IBD Watch^®

^{Timely Information for Practicing Physicians}

New and Emerging Roles for TNF Antagonists in Managing Crohn’s Disease

Special Issue Based on a CME Satellite Symposium held on May 23, 2006 in Los Angeles, CA

This Special Issue was Supported by an Unrestricted Educational Grant from Abbott

This symposium focused on discussion of three emerging concepts in the management of Crohn’s disease (CD): 1) TNF antagonists should be used as induction therapy early in the course of disease; 2) long-term maintenance of remission is achievable with continued and programmed use of TNF antagonists in CD; and 3) the safety profiles of TNF antagonists support early and long-term use of these agents in patients with CD, provided that appropriate screening and monitoring procedures are followed.

Introduction by William Sandborn, MD, Program Chair. Evidence-based treatment of CD goes back to 1979 when the National Cooperative Crohn’s disease trial demonstrated that sulfasalazine was modestly effective in inducing remission in CD patients and that systemic corticosteroids were highly effective induction therapies, albeit with significant side effects. In 1980, the first reports of open label therapy with metronidazole for perianal CD appeared and Present reported that 6-mercaptopurine was effective for long-term maintenance of remission in CD. In 1993, Singleton published the results of a placebo-controlled trial suggesting that 4 gm of mesalamine was effective for the treatment of active CD, and in 1994, the first large-scale placebo-controlled trials of enteric-coated budesonide demonstrated an effective induction therapy while lessening the toxicity of steroid therapy.  In 1995, Feagan reported the use of methotrexate for induction and maintenance of a steroid-free remission, and in 1998, the first generation biologic agent, infliximab, was introduced. ¨ In 2007, it is expected that 2 additional anti-TNF agents, certolizumab and adalimumab, and natalizumab, an anti-alfa4 integrin inhibitor, will be introduced for treatment of CD. The limitations of current therapies that we hope to answer with the broader use of immunosuppressives and the second generation biologic agents are: 1) whether 5-ASA agents effectively induce or maintain remission in patients; 2) preventing the dose-related toxicities and potential impact of long-term responses due to systemic corticosteroid induction therapy; 3) how to utilize budesonide’s short-term efficacy  for mild-to-moderate patients, with it’s limited benefit when administered up to 1 year and beyond; 4) identifying the optimal dose of immunosuppressive agents (azathioprine and 6-mercaptopurine) remains unclear and toxicities associated with use of these agents may be under-reported; and 5) while infliximab has been an important addition, it does have limitations including infusion reactions, the need to administer concomitant immunosuppressive agents, and relapse and immunogenicity concerns when the drug is stopped.

Can early intervention with TNF antagonists improve patient outcomes in CD? Presenter: Bruce Sands, MD, MS. Given that poor outcomes may be associated with current therapies, there is increased interest in early intervention with anti-TNF agents. The prevailing therapeutic pyramid is a “step-up” approach which begins with 5-ASAs, progresses to antibiotics, topical and/or systemic steroids, and finally to immune modulators and anti-TNF therapy. While this strategy is not evidence based, its premise is that most patients have mild disease and will respond to the more benign treatments used initially, while those who do not respond can be moved up to newer and more effective therapies. The limitation of this strategy is its focus on short-term symptomatic relief, rather than longer term remission, which may be achievable with earlier use of immunomodulators and anti-TNF agents. ¨ Evidence has shown that active CD has more impact on quality-of-life than class III/IV angina. The probability of surgery approaches 60% at 10 years post-diagnosis; surgery is associated with short- and long-term disabilities, reduced work capacity, and possible CD relapse. Current thinking is to begin treatment after appearance of symptoms with a goal of prevention of complications associated with disease progression; the key issue is whether earlier intervention with anti-TNF agents can improve patient outcomes. Studies of biologic agents in the treatment of rheumatoid arthritis (RA) have clearly demonstrated that a “top-down” approach involving earlier intervention with anti-TNF agents can prevent progression of RA. In CD, the ACCENT I and II trials demonstrated that, at 1-year follow-up, mucosal healing in fistulizing and non-fistulizing disease was achieved with maintenance dosing of infliximab, which resulted in a significant reduction in hospitalizations and CD-related surgeries. The first “step-up” versus “top-down” open label trial in 129 newly diagnosed patients showed that a “top-down” regimen of infliximab induction plus azathioprine followed by episodic infliximab and steroid taper was superior (CDAI <150 & no steroids and mucosal healing) to a “step-up” regimen of steroid taper followed by azathioprine/methotrexate followed by infliximab. ¨ The key question is what patients are appropriate candidates for early anti-TNF intervention? Clinical predictors of poor outcomes with conventional therapies include smoking, need for glucocorticoids and pediatric onset of CD.  Higher numbers of positive antibodies to microbial antigens is a predictor of disease progression and surgery; genetic markers such as Nod2 status are associated with a high risk of progression to surgery. A 5-year follow-up study showed that age < 40 yrs., presence of perianal lesions and use of steroids at first flare are clinical characteristics of patients at risk of progression to disabling CD and possible candidates for a “top-down” therapeutic approach.

Achieving long-term maintenance of remission in CD: Are all TNF antagonists created equal? Presenter: Jean-Frederic Colombel, MD. Three anti-TNF agents (infliximab, adalimumab and certolizumab pegol) have shown efficacy for maintenance of remission in patients with moderate-to-severe CD. Relative efficacy of these three anti-TNFs was assessed using remission and response rates from three clinical trials: ACCENT 1 with infliximab; CHARM with adalimumab; and PRECISE 2 with certolizumab. The three trials were similar in design including randomization to either placebo or anti-TNF therapy after a 2-6 week open-label trial with the active agent. Rates of remission (CDAI <150) and improvements of CDAI scores of ≥ 70 points and ≥ 100 points were evaluated at week 26 or week 30. While both ACCENT 1 and CHARM were 1-year trials, PRECISE 2 was a 26 week trial. Noteworthy differences in trial design that must be taken into account include patient selection (e.g., previous use of anti-TNF agents), randomization criteria, and definition of response.  ¨ Based on review of the available data, infliximab, adalimumab and certolizumab have broadly similar clinical efficacy for maintenance of remission Week 26-30 in active CD. However, only infliximab and adalimumab have demonstrated maintenance of remission out to 1 year. Other key differences that can influence anti-TNF treatment selection include route of administration (intravenous vs. subcutaneous), immunogenicity, safety and long-term cost-effectiveness. Editor’s note: In the CHARM trial, presented at the 2006 DDW annual meeting, maintenance adalimumab therapy also significantly increased the number of patients with steroid-free remission compared to placebo (35 percent vs. 3 percent at week 26) as well as complete fistula closure (36 percent vs 14 percent).

Update on the long-term safety of TNF antagonists in CD. Presenter: Maria T. Abreu, MD. Infliximab and adalimumab have well established safety profiles derived from large-scale controlled clinical trials in RA and CD patients and significant post-marketing surveillance. The long-term safety profile of certolizumab is not as well established; however, its short-term safety profile is similar to that of infliximab and adalimumab. Class-associated safety issues include risk of tuberculosis and other infections, lymphoma, demyelinating disorders and formation of antibodies to TNF antagonists. While hundreds of thousands of patients have been treated with TNF antagonists, pre-screening for tuberculosis is good clinical practice. Problems arise when tuberculosis symptoms are attributed to the underlying CD and extra-pulmonary manifestations are allowed to persist. In RA clinical trials there has been no difference in the rates of serious infections in patients receiving TNF antagonists compared to conventional therapy (i.e., methotrexate). The TREAT registry of infliximab CD patients reported a higher probability of serious infections associated with the use of corticosteroids and narcotic analgesics than with infliximab (2.28, 2.41 and 0.98 ORs, respectively). While the absolute risk is low, CD patients have a more than three-fold increased risk of developing opportunistic infections. A recent meta-analysis found a four-fold higher risk of lymphoma in IBD patients treated with azathioprine or 6-mercaptopurine compared to the general population. In RA post-marketing surveillance, none of the biologic agents have shown an increase in the rate of lymphoma per 100 patient years of exposure relative the background incidence, which is higher in the RA patient population. A recently published meta-analysis in JAMA examined the risk of malignancy or serious infection in RA patients; the pooled odds ratio for patients receiving either adalimumab or infliximab showed a three-fold increased risk of malignancy and a two-fold increased risk of serious infection than in the control group. ¨ With regard to autoantibodies, there appears to be a higher rate of conversion to ANA positivity in infliximab patients than in adalimumab and etanercept patients in RA clinical trials. With regard to demyelinating conditions, a recent UK study found a higher risk of MS and demyelinating disorders in IBD patients than in the general population.  ¨ The potential consequences of immunogenicity reactions to TNF antagonists include infusion reactions, decreased efficacy and secondary loss of response. Based on the ACCENT trial results, use of episodic infliximab without concomitant immunomodulators was associated with a significantly higher incidence of formation of antibodies to infliximab (ATI). Conversely, maintenance therapy with infliximab is associated with a relatively low rate of antibody formation, even without concurrent administration of immunomodulators. Data have shown that patients who develop high ATI levels have shorter durations of response to a course of infliximab. With regard to antibody against adalimumab (AAI), in the CLASSIC I and II trials there was a 0.7% and 3.7% incidence of AAI, respectively, in patients treated with adalimumab. Nevertheless, blood levels of adalimumab are higher in patients treated with concomitant methotrexate.  With certolizumab, 12% of patients in the CD trial developed antibodies against certolizumab and plasma concentrations of certolizumab were lower in antibody-positive patients, suggesting that antibodies do have an effect on the pharmacokinetics of certolizumab.  Thus, concomitant immunomodulators reduce antibody production to all three, but the potential risk of combination therapy needs to be taken into consideration with respect to the small advantage of reduced antibodies.

This web site is supported through educational grants from     

Note: By clicking on the above logos you are leaving this educational site

Comments or requests to unsubscribe can be e-mailed to info@ibdwatch.com