Reports

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PRIORITY PRESS - Digestive Disease Week (DDW 2014)

Chicago, Illinois / May 3-6, 2014

Chicago - Oral and poster presentations at DDW 2014 reflected the changes that have evolved in the approach to treatment of inflammatory bowel disease as new data have been accumulated on the use of the tumor necrosis factor alpha (TNF) inhibitors. New comparative data for TNF inhibitors as monotherapy and in combination with thiopurines were reported along with advances in optimizing single-agent and combination therapy. Analysis of trial data weighing relative benefit versus relative harm suggests that biologics may be safer than immunosuppressives.

“There has been a paradigm shift in the therapeutic approach to IBD,” Dr. Gary Lichtenstein, University of Pennsylvania School of Medicine, Philadelphia, acknowledged. “Our goals of therapy have evolved,” he declared. “In the past we treated based on symptoms, but now we recognize that reducing hospitalization, surgery, and the social and occupational burdens on patients is also a goal. Mucosal healing has given us the opportunity to strive further and improve the overall outcome of patients, recognizing that safety and tolerability of medications is critical. Biologics are the most effective therapies we have,” Dr. Lichtenstein stated.

Safety of Monotherapy

Few comparative data are available on which to base decisions about optimal therapy in patients with ulcerative colitis (UC). A study looked at the relative benefit versus harm for long-term monotherapy with biologic agents compared with thiopurines in UC, using a new metric developed by Dr. Eric D. Shah, Cedars-Sinai Medical Center, Los Angeles (Abstract 5). Data were extracted from 14 Phase 3 randomized, placebo-controlled trials of single-agent therapy in active UC, including 10 trials of biologics infliximab, adalimumab, golimumab, and vedolizumab and 4 trials of immunomodulators tacrolimus and 6-mercaptopurine/azathioprine. For each agent, Dr. Shah and his colleagues calculated the ratio of the number needed to harm (NNH), based on study withdrawals due to adverse events, divided by the number needed to treat (NNT) based on efficacy endpoints in clinical trials. For induction immunosuppressive therapy, there was no evidence for excess harm with tacrolimus, although an NNH of 14 (RR=2.8, 95% CI 0.7-10.5) was reported with immunosuppressive maintenance therapy. For biologics, the ratio was favourable for induction, maintenance, and combined induction/maintenance therapy. “On the other hand, our data suggest that azathioprine as monotherapy causes harm,” Dr. Shah added.

Combination Therapy vs Monotherapy

Researchers from the Centre Hospitalier Universitaire de Montpellier, France, reported that combination therapy with the TNF inhibitor infliximab and an immunosuppressive is significantly more effective than anti-TNF monotherapy at 6 months in patients with moderate-to-severe UC (Abstract Sa1273). Dr. Dimitri Christophorou presented a meta-analysis of data from 3 controlled trials, including UC SUCCESS (Panaccione R et al. Gastroenterology 2014;146:392-400) and ACT 1 and 2 (Gastroenterology 2009;137:4:1250-60), in which 765 patients were treated with infliximab either alone or combined with azathioprine. After 6 months, a significantly higher proportion of patients on combination therapy (48.60%; P<0.0001) had achieved and maintained clinical remission compared with patients on TNF inhibitor alone (29.89%; P<0.0001). The difference was maintained at 12 months (48.60% vs 34.1%, respectively), although it was no longer statistically significant, probably due to the lack of trial data, Dr. Christophorou commented.

Another meta-analysis indicated that although adalimumab-immunosuppressive combination therapy was slightly superior to monotherapy for induction of remission in Crohn's disease (CD) (OR 0.79; P=0.01), the rates of induction of clinical response and maintenance of remission/response and need for dose escalation after 1 year were similar with both treatments (Abstract Sa1106).

Immunosuppressive Dose in Combination

Addition of an immunosuppressive to infliximab leads to higher trough levels and a lower presence of antibodies compared with monotherapy, but there is no beneficial effect of adding an immunosuppressive to adalimumab, according to a Dutch study presented by Dr. Andrea E. van der Meulen-de Jong  (Abstract 208). In a retrospective study of 217 IBD patients (80% with CD) treated at the Leiden University Medical Centre, a decreased rate of antibody formation was observed in patients on infliximab combination vs monotherapy (5.7% vs 29.8%; P=0.001).  Infliximab combination therapy was also associated with significantly higher mean trough levels compared with monotherapy (7.5 vs 4.6 μg/mL, P=0.04). Trough levels and antibodies were measured at Sanquin laboratories in Amsterdam. Trough levels were categorized as normal at 3-7 μg/mL and antibodies as positive if >12 AE/mL. Timing of starting on an immunosuppressive did not affect trough levels of infliximab or adalimumab, but patients who started on infliximab simultaneously with an immunosuppressive had lower antibody formation compared with patients who started the immunosuppressive later (2.4% vs 18.2%, P=0.04). Immunosuppressive dose did not appear to affect antibody formation with either TNF inhibitor.

Dose Optimization

Dose optimization in patients who have had an initial response to infliximab is required more frequently in UC than in CD cases, possibly reflecting a higher burden of inflammation, according to a retrospective study from Mount Sinai Hospital, Toronto (Abstract Su1412).
Dr. Sarah O'Donnell and colleagues identified 211 patients who received infliximab (≥4 infusions) for treatment of CD (67%) or UC (33%) between 2008 and 2013. By October 2013, 70% of cases receiving maintenance during the study period continued on therapy, with 49% receiving dose optimization, i.e., an increase from 5 mg/kg to 10 mg/kg or a reduction in the dosing interval to <8 weeks. Dose optimization occurred in 67% of UC patients compared with 49% of CD patients (P=0.015), reflecting more dose increases in UC than CD (38% vs 18%, P=0.002) rather than interval reductions. Time to dose optimization was also significantly lower in UC vs CD. Trough levels, evaluated by Prometheus Anser assay, were similar in UC and CD patients.

Monotherapy

The benefits of increased trough level and decreased antibody formation obtained with combination therapy might be achievable with “optimized monotherapy,” Dr. Byron B. Vaughn, Beth-Israel Deaconess Medical Center, Boston, Massachussetts, and his colleagues believe. In a pilot study, patients on optimized monotherapy, defined as proactive therapeutic infliximab trough concentration monitoring, with titration to a target concentration (5-10 μg/mL) and continued monitoring at regular intervals,” did very similarly to combination therapy,” Dr. Vaughn reported (Abstract 211). Of the 31 study patients (84% CD), 11 (35%) underwent a dose escalation, with additional dose escalations in 10, and 2 patients had dose de-escalation. Overall, 26 (83%) patients achieved a trough concentration >5 μg/mL. No patient stopped therapy at the end of the study period and the median follow-up time to date is 3.4 years (range 1-5 years). “We think optimized monotherapy ultimately may be as effective as combination therapy,” Dr. Vaughn declared. “It needs to be validated prospectively, since it is not yet clear whether it is going to be effective as an initial monotherapy in treatment-naïve patients or whether patients should have 6-12 months of combination therapy followed by de-escalation to monotherapy if they have responded,” he noted.

Summary

During a session summarizing the best current treatment in IBD, Dr. William Sandborn, Division of Gastroenterology, University of California San Diego, La Jolla, said that in UC, 50% of patients will respond to mesalamine and the remaining patients should receive top-down therapy with steroids budesonide, prednisone, followed by combination therapy with azathioprine and an anti-TNF agent. “In CD, a tapered course of steroids is likely to be effective in low-risk patients, but in high-risk patients, combination therapy with azathioprine and an anti-TNF agent is the best option. In both UC and CD the approach should involve optimization of therapies and treating to target," Dr. Sandborn emphasized.