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Lofberg and colleagues concluded that in the subgroup of patients from the CARE trial who had 1 or more draining fistula at baseline, adalimumab treatment resulted in clinically meaningful rates of complete fistula healing by week Importantly, these results were durable, lasting until the assessment at week Although infliximab has been shown effective in short-term clinical trials for both induction and maintenance of response and remission in CD, less is known regarding the long-term durability of therapy.

Dibb and colleagues evaluated CD patients who had received treatment with infliximab between October and October The investigators created a database of patients, which recorded demographic characteristics, smoking status, the concomitant use of immu-nosuppressant agents, observations regarding disease type and anatomy, and assessments of adverse events and time to loss of response.

Loss of response to infliximab was defined as a requirement to either reduce the dosing interval or to increase the dose in order to recapture response. The median patient age was 39 years range: The extent of CD involvement represented included ileal An induction regimen of infliximab was administered at 0, 2, and 6 weeks. Among the remaining patients, most received scheduled infliximab maintenance therapy q 8 weekly or q 12 weekly , although The mean duration of infliximab therapy was No significant difference in the loss of response to infliximab was observed between patients who received 8-weekly doses versus weekly doses of maintenance therapy.

A response at 5 years was observed in a higher proportion of non-smokers compared with smokers Neither disease location nor age had a significant effect on the durability of infliximab response. An allergic reaction to infliximab was recorded in 9. Dyspnea leading to infliximab discontinuation occurred in 2 patients, and depression in 1 patient led to discontinuation of the drug. Perianal involvement and smoking increased the risk of poor long-term outcomes with infliximab therapy. The investigators also noted that due to the high proportion of patients who received concomitant treatment with immunosuppressant agents, the effect of these drugs on the durability of infliximab therapy could not be determined.

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Eligible patients had moderate-to-severe CD, a CDAI score between and , and a history of infliximab failure either due to lost response or the development of hypersensitivity reactions. A total of patients received certolizumab pegol mg at weeks 0, 2, and 4 as part of the open-label induction phase. Clinical response, defined as a decrease in CDAI of or more points from baseline, was assessed at week 6; nonresponders were withdrawn from the study.

Treatment was continued through week Remission was defined by a CDAI score of points or less. No significant difference in either the rates of response or remission was observed between the two certolizumab pegol schedule groups Table 2. The rate of patients achieving a CDAI response was also similar between the two groups The proportion of patients achieving remission was also not significantly different between the everyweek and everyweek treatment groups Sandborn and colleagues noted that over half For responding patients, a maintenance regimen schedule every 4 weeks was similar in efficacy to every 2 weeks.

The alphaintegrin receptor antagonist natalizumab is currently approved to treat CD. However, natalizumab therapy is associated with the development of progressive multifocal leukoencephalopathy PML , an opportunistic infection related to the presence of JC virus. Accordingly, natalizumab was removed from the US market, but was recently returned under a special prescription program requiring careful safety monitoring and data collection.

Several programs have been established to monitor the safety and efficacy of natalizumab. A pregnancy registry has also been initiated. Here, Sands and colleagues reported updated efficacy and safety data on natalizumab from these programs. Through September , approximately 48, patients CD and MS have been exposed to natalizumab through either a clinical study or post-marketing setting. Of over 35, patients currently receiving natalizumab, were being treated for CD. As of November , 3 cases all MS patients of PML had been confirmed among patients receiving natalizumab in the post-marketing setting; all 3 of these patients were alive at the time of preparation of this abstract.

A total of 64 women had been prospectively enrolled in the pregnancy registry at the time of this abstract; 27 healthy babies were delivered to 27 patients with no report of natalizumab-associated birth defects. Sands and colleagues concluded that according to the cumulative data available through each of these registries, the safety of natalizumab is similar to that observed during clinical trials. CD has a large economic burden.

The investigators obtained information from a database of beneficiaries compiled from 40 large self-insured employers in the United States between and Active employees with moderate-to-severe CD were identified and included if they had a record of receiving treatment immunosuppressant agents, corticosteroids, or biologic therapy within 6 months of a diagnosis of CD.

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Each CD patient was matched to 3 control employees without CD. Patient enrollment into this study was continued on a rolling basis for 1 year. All cost estimations are in US dollars. A total of 1, CD patients and 3, individuals without CD were included. The salary growth rate was determined at a compounded annualized rate, and adjusted for inflation.

Employees with CD experienced a 0. The investigators concluded that CD was associated with an important economic burden with significant increases in both direct and indirect adjusted medical costs, in comparison to unaffected controls. Additionally, CD patients have a lower annual salary growth, suggesting that career progression was limited by the disease. Shifting opinions on this subject have resulted from a lack of strong data supporting the benefit of combination therapy. In contrast, combined therapy with methotrexate and an anti-TNF is a standard of care in rheumatoid arthritis treatment, because the combination is synergistically effective and methotrexate is protective against the formation of anti-drug antibodies.

Furthermore, a biologic rationale for combination therapy has been documented. In vitro data suggest that both azathioprine and methotrexate increase lymphocyte apoptosis, which is one of the putative mechanisms of action of TNF antagonists. However, given the lack of empiric data to support these concepts in CD and widespread concerns regarding the possibility of increased toxicity, particularly opportunistic infections, considerable resistance to the use of combination therapy exists among clinicians.

Furthermore, during the past 4 years, concerns regarding rare cases of hepato-splenic T-cell lymphoma in young patients have resulted in increased use of TNF antagonist monotherapy at many IBD centers. SONIC has clearly shown that combination therapy is more effective than monotherapy with either azathioprine or infliximab.

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Corticosteroid-free remission rates were substantially higher for the combination at both 6-month and 1-year time points. The relative magnitude of the effect suggests an additive treatment effect, in distinction from true synergy. In addition, subgroup analyses provide further important information regarding optimal treatment strategies. The SONIC investigators assessed all patients at the baseline visit for active inflammation, by colonoscopy and measurement of the serum concentration of C-reactive protein CRP.

Patients without these characteristics showed no benefit over azathioprine monotherapy. These findings generate two important conclusions. First, the sickest patients are the most appropriate candidates for combination therapy. Second, objective assessment for active inflammation is mandatory before initiating combination therapy. Finally, SONIC provides important information regarding the risk of serious infection in patients receiving combination therapy. In contrast to the widely held belief that combination therapy is associated with a greater risk of serious infection than monotherapy with either azathioprine or infliximab, SONIC patients who received combination therapy were no more likely to develop infectious complications than those assigned to either monotherapy arm.

These results should change clinical practice. Mucosal healing is a goal of therapy that has received increased attention in recent years. Conceptually, if we are to favorably alter the natural history of IBD, mucosal ulceration must be both treated and prevented. Our traditional treatment approach has relied on evaluating symptoms to guide therapy.

However, corticosteroids control symptoms remarkably well but their use is not associated with high rates of complete mucosal healing or any change in longterm outcomes. It is possible that if mucosal healing becomes a primary treatment goal, higher rates of complication-free survival and reduced rates of hospitalization might be expected.

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Data do exist to support this notion. For example, studies in at least two of the three currently approved anti-TNF therapies have demonstrated that treatment decreases rates of hospitalization and surgery. The next step in the validation of this strategy would be to confirm the link between mucosal healing and prevention of those same major complications. Data from the EXTEND trial do not make this link explicit but the trial does provide compelling evidence that adalimumab can heal the colonic mucosa. As with all mucosal healing studies, interpretation of the data is complicated by our lack of insight into the clinical significance of the outcomes measured, as well as the heterogeneity of disease severity among the patients studied.

Although only borderline statistical significance was observed for the primary outcome measure, all of the secondary endpoints in EXTEND were statistically significant. Based on the consistency of these data, we can conclude that adalimumab is effective in healing the mucosa. Although it is tempting to compare the results of EXTEND to other mucosal healing trials of TNF antagonists, such contrasts should be discouraged because of differences in trial design, patient populations, outcome measures, and methods of analysis. The CARE trial was an open-label experience with adalimumab therapy.

Because the study assessed a large number of patients, it was possible to examine a subgroup of participants with fistulizing CD. The results show a benefit for adalimumab administration in closing fistulas. Dibb and colleagues preformed an open-label, retrospective review of the long-term outcomes of infliximab therapy.

In this real-world experience, the proportion of patients with long-term, steroid-free remission was low. Although the results call into question the durability of response with TNF antagonists, they are difficult to interpret because of the inability of the retrospective design to control for potential confounding factors. For example, the abstract provides no information on why patients stopped infliximab.

Was it due to patient or clinician preference, economic reasons, lack of efficacy, or poor tolerability? These are all reasons why patients discontinue maintenance therapy. Furthermore, these results are in direct contrast to prospectively collected observational data from Rutgeerts and colleagues that were recently published in Inflammatory Bowel Disease.

The discordance between the two studies underscores the need for further long-term study addressing this question. The WELCOME study evaluated the efficacy of two different dose regimens of certolizumab pegol in the treatment of patients with a secondary loss of response or intolerance to infliximab. Following a standard induction regimen of certolizumab pegol, responding patients were randomly assigned to an intense regimen consisting of mg of drug every 2 weeks or conventional once-monthly dosing.

This is an important finding, suggesting that certolizumab pegol is a valuable treatment option for an important clinical problem. Although the more intense dosing schedule in the maintenance phase did not translate into greater efficacy as a maintenance therapy, neither did it increase the rate of adverse events. This finding provides further reassurance for patients who are administered overlapping anti-TNF regimens due to drug failure, because a strong relationship between adverse events and drug exposure was not demonstrated.

Sands and associates evaluated safety issues associated with the alpha-4 integrin antagonist natalizumab. Since the introduction of natalizumab therapy for CD, its use has been restricted to patients who are refractory to other forms of medical therapy, due to concern for the risk of developing progressive multifocal leukoencephalopathy PML. This abstract presents data from two large post-marketing surveillance programs that are mandated by regulatory authorities in both the United States and Europe.

Both multiple sclerosis and CD patients were evaluated. These are important data because gastroenterologists have been reluctant to utilize natalizumab, due to the perception that it is less safe than other biologics.


The current data suggest that this is not the case and that the overall rates of serious infectious complications are similar to those with TNF antagonists. The cases of PML observed have been detected early in the course of the disease and pheresis therapy to remove the drug from the blood has been initiated. These measures seem to have improved the outcome of patients who developed this serious complication.

However, the stigma of neurological complications from PML has greatly influenced prescribing behavior. Whether this is appropriate remains an open question. The final study addresses the economic burden and impact of CD. This information will be of interest to both employers and third party payers. The authors have demonstrated that patients with the disease have a slower rate of growth in annual salary and are likely disadvantaged in the work force.

Overall, these studies reflect many of the current opportunities and challenges associated with the new era of biologic therapy for CD. Multiple new biologic agents are on the horizon and hold out the promise of better long-term outcomes for our patients. Future research will continue to focus on strategies that will ultimately alter the natural history of the disease. Circle the correct answer for each question below.

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National Center for Biotechnology Information , U. Gastroenterol Hepatol N Y. Author information Copyright and License information Disclaimer. Open in a separate window. Cordoba J, Minguez B. The treatment of hepatic encephalopathy. Non-absorbable disaccharides for hepatic encephalopathy: Treatment of hepatic encephalopathy. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy.

Conn H, Bircher J. Adverse reactions and side effects of lactulose and related agents.


Conn H, Bircher J, editors. Results from a Phase 3 Placebo-Controlled Trial. Rifaximin for the treatment of hepatic encephalopathy. Expert Rev Anti Infect Ther. The effect of multiple-dose, oral rifaximin on the pharmacokinetics of intravenous and oral midazolam in healthy volunteers. Bass , MD, PhD. Suggested Reading Bass NM. Rifaximin, a nonabsorbed oral antibiotic, in the treatment of hepatic encephalopathy: The role of hepatic encephalopathy in the era of MELD. Protein restriction in hepatic encephalopathy: Complete fistula healing stratified by anti-TNF history: One Year Data from the Sonic Study: Biological therapies for inflammatory bowel diseases.


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Frontiers in Physiology | Gastrointestinal Sciences

About Frontiers Research Topics. View all Learn More Submit your manuscript. Scope Gastrointestinal Sciences aims to publish significant basic and clinical research findings in the field. This section has no chief editors. Learn more View all Suggest a Topic. Further, we enthusiastically encourage submissions of research findings that demonstrate the mechanisms that underlie the regulation of the gastrointestinal tract and its organs by dietary factors, the microbial community, and the innate immune system of the gut. In addition to articles addressing normal and adaptive physiologic mechanisms of regulation, the specialty section is interested in reports that demonstrate the pathways resulting in organ failure or disease when normal adaptive physiologic mechanisms are disrupted.

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