IBD Watch^®

Innovative Strategies for Biologic Therapy in Crohn’s Disease

Special Issue Based on a CME Satellite Symposium Held on May 22, 2007 in Washington, DC

 This educational symposium focused on an expert panel discussion on selecting initial biologic therapy for patients with Crohn’s disease (CD), as well as selecting alternative therapies for such patients who lose responsiveness or develop intolerance to an initial biologic agent.

Introduction. William J. 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 patients with CD 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 (6-MP) was effective for the long-term maintenance of remission in patients with CD. In 1993 Singleton and Hanauer published the results of a placebo-controlled trial suggesting that mesalamine, 4 g, was effective for the treatment of active CD (recent evidence now suggests otherwise), and in 1994 the first large-scale placebo-controlled trials of enteric-coated budesonide demonstrated this drug’s effectiveness as induction therapy and its more favorable toxicity profile than that of steroids. In 1995 Feagan reported the use of methotrexate for the induction and maintenance of steroid-free remission, and in 1998 the first-generation biologic agent infliximab was introduced. In 2007 adalimumab, a new anti–tumor necrosis factor (TNF) agent, was approved for the treatment of patients with CD, and two additional biologic agents, certolizumab pegol, an anti-TNF agent, and natalizumab, an anti-alfa₄ integrin inhibitor, are in regulatory review. ¨ The traditional step-up treatment paradigm consists of mesalamine, antibiotics, and budesonide, followed by systemic corticosteroids, azathioprine, 6-MP, and methotrexate, followed by an anti-TNF agent. When the step-up paradigm fails, surgery is the final option. There is a growing consensus that it might be more appropriate to use the most effective agents (biologics) first in a top-down paradigm to change the natural history of the disease. The complications of CD typically develop over a number of years and include strictures, fistulas, and abscesses. Those complications inevitably lead to surgery in up to 80% of patients after 20 years. Postsurgical endoscopic recurrence of CD occurs in up to 80% of patients at 1 year, and clinical recurrence is seen in 50% to 60% of patients at 5 years. A substantial number of patients will experience surgical recurrence by 5 years. Outcome measures that will ultimately determine the impact of top-down treatment strategies include the treatment of symptoms, induction of remission, maintenance of response and remission, steroid-sparing, prevention of postoperative CD recurrence, induction and maintenance of fistula closure, healing of the bowel and, ultimately, disease modification.

Achieving optimal outcomes with TNF antagonists in patients with CD. Brian G. Feagan, MD. The availability of new therapies has prompted a re-examination of the essential principles of standard therapy for managing CD. The traditional approach has been to focus on controlling the symptoms of the disease. However, multiple epidemiologic studies have shown that patients who receive conventional treatments experience considerable morbidity from the disease, with the majority ultimately requiring bowel resection. Recent evidence also indicates that a small increase in mortality is detectable in these patients. Thus, our current diagnostic and therapeutic approach to CD is suboptimal and requires modification. ¨ The initiation of a more aggressive approach to CD therapy requires the validation of several concepts. First, prognostic markers must be identified that can be used to risk-stratify patients. Unfortunately, no prognostic markers for CD have been identified. Corticosteroid therapy, cigarette smoking, age of onset, and presence of perianal disease are the most robust clinical predictors of aggressive CD. In addition, there is a growing interest in serologic markers as predictors of risk for rapid disease progression. Recent data show that patients with CD who have a high number of seropositive markers are more likely to experience disease progression than are patients who are seronegative. Although advances have taken place in the endoscopic measurement of disease activity in patients with CD, the role of endoscopy as the gold standard of CD activity remains unclear. If a strong correlation can be demonstrated between endoscopic healing and long-term outcomes (eg, a reduction in the incidence of complications or the need for surgery), the management of endoscopic disease has the potential to alter the natural history of the disease. ¨ A second issue is the nature of the disease-modifying intervention. Aggressive treatment will most likely involve combination therapy of an antimetabolite and a biologic agent. Data from rheumatoid arthritis trials indicate that the combination of a TNF antagonist and an antimetabolite introduced early in the course of the disease is more effective than sequential monotherapy. Two randomized, controlled trials of TNF antagonists in CD suggest that the early introduction of these agents may be superior to the delayed treatment mandated by the step-up approach. The most compelling new data are derived from the CHARM study of adalimumab maintenance therapy and the finding of a significantly reduced risk of hospitalizations compared with placebo. Thus, it seems likely that we are moving toward a broader and earlier use of biologic agents in CD; however, a shift toward early, more aggressive therapy with biologics should consider the potential adverse effects of these agents and focus on the patient subtypes at highest risk. The use of serologic markers appears to be an important advance for identifying patients at the highest risk of aggressive CD.

Thee patient who fails biologic therapy: Where do we go from here? Paul J. Rutgeerts, MD, PhD, FRCP, AGAF. ¨ The question of how to deal with patients who experience primary failure to anti-TNF therapy is more complex. Subanalyses of the CHARM and PRECISE-2 studies, in which patients were treated with maintenance adalimumab for 56 weeks or certolizumab pegol for 26 weeks, respectively, showed lower rates of clinical response and remission in patients who had been previously exposed to infliximab than in patients who were infliximab-naïve, although significantly higher rates of clinical response and remission were achieved with active drug than with placebo. In a subanalysis of the ENCORE study, natalizumab maintenance therapy through 12 weeks was significantly more effective than placebo in achieving clinical response and remission in infliximab failures, but these rates were modest and significantly lower than those seen in biologic-naïve patients. This raises the question of whether switching a patient who fails a TNF antagonist to another class of agents is beneficial. ¨ Minimizing the incidence of primary failures to anti-TNF therapy is accomplished by adhering to the following guidelines: use the drug only for the appropriate indication, be sure that the patient has active disease (verify with colonoscopy and magnetic resonance imaging), exclude reasons other than active disease as the cause of symptoms (eg, short bowel syndrome, intercurrent infection, underlying irritable bowel syndrome), and avoid using biologics in patients with symptomatic strictures—consider surgery instead. ¨ When dealing with primary failure to anti-TNF therapy, observe the following guidelines: dose increase is rarely effective unless the initial dose was calculated based on a very low body weight; switch to another anti-TNF agent; when available, switch to another class of agents; finally, consider initiating or increasing the dose of steroids and consider surgery.

Using biologic agents as monotherapy in CD: Efficacy and safety implications. Maria T. Abreu, MD. There are safety issues associated with both conventional and biologic therapies in CD. Prolonged therapy with corticosteroids is associated with a range of toxicities, including metabolic abnormalities, osteoporosis, and gastrointestinal and endocrine abnormalities. A published retrospective case-control study has shown that corticosteroid use, especially at higher doses, is associated with an increased risk for intra-abdominal or pelvic abscesses. Immunomodulators (6-MP and azathioprine) that are commonly used to treat patients with CD have been associated with significant hematologic toxicities, metabolic abnormalities, immunologic dysregulation, and rare malignancies such as hepatosplenic T-cell lymphoma. ¨ Safety issues with biologic agents used to treat CD patients have also been raised, especially an increased incidence of lymphoma and other malignancies, and rarer events such as demyelinating diseases, lupus-like syndrome, and autoantibody formation. Reports in the literature show that some patients receiving anti-TNF agents may be infected with an intracellular pathogen such as tuberculosis. For those patients the suppression of TNF-alfa can reactivate the pathogen. As a consequence tuberculosis screening has become routine for patients receiving anti-TNF therapy. ¨ For some biologic agents, issues of immunogenicity that impact long-term efficacy and tolerability have also been raised, but a review of the latest data reveals that many of the safety issues associated with biologic therapy are manageable and some may be due to the fact that these agents are often used in combination with immunomodulators. Recently published data show a higher incidence of hepatosplenic T-cell lymphoma in pediatric patients receiving both immunomodulators and infliximab. This raises the question of whether biologic agents can maintain remission on a long-term basis as monotherapy without the need for concomitant immunosuppressive agents or corticosteroids. Several recent studies have shown that the concomitant use of immunosuppressive agents (methotrexate, azathioprine, 6-MP) does not impact the long-term efficacy of maintenance therapy with infliximab, adalimumab, or natalizumab in patients with moderate-to-severe CD. In addition, infliximab and adalimumab have been effective in allowing tapering or discontinuation of corticosteroid therapy in patients with CD who had been steroid-dependent. Thus, it may be possible to reduce the risk of toxicity while maintaining efficacy through the prudent use of biologic therapy for the long-term maintenance of selected patients with moderate-to-severe CD. ¨ It can be concluded that monotherapy with biologic agents appears to be as effective as combination therapy with immunomodulators in maintaining remission in CD for at least 1 year. Further, biologic monotherapy may be a safer and equally effective approach for long-term therapy in CD. 

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