Refining the Therapeutic Landscape in Anti-TNF Therapy for Crohn's Disease: An Expert Interview With David A. Schwartz, MD

Editor's Note:

Recent advances in the treatment of inflammatory bowel disease have focused on the development of biologic agents (eg, monoclonal antibodies, recombinant proteins or peptides, antisense oligonucleotides) targeted at neutralizing specific proinflammatory proteins. Specifically, monoclonal antibodies targeting tumor necrosis factor (TNF)-alpha have proven to be highly effective in the management of Crohn's disease. The anti-TNF agents -- ranging from the introduction of infliximab, a chimeric monoclonal antibody against TNF-alpha a decade ago; to the fully human IgG1 anti-TNF-alpha monoclonal antibody adalimumab, approved in early 2007; to the just approved certolizumab pegol, a humanized anti-TNF Fab' monoclonal antibody fragment linked to polyethylene glycol -- have demonstrated efficacy for induction and maintenance of remission in patients with moderate-to-severe Crohn's disease. These agents have reset the level for what is considered an acceptable symptomatic response to therapy in Crohn's disease, paving the way for clinicians to look ahead to the possibility of modifying the natural history of the disease. Against the backdrop of this continued evolution in the therapeutic armamentarium against Crohn's disease, Medscape spoke with David A. Schwartz, MD, Associate Professor at Vanderbilt University School of Medicine in Nashville, Tennessee; and Director of the IBD Center at Vanderbilt University Medical Center, to discuss the latest information on the use of the TNF antagonists, as framed by data presented at Digestive Disease Week (DDW) 2008.

Medscape: On the basis of your clinical experience, what do you think are the key issues currently facing the treating physician in terms of defining the role of the TNF antagonists in the medical management of Crohn's disease, and how do the emerging clinical data affect daily treatment decisions in this context?

Dr. Schwartz: This is a very exciting time for those of us who take care of patients with Crohn's disease. In the last year or so, we have seen the addition of 3 new biologics to our armamentarium, including adalimumab, natalizumab, and certolizumab pegol. Because Crohn's disease can be such a difficult disease to treat, it is beneficial to have more therapeutic options. We have started to use these new agents in our anti-TNF-naive patients and in those with an attenuated response to infliximab. Along with these new agents, new treatment philosophies have begun to emerge, including the early-intervention or top-down approach.

What to do with patients who had previously done well on infliximab but then lost response is an important clinical issue. Two studies presented at this year's DDW meeting looked at this problem and reported promising results. The first evaluated patients who were in the 6-week open-label part of the WELCOME trial [WELCOME = 26-Week open-label trial Evaluating the clinical benefit and tolerability of certoLizumab pegol induCtiOn and Maintenance in patients suffering from Crohn's disease with prior loss of response or intolErance to infliximab]. This 539-patient phase 3b multicenter study examined the efficacy of certolizumab pegol in Crohn's disease patients who had previously received infliximab but either lost response or became intolerant.^[1] In this difficult patient subset, at week 6, 62% of patients achieved a response and 39% achieved remission. These findings were very similar to the results obtained in the PRECiSE [Pegylated antibody fragment Evaluation in Crohn's disease Safety and Efficacy] 2 trial suggesting that prior exposure to infliximab does not decrease response rates with certolizumab.^[2]

In another study presented at this year's meeting, Panaccione and colleagues^[3] reported on the efficacy of adalimumab in patients with moderately to severely active Crohn's disease after infliximab failure; they reported the 1-year follow-up data from an ongoing open-label extension study of GAIN [Gauging Adalimumab efficacy in Infliximab Nonresponders] assessing whether it was possible to maintain response and remission in this difficult patient subset. The GAIN^[4] trial had demonstrated that adalimumab was significantly more effective than placebo in inducing remission in patients previously exposed to infliximab. In this 1-year follow-up to that study, they found that remission was preserved in 40% of patients and that 66% of patients maintained response.

The goal of early intervention, or top-down treatment, is to try and alter the natural history of Crohn's disease by intervening with immunomodulators and/or biologics early on in the disease course. This approach was really brought to the forefront in the study by D'Haens and colleagues.^[5] In this trial, patients with early (diagnosis within the past 4 years and never on steroids, immunomodulators, or a biologic) Crohn's disease were randomized to standard "step-up" treatment (patients had to fail 2 steroid courses before starting immunomodulators) or "top-down" treatment (patients received both azathioprine initially and the induction sequence of infliximab 5 mg/kg at 0, 2, and 6 weeks; the infliximab was discontinued at this point and the azathioprine continued; those who flared despite the azathioprine were allowed to receive additional infliximab infusions). Patients who were randomized to the "top-down" strategy were much more likely to be in remission off steroids at 1 year (62% vs 42%; P = 03). Exploratory analyses of all of the new TNF antagonist trials have demonstrated superior results for those patients treated early in their disease course.^[6,7] During this year's meeting, Schnitzler and colleagues^[8] examined whether the introduction of infliximab had changed the natural course of Crohn's disease in their patients. In this study, they compared the number of surgeries and hospitalizations that occurred in their 614-patient cohort before and after the start of infliximab therapy. They found that the rate of major abdominal surgery was reduced by 15% after the start of infliximab. Those patients who were placed on maintenance (scheduled) treatment from the onset were about half as likely to require hospitalization as those patients on episodic therapy.

Medscape: Let's turn our attention to the issue of safety. The majority of data regarding the safety of the anti-TNF agents derive from the published rheumatology literature given the longer clinical experience with these agents in that setting. Against this background and with the adverse-event profile more established in rheumatology, what can you tell us about the overall safety of these agents in Crohn's disease?

Dr. Schwartz: The safety of the anti-TNF agents is of the utmost importance to patients and clinicians. As mentioned, because the anti-TNF antibodies have been used longer in rheumatology, most of the safety data with these drugs have been extrapolated from this literature. At this year's DDW meeting, longer-term safety data were reported for all 3 of the TNF antagonists currently approved for the treatment of Crohn's disease.

Two studies examined the safety of infliximab in different clinical settings. The first reported the interim analysis of the ENCORE (European National Crohn's Observational) registry.^[9] The ENCORE registry is an observational postmarketing safety surveillance registry. ENCORE is the European equivalent of the TREAT registry (the Crohn's disease Therapy, Resource, Evaluation, and Assessment Tool),^[10] and was launched to collect long-term safety data for Crohn's disease patients treated with infliximab or nonbiologic therapies. In this present study,^[9] the authors reported data for the first 2008 patients who were enrolled (1166 received infliximab) in this surveillance registry. The median follow-up was about 13 months. The study authors found no new safety signals in this cohort, with the overall incidence of adverse events being slightly higher in the infliximab-treated group (54% vs 41%), including a slightly higher rate of serious infections (2.8% vs 1.7%). It should be kept in mind that the patients who received infliximab were sicker and were more likely to be on concomitant immunosuppressives and steroids.

The second study that examined the safety of infliximab compared the rate of serious bacterial infections in Crohn's patients treated with infliximab, steroids, or immunosuppressants.^[11] The authors queried a healthcare utilization database from British Columbia for Crohn's patients. They identified nearly 11,500 patients and 16,699 treatment episodes with 1 of these 3 drug classes. A total of 104 serious bacterial infections requiring hospitalization were identified. The risk for infection was higher in patients treated with multiple agents, including infliximab and steroids (relative risk [RR] = 1.4; 0.6-3.5), and combination of infliximab and immunosuppressive agents more than doubled the risk (RR = 2.4; 1.2-4.9). Steroids alone also seemed to increase the risk for infection (RR = 1.6; 0.9-2.8). Last, infliximab alone did not seem to increase the risk for serious bacterial infections. These findings lend more support to the concept of monotherapy when using an anti-TNF agent.

Colombel and colleagues^[12] reported on the overall safety of adalimumab in Crohn's disease clinical trials. The investigators reviewed the safety data from all of the pivotal Crohn's disease trials using this agent; this included 2228 patients. They found that the rate of serious infections had not changed from the initial analysis of nearly 1500 patients in 2006 (6/100 patient-years vs 5.2 per 100 patient-years) and was similar to the results reported for other anti-TNF agents.

In another study presented at DDW 2008, Lichtenstein and colleagues^[13] reported long-term safety data for certolizumab pegol. Safety data were pooled and analyzed from 6 phase 2-4 trials. The authors found that the overall risk for treatment emergent adverse events was 61% in patients treated for 6 or more months with certolizumab pegol compared with 41% for those who received placebo. Of note, it appeared as if the rate of adverse events did not increase with the length of exposure and plateaued after 6 months on treatment.

Additionally, Siegel and colleagues^[14] performed a meta-analysis of all the adult Crohn's disease TNF antagonist clinical trials to determine the rate of non-Hodgkin's lymphoma in patients treated with this class of agents. The analysis included only trials that had a follow-up of at least 48 weeks; this included 8843 patients from 26 studies. The rates were then compared with the expected rate from the SEER [Surveillance Epidemiology & End Results] registry and with estimates from a meta-analysis performed recently to determine the rate of lymphoma associated with immunomodulator use in inflammatory bowel disease.^[15] They found that the overall risk for lymphoma with an anti-TNF agent was low, but elevated, at a rate of 5.5 per 10,000 patient years.

Medscape: Adalimumab was FDA approved in early 2007 for the treatment of adult patients with moderately to severely active Crohn's disease. Now that we're about 1 year post-approval, new data were presented at this year's DDW meeting regarding this fully human IgG1 anti-TNF-alpha monoclonal antibody. What can you tell us about these studies?

Dr. Schwartz: A number of studies presented at this year's meeting reported new data on adalimumab. I believe the 2 most provocative of these examined the long-term remission rates with adalimumab and the benefits of dose adjustment. Panaccione and colleagues^[16] presented the 1-year open-label follow-up data for patients who were enrolled in the CHARM (Crohn's trial of the fully Human antibody Adalimumab for Remission Maintenance) trial. [CHARM was a 56-week trial that enrolled 854 patients with moderate-to-severe Crohn's disease and evaluated adalimumab for the maintenance of clinical remission.] Patients who completed this 56-week CHARM trial were eligible to roll over into an open-label extension study in which those receiving adalimumab were allowed to continue the dosing schedule they were on in CHARM (40 mg every other week or 40 mg weekly). Patients were allowed to change to weekly dosing if they flared or lost response (total treatment, 2 years). A total of 467 patients were enrolled in this open-label extension study. Data showed that remission seemed to be very durable, with 79% of the 123 randomized responders [patients with ≥ 70-point decrease from baseline Crohn's Disease Activity Index (CDAI) score at week 4] who were in remission at the end of the CHARM trial able to maintain remission during the additional 1-year open-label extension.

The second study examined an important issue in clinical practice. Sandborn and colleagues^[17] addressed the question of whether it is helpful to shorten the dosing interval with adalimumab for those patients who have an attenuated response. Clinicians certainly do this with infliximab with good success, but have had little guidance with regard to whether this is an efficacious option for patients on adalimumab. In this study, the authors assessed those patients who were initially randomized in CHARM to adalimumab 40 mg every other week who had to increase to weekly dosing with adalimumab during the trial. In the CHARM trial, at/after week 12, patients were allowed to move in a stepwise fashion to open-label every other week and then to open-label weekly dosing with adalimumab for flares or nonresponse. Of the 260 patients initially randomized to 40 mg every other week, 71 (27%) had to eventually change to weekly dosing because of flares or nonresponse. Forty-nine (69%) of these patients were able to obtain a response (100-point decrease in CDAI) and 32 (45%) were able achieve remission. There was no clear clinical or demographic factor that seemed to predict the need for weekly dosing. These data suggest that dose escalation with adalimumab is a reasonable strategy for patients.

Medscape: What, in your clinical experience, are the key factors to consider as part of a comprehensive management strategy when selecting the most appropriate initial agent for the biologic (ie, TNF antagonist)-naive patient?

Dr. Schwartz: The main factors that come into play when trying to decide on a treatment option for an individual patient include the safety and efficacy of the agent. As we discussed previously, safety and efficacy seem to be similar among the 3 anti-TNF therapies that are currently available for Crohn's disease. Therefore, the other key factors that I take into consideration when deciding on an agent to prescribe for an anti-TNF-naive patient include adherence issues, patient preference, and mode of delivery. We know from studies done with 5-aminosalicylic acid in ulcerative colitis that adherence with prescribed treatment is important for maintaining remission.^[18] Thus, for the minority of patients who have a history of nonadherence, infliximab has the advantage of requiring the patient to come in to the clinic for an infusion in order to receive treatment. This allows physicians to monitor how the patient is doing and to obtain laboratory studies if needed. In my practice, for the majority of patients, I generally present all 3 TNF antagonist options and allow the patient to select his/her therapy. Most patients find the option of subcutaneous therapy with no time needed away from work to be appealing. Indeed, a study presented during this year's DDW meeting reflects this preference. In this small study, 50 patients with inflammatory bowel disease were sent a survey regarding their opinion about the anti-TNF agents and their mode and schedule of delivery.^[19] Fifty-four percent of respondents preferred the subcutaneous route of administration. In addition, 100% of patients who had received both intravenous and subcutaneous anti-TNF therapy preferred the subcutaneous route. The main reasons given for this preference included that the infusions were painful as well as the autonomy that subcutaneous administration provided.

Medscape: Were there any other data presented during DDW 2008, or in the recent literature, that could help put this information into better clinical context?

Dr. Schwartz: As discussed previously, this is a very exciting time for clinicians who treat patients with inflammatory bowel disease. There are several new therapeutic options available and we are getting better at improving patients' quality of life and preventing complications associated with Crohn's disease. This was reflected in a study presented during DDW 2008. Feagan and colleagues^[20] reported data evaluating the effect of certolizumab pegol on quality-adjusted life-years for subjects in the two 26-week induction and maintenance trials, PRECiSE 1 and PRECiSE 2. In this analysis, a significant gain in quality-adjusted life-years was observed with certolizumab pegol in both trials: PRECiSE 1 (0.0659; P = .001); PRECiSE 2 (0.0690; P = .015).

In addition, investigators are beginning to show that the use of anti-TNF agents may be altering the natural history of Crohn's disease. As discussed previously, Schnitzler and colleagues^[8] demonstrated a 15% reduction in the need for major abdominal surgery in Crohn's disease patients after the start of infliximab therapy.

Given the slight increased risk of infection and lymphomas associated with anti-TNF therapy, as mentioned above, not all Crohn's disease patients will need or warrant treatment with a biologic. Ideally, clinicians must be able to identify those patients who might benefit the most from early intervention with an anti-TNF agent before they develop complications. Indeed, we are getting better at doing this, as 2 studies presented during this year's meeting underscored. Investigators reported data on the predictive value of new serologic markers (anti-laminarin IgA and anti-chitin IgA) that may help predict aggressive Crohn's disease.^[21,22] These markers seem to be associated with an increased risk of developing a stricture or fistula and with a higher chance for surgery.

This activity is supported by an independent educational grant from Abbott.