated Fab fragment of a humanized antibody to TNF. Post hoc analysis of a phase II trial suggested its effect was most notable in patients with high C-reactive protein (CRP) levels; thus, the 2 pivotal trials of certolizumab stratified patients by CRP levels and primary efficacy analyses were conducted in patients with high CRP levels at baseline.  However, no differences in efficacy were noted among patients with high CRP and the overall population. The PRECISE 1 phase III trial evaluated efficacy for both induction and maintenance of remission with certolizumab. Patients were randomized to placebo or certolizumab 400 mg every 4 weeks. At the end of the 26-week trial, 23% of patients receiving active drug had been in remission at both weeks 6 and 26, compared with 16% of placebo patients. The PRECISE 2 phase III trial evaluated 6-week responders to open-label certolizumab. At week 6, 64% of patients had responded to certolizumab; at week 26, 63% of certolizumab-treated patients had responded compared with 36% of patients on placebo, and 48% of patients were in remission at week 26 versus 29% on placebo. Thus, all 3 TNF antagonists appear to be effective for both induction and maintenance of remission in CD.   

Safety and tolerability of TNF Antagonists in CD: Edward V. Loftus, MD. Patients receiving TNF antagonists who present with fever or respiratory symptoms should be tested for opportunistic infections such as tuberculosis, histoplasmosis and listeria, which have been observed with TNF antagonists. Patients receiving TNF antagonists should be cautioned about the risk of lymphoma. There have been 6 recent observations of hepatosplenic T-cell lymphoma in pediatric and early adult CD patients treated with infliximab. However, all of the cases reported also included concomitant administration of 6-mercaptopurine or azathioprine. Demyelinating disorders such as optic neuritis have been associated with TNF antagonists in approximately 1 out of 1,000 patients. ¨ The TREAT registry has enrolled more than 6,000 adult patients with CD from community and academic practices. Of those patients, 3,179 patients have received infliximab and 3,111 patients have not received infliximab. Mean length of time in the registry has been 1.9 years. To date, there have been no differences noted in mortality between patients on infliximab and those on other therapies. Age, duration of CD, prednisone use, and narcotic analgesic use were each predictors of mortality. Predictors of serious infection were duration of CD, moderate to severe activity, prednisone use and narcotic analgesic use. There has been no significant difference between infliximab patients and non-infliximab patients in the incidence of cancer in the TREAT registry.

The benefits of TNF antagonists beyond remission: Uma Mahadevan, MD. Potential options for the medical management of inflammatory bowel disease, particularly CD, are increasing at an unprecedented rate. Thus, it is feasible to look beyond maintenance of remission to more aggressive end points such as steroid sparing, fistula and mucosal healing, quality of life, reduced hospitalizations and surgeries, all of which may eventually impact the natural history of the disease. Beaugerie et al found that patients with perianal disease as well as those that required administration of corticosteroids at first flare were more likely to have disabling CD at 5 years. The TREAT registry data have shown that patients on corticosteroids have a higher risk of serious infection and mortality. The ACCENT I trial results at 54 weeks showed that patients on infliximab can be successfully maintained in remission and weaned off corticosteroids. Lemann and others reported that 75% of patients on an induction regimen of infliximab and azathioprine or 6-mercaptopurine were in remission at week 12 and off steroids and 40% of this group remained in remission and off steroids up to 52 weeks. ¨ In the Step-up versus Top-down Trial, Hommes and coworkers reported on 129 newly diagnosed CD patients naïve to steroids or immunomodulators who were randomized to 2 arms: induction steroid therapy followed by steroids for flares, with the addition of azathioprine or methotrexate and infliximab as needed for additional flares (step-up); or infliximab and azathioprine for induction followed by episodic infliximab followed by steroids as needed for flares (top-down). At 12 months, 62% of patients on the top-down regimen were in remission, off steroids and without surgery versus 42% of patients in the step-up regimen. ¨ The CHARM study demonstrated the steroid-sparing properties of adalimumab as well. At weeks 26 and 56, significantly more adalimumab patients at doses of 40 mg every other week were in clinical remission and steroid free than the placebo group (35%, 29% vs. 3%, 6%, respectively). ¨ The ACCENT 2 Trial was the first randomized controlled trial to look at fistula healing as a primary end point. At week 54, 49% of infliximab 5 mg maintenance patients had fistula response versus 27% of placebo patients, and 40% of patients had complete fistula closure versus 23% of placebo patients. The CHARM study demonstrated the fistula healing properties of adalimumab as well with 37% of patients receiving adalimumab 40 mg every other week having complete healing of their draining fistulas at the last 2 visits versus 13% of placebo patients. Maintenance of fistula healing was also significantly better in the adalimumab group when compared to placebo at weeks 26 and 56. ¨ The ACCENT trial showed significantly better mucosal healing at week 54 with regularly administered infliximab when compared to episodically administered infliximab (50% versus 7%). The Step-up Top-down Study also documented ulcer reducing properties of infliximab/azathioprine versus standard corticosteroid doses (88% versus 47%) and complete ulcer healing at 1 year in 71% of infliximab/azathioprine patients versus 30% of corticosteroid patients. ¨ The ACCENT II Trial demonstrated a significant reduction in both hospitalizations and surgical procedures for patients treated with infliximab when compared to the placebo group. Thus, TNF antagonists have enabled patients with moderate to severe CD to achieve remission and impact the natural history of the disease.

Future prospects for patients who fail infliximab therapy: Maria T. Abreu, MD. Patients who do no respond to initial therapy with infliximab may fail for a variety of reasons including lack of inflammation, a mechanism of inflammation that is not TNF-dependent, normal CRP levels, pANCA positivity, or a polymorphism in the IgG Fc receptor IIIa. Several therapeutic options exist for patients who do not respond to infliximab, have inadequate responses, experience tachyphylaxis, or are intolerant to infliximab. These options include second generation TNF inhibitors such as adalimumab or certolizumab.  Data currently available on CD and rheumatoid arthritis suggest that the overall initial responses to different TNF inhibitors are similar. What remains to be determined is whether these data support the efficacy of switching to another TNF inhibitor when one or more agents fail. Experience from trials in patients with rheumatoid arthritis has demonstrated that response to a second TNF inhibitor is lower than that experienced with the first, and will be comparable to the initial agent if it was discontinued as a result of adverse events. Patients who do not respond to 2 TNF inhibitors will likely not respond to a third.  ¨ A modest proportion of patients with CD require higher doses of maintenance infliximab. Most data on the use of adalimumab as a second-line TNF inhibitor stem from a few small uncontrolled studies with varied end points across trials and with dose escalation necessary in up to 79% of patients. Recently published data from the 4-week double-blind placebo controlled GAIN study of 325 patients who failed infliximab showed a significantly higher remission rate in adalimumab patients versus the placebo group (21% vs. 7%). Data from the CHARM and PRECISE II trials suggest that a greater proportion of patients with no prior exposure to TNF inhibitors maintain a response to adalimumab or certolizumab than do patients with prior exposure. ¨ Patients with CD may have disease processes or inflammation that is driven by mechanisms independent of TNF.  In these cases, switching TNF inhibitors would be of little utility and would prolong time to remission if alternative therapies were available. Alternative therapeutic options for primary nonresponders to TNF inhibitors and those who consistently have inadequate responses or who are intolerant include anti-adhesion molecules or immune-stimulating strategies.  

This special issue is produced by MDG and supported by an educational grant from