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Navigating the complex landscape of IBD therapies
I provided an update on existing, new, and upcoming medical therapies for Crohn’s disease (CD) and ulcerative colitis (UC), with a focus on studies presented at Digestive Disease Week® 2017.
In one study of over 13,000 inflammatory bowel disease (IBD) patients in Medicare/Medicaid databases, it was found that among those treated with corticosteroids in the previous year, patients started on a tumor necrosis factor (TNF) inhibitor within the next year had mortality rates that were at least 22% lower than those of patients treated with prolonged corticosteroids over the next 12 months (Gastroenterology. 2017;152[5 Suppl 1]:S65-5). Initial results of the CALM study were presented, comparing a treat-to-target (T2T) algorithmic medical escalation approach in moderate to severe CD to a more conventional approach. Medical therapy was primarily adalimumab based and was escalated based on “success criteria,” which included not only symptomatic remission but also normalization of serum C-reactive protein and fecal calprotectin. At week 48, the rate of endoscopic remission was significantly higher (45.9%) in the T2T group than in conventionally managed patients (30.3%, P = .01), thus demonstrating the superiority of a T2T approach (Gastroenterology 2017;152[5 Suppl 1]:S155).
Ustekinumab is a monoclonal antibody to interleukins 12 and 23, and was approved for moderate to severe CD last year on the basis of the pivotal UNITI-1, UNITI-2, and IM-UNITI trials (N Engl J Med. 2016;375:1946-60). A weight-based intravenous loading dose was shown to be effective at inducing clinical response in both patients who had failed or were intolerant to anti-TNF therapy and those who had not. The responders in both induction trials were randomized to two subcutaneous doses of ustekinumab or placebo, and at the end of the 44-week trial, the drug met multiple efficacy endpoints, including clinical remission, clinical response, steroid-free remission, and sustained clinical remission. In another abstract, the rate of tuberculosis reactivation within the clinical development program of ustekinumab across all indications (6,581 patients, over 12,000 patient-years of follow-up) was significantly lower at 0.02 cases per 100 patient-years compared with the rates seen in the golimumab (0.24 per 100) and infliximab (0.39 per 100) development programs (Gastroenterology 2017;152[5 Suppl 1]:S596), illustrating that the safety profile of ustekinumab may be significantly different from that of anti-TNF agents.
Tofacitinib, which inhibits mainly JAK1 and JAK3 receptors, is an emergent oral small molecule drug for UC. Three phase 3 randomized placebo-controlled trials (OCTAVE-1, OCTAVE-2, and OCTAVE Sustain) of tofacitinib treatment in moderately to severely active UC patients have been recently published (N Engl J Med. 2017;376:1723-36). The rates of clinical remission at week 8 were significantly greater in patients who were treated with 10 mg tofacitinib than placebo in both induction trials, and results were similar regardless of anti-TNF exposure status. Clinical responders in the induction studies were randomized to placebo or two doses of tofacitinib. At week 52, remission rates were significantly higher in the patients treated with 10 mg tofacitinib twice daily and 5 mg tofacitinib twice daily than those receiving placebo. The percentages of tofacitinib-treated patients who achieved mucosal healing were significantly greater than those in the placebo group. Serious infections occurred significantly more frequently in the tofacitinib than placebo group during induction, but not during maintenance. However, rates of herpes zoster were higher with maintenance therapy at 10 mg twice daily (5.1%) than with placebo (0.5%). A recently published phase 2 study of filgotinib, a selective JAK1 inhibitor, reported that the remission rate at week 10 was significantly higher in active CD patients receiving 200 mg of filgotinib daily than in those receiving placebo (Lancet 2017;389:266-75). A phase 2 trial of another selective JAK1 inhibitor, upadacitinib (ABT-494), for induction therapy in CD patients with a history of failure or intolerance to TNF-antagonists, was presented at DDW (Gastroenterology 2017;152[5 Suppl 1]:S1308-9). Higher rates of clinical remission at week 16 were seen in patients on 6 mg upadacitinib twice daily than placebo, and several doses of upadacitinib were significantly better than placebo for inducing endoscopic remission at week 12 or 16. Serious adverse events were seen in 9%-15% of CD patients treated with these two agents (vs. 4%-5% in placebo-treated patients).
Smad7 regulates the signaling of transforming growth factor (TGF)-beta1, an anti-inflammatory cytokine. Mongersen is an orally delivered anti-sense oligonucleotide that inhibits Smad7 and restores TGF-beta1 signaling, and is being developed for CD. The efficacy of induction therapy for active CD patients with limited active disease (terminal ileum or proximal colon) was demonstrated in a phase 2 study (N Engl J Med. 2015;372:1104-13). Interestingly, this study showed significantly higher rates of clinical remission at day 15 with mongersen. However, there were no endoscopic data available in this trial, baseline serum C-reactive protein concentrations were low, and did not decrease significantly. This drug appears to be well tolerated, and serious adverse events were not significantly higher than for placebo. In a phase 1b study, correlations between clinical and endoscopic outcomes were explored, and among 52 CD patients, SES-CD reductions of at least 25% at week 12 were seen in 37% of mongersen-treated patients (Gastroenterology. 2017;152[5 Suppl 1]:S198).
In summary, the future of IBD medical therapy is bright due to the recent introduction of therapies with novel mechanisms of action and favorable safety profiles (e.g., vedolizumab and ustekinumab), potentially lower-cost biosimilars, and multiple compounds in the drug development pipeline.
Dr. Loftus is professor of medicine, Mayo Clinic College of Medicine, director of the Inflammatory Bowel Disease Interest Group, the division of gastroenterology and hepatology, Rochester, Minn. He made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
I provided an update on existing, new, and upcoming medical therapies for Crohn’s disease (CD) and ulcerative colitis (UC), with a focus on studies presented at Digestive Disease Week® 2017.
In one study of over 13,000 inflammatory bowel disease (IBD) patients in Medicare/Medicaid databases, it was found that among those treated with corticosteroids in the previous year, patients started on a tumor necrosis factor (TNF) inhibitor within the next year had mortality rates that were at least 22% lower than those of patients treated with prolonged corticosteroids over the next 12 months (Gastroenterology. 2017;152[5 Suppl 1]:S65-5). Initial results of the CALM study were presented, comparing a treat-to-target (T2T) algorithmic medical escalation approach in moderate to severe CD to a more conventional approach. Medical therapy was primarily adalimumab based and was escalated based on “success criteria,” which included not only symptomatic remission but also normalization of serum C-reactive protein and fecal calprotectin. At week 48, the rate of endoscopic remission was significantly higher (45.9%) in the T2T group than in conventionally managed patients (30.3%, P = .01), thus demonstrating the superiority of a T2T approach (Gastroenterology 2017;152[5 Suppl 1]:S155).
Ustekinumab is a monoclonal antibody to interleukins 12 and 23, and was approved for moderate to severe CD last year on the basis of the pivotal UNITI-1, UNITI-2, and IM-UNITI trials (N Engl J Med. 2016;375:1946-60). A weight-based intravenous loading dose was shown to be effective at inducing clinical response in both patients who had failed or were intolerant to anti-TNF therapy and those who had not. The responders in both induction trials were randomized to two subcutaneous doses of ustekinumab or placebo, and at the end of the 44-week trial, the drug met multiple efficacy endpoints, including clinical remission, clinical response, steroid-free remission, and sustained clinical remission. In another abstract, the rate of tuberculosis reactivation within the clinical development program of ustekinumab across all indications (6,581 patients, over 12,000 patient-years of follow-up) was significantly lower at 0.02 cases per 100 patient-years compared with the rates seen in the golimumab (0.24 per 100) and infliximab (0.39 per 100) development programs (Gastroenterology 2017;152[5 Suppl 1]:S596), illustrating that the safety profile of ustekinumab may be significantly different from that of anti-TNF agents.
Tofacitinib, which inhibits mainly JAK1 and JAK3 receptors, is an emergent oral small molecule drug for UC. Three phase 3 randomized placebo-controlled trials (OCTAVE-1, OCTAVE-2, and OCTAVE Sustain) of tofacitinib treatment in moderately to severely active UC patients have been recently published (N Engl J Med. 2017;376:1723-36). The rates of clinical remission at week 8 were significantly greater in patients who were treated with 10 mg tofacitinib than placebo in both induction trials, and results were similar regardless of anti-TNF exposure status. Clinical responders in the induction studies were randomized to placebo or two doses of tofacitinib. At week 52, remission rates were significantly higher in the patients treated with 10 mg tofacitinib twice daily and 5 mg tofacitinib twice daily than those receiving placebo. The percentages of tofacitinib-treated patients who achieved mucosal healing were significantly greater than those in the placebo group. Serious infections occurred significantly more frequently in the tofacitinib than placebo group during induction, but not during maintenance. However, rates of herpes zoster were higher with maintenance therapy at 10 mg twice daily (5.1%) than with placebo (0.5%). A recently published phase 2 study of filgotinib, a selective JAK1 inhibitor, reported that the remission rate at week 10 was significantly higher in active CD patients receiving 200 mg of filgotinib daily than in those receiving placebo (Lancet 2017;389:266-75). A phase 2 trial of another selective JAK1 inhibitor, upadacitinib (ABT-494), for induction therapy in CD patients with a history of failure or intolerance to TNF-antagonists, was presented at DDW (Gastroenterology 2017;152[5 Suppl 1]:S1308-9). Higher rates of clinical remission at week 16 were seen in patients on 6 mg upadacitinib twice daily than placebo, and several doses of upadacitinib were significantly better than placebo for inducing endoscopic remission at week 12 or 16. Serious adverse events were seen in 9%-15% of CD patients treated with these two agents (vs. 4%-5% in placebo-treated patients).
Smad7 regulates the signaling of transforming growth factor (TGF)-beta1, an anti-inflammatory cytokine. Mongersen is an orally delivered anti-sense oligonucleotide that inhibits Smad7 and restores TGF-beta1 signaling, and is being developed for CD. The efficacy of induction therapy for active CD patients with limited active disease (terminal ileum or proximal colon) was demonstrated in a phase 2 study (N Engl J Med. 2015;372:1104-13). Interestingly, this study showed significantly higher rates of clinical remission at day 15 with mongersen. However, there were no endoscopic data available in this trial, baseline serum C-reactive protein concentrations were low, and did not decrease significantly. This drug appears to be well tolerated, and serious adverse events were not significantly higher than for placebo. In a phase 1b study, correlations between clinical and endoscopic outcomes were explored, and among 52 CD patients, SES-CD reductions of at least 25% at week 12 were seen in 37% of mongersen-treated patients (Gastroenterology. 2017;152[5 Suppl 1]:S198).
In summary, the future of IBD medical therapy is bright due to the recent introduction of therapies with novel mechanisms of action and favorable safety profiles (e.g., vedolizumab and ustekinumab), potentially lower-cost biosimilars, and multiple compounds in the drug development pipeline.
Dr. Loftus is professor of medicine, Mayo Clinic College of Medicine, director of the Inflammatory Bowel Disease Interest Group, the division of gastroenterology and hepatology, Rochester, Minn. He made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
I provided an update on existing, new, and upcoming medical therapies for Crohn’s disease (CD) and ulcerative colitis (UC), with a focus on studies presented at Digestive Disease Week® 2017.
In one study of over 13,000 inflammatory bowel disease (IBD) patients in Medicare/Medicaid databases, it was found that among those treated with corticosteroids in the previous year, patients started on a tumor necrosis factor (TNF) inhibitor within the next year had mortality rates that were at least 22% lower than those of patients treated with prolonged corticosteroids over the next 12 months (Gastroenterology. 2017;152[5 Suppl 1]:S65-5). Initial results of the CALM study were presented, comparing a treat-to-target (T2T) algorithmic medical escalation approach in moderate to severe CD to a more conventional approach. Medical therapy was primarily adalimumab based and was escalated based on “success criteria,” which included not only symptomatic remission but also normalization of serum C-reactive protein and fecal calprotectin. At week 48, the rate of endoscopic remission was significantly higher (45.9%) in the T2T group than in conventionally managed patients (30.3%, P = .01), thus demonstrating the superiority of a T2T approach (Gastroenterology 2017;152[5 Suppl 1]:S155).
Ustekinumab is a monoclonal antibody to interleukins 12 and 23, and was approved for moderate to severe CD last year on the basis of the pivotal UNITI-1, UNITI-2, and IM-UNITI trials (N Engl J Med. 2016;375:1946-60). A weight-based intravenous loading dose was shown to be effective at inducing clinical response in both patients who had failed or were intolerant to anti-TNF therapy and those who had not. The responders in both induction trials were randomized to two subcutaneous doses of ustekinumab or placebo, and at the end of the 44-week trial, the drug met multiple efficacy endpoints, including clinical remission, clinical response, steroid-free remission, and sustained clinical remission. In another abstract, the rate of tuberculosis reactivation within the clinical development program of ustekinumab across all indications (6,581 patients, over 12,000 patient-years of follow-up) was significantly lower at 0.02 cases per 100 patient-years compared with the rates seen in the golimumab (0.24 per 100) and infliximab (0.39 per 100) development programs (Gastroenterology 2017;152[5 Suppl 1]:S596), illustrating that the safety profile of ustekinumab may be significantly different from that of anti-TNF agents.
Tofacitinib, which inhibits mainly JAK1 and JAK3 receptors, is an emergent oral small molecule drug for UC. Three phase 3 randomized placebo-controlled trials (OCTAVE-1, OCTAVE-2, and OCTAVE Sustain) of tofacitinib treatment in moderately to severely active UC patients have been recently published (N Engl J Med. 2017;376:1723-36). The rates of clinical remission at week 8 were significantly greater in patients who were treated with 10 mg tofacitinib than placebo in both induction trials, and results were similar regardless of anti-TNF exposure status. Clinical responders in the induction studies were randomized to placebo or two doses of tofacitinib. At week 52, remission rates were significantly higher in the patients treated with 10 mg tofacitinib twice daily and 5 mg tofacitinib twice daily than those receiving placebo. The percentages of tofacitinib-treated patients who achieved mucosal healing were significantly greater than those in the placebo group. Serious infections occurred significantly more frequently in the tofacitinib than placebo group during induction, but not during maintenance. However, rates of herpes zoster were higher with maintenance therapy at 10 mg twice daily (5.1%) than with placebo (0.5%). A recently published phase 2 study of filgotinib, a selective JAK1 inhibitor, reported that the remission rate at week 10 was significantly higher in active CD patients receiving 200 mg of filgotinib daily than in those receiving placebo (Lancet 2017;389:266-75). A phase 2 trial of another selective JAK1 inhibitor, upadacitinib (ABT-494), for induction therapy in CD patients with a history of failure or intolerance to TNF-antagonists, was presented at DDW (Gastroenterology 2017;152[5 Suppl 1]:S1308-9). Higher rates of clinical remission at week 16 were seen in patients on 6 mg upadacitinib twice daily than placebo, and several doses of upadacitinib were significantly better than placebo for inducing endoscopic remission at week 12 or 16. Serious adverse events were seen in 9%-15% of CD patients treated with these two agents (vs. 4%-5% in placebo-treated patients).
Smad7 regulates the signaling of transforming growth factor (TGF)-beta1, an anti-inflammatory cytokine. Mongersen is an orally delivered anti-sense oligonucleotide that inhibits Smad7 and restores TGF-beta1 signaling, and is being developed for CD. The efficacy of induction therapy for active CD patients with limited active disease (terminal ileum or proximal colon) was demonstrated in a phase 2 study (N Engl J Med. 2015;372:1104-13). Interestingly, this study showed significantly higher rates of clinical remission at day 15 with mongersen. However, there were no endoscopic data available in this trial, baseline serum C-reactive protein concentrations were low, and did not decrease significantly. This drug appears to be well tolerated, and serious adverse events were not significantly higher than for placebo. In a phase 1b study, correlations between clinical and endoscopic outcomes were explored, and among 52 CD patients, SES-CD reductions of at least 25% at week 12 were seen in 37% of mongersen-treated patients (Gastroenterology. 2017;152[5 Suppl 1]:S198).
In summary, the future of IBD medical therapy is bright due to the recent introduction of therapies with novel mechanisms of action and favorable safety profiles (e.g., vedolizumab and ustekinumab), potentially lower-cost biosimilars, and multiple compounds in the drug development pipeline.
Dr. Loftus is professor of medicine, Mayo Clinic College of Medicine, director of the Inflammatory Bowel Disease Interest Group, the division of gastroenterology and hepatology, Rochester, Minn. He made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
Role of fidaxomicin for C. difficile infection continues to evolve
SAN FRANCISCO– The role of fidaxomicin for treating mild to moderate Clostridium difficile infection is still finding its way, according to Sarah Doernberg, MD.
For now, fidaxomicin, a narrow spectrum macrocyclic antibiotic, may be appropriate for those at high risk for relapse and/or those requiring concomitant antibiotics – but its high price tag may be prohibitive.
“I think a lot of centers have taken the fidaxomicin data, which were based on patients with initial infection or a single relapse, and extrapolated it to patients with multiple relapses,” Dr. Doernberg, medical director of adult antimicrobial stewardship at UCSF Medical Center, said at the UCSF Annual Advances in Internal Medicine meeting.
In a recent analysis, researchers collected real-world data on implementation of fidaxomicin for CDI patients at seven hospitals in the United Kingdom (Eur J Clin Microbiol Infect Dis. 2016 Feb;35[2]:251-9). In two hospitals where fidaxomicin was used as the first-line treatment for all primary and recurrent episodes, the recurrence rate reduced from 10.6% to 3.1% and from 16.3% to 3.1%, with a significant difference in 28-day mortality, from 18.2% to 3.1%; (P less than .05) and 17.3% to 6.3% (P less than .05). In the remaining five hospitals that used fidaxomicin in selected patients only, the changes in recurrence rates and mortality were less marked.
Other studies have found that fidaxomicin has a similar cure rate, compared with vancomycin (around 88%) but a lower recurrence rate (13%-15%, compared with 25%-27%, respectively; see N Engl J Med. 2011 Feb 3;364[5]:422-31). However, the general cost for a course is significantly more, compared with metronidazole and vancomycin, making fidaxomicin less cost effective as a first-line agent in most cases (Clin Infect Dis. 2013 Aug 15; 57[4]:555-61).
“Our guidelines recommend it in patients who have a very high risk for relapse who would not be candidates for fecal transplant down the line, which generally means immunocompromised patients,” Dr. Doernberg said.
Additional considerations when treating CDI include stopping unnecessary antibiotics, shortening the antibiotic course, narrowing the antibiotic spectrum, and stopping acid-suppressive medication when possible, especially proton pump inhibitors. “Do no use anti-peristaltic agents until acute symptoms of CDI improve,” she said.
Dr. Doernberg disclosed that she is a consultant for Actelion. She has also conducted prior research studies with Cerexa, Cubist, and Merck.
SAN FRANCISCO– The role of fidaxomicin for treating mild to moderate Clostridium difficile infection is still finding its way, according to Sarah Doernberg, MD.
For now, fidaxomicin, a narrow spectrum macrocyclic antibiotic, may be appropriate for those at high risk for relapse and/or those requiring concomitant antibiotics – but its high price tag may be prohibitive.
“I think a lot of centers have taken the fidaxomicin data, which were based on patients with initial infection or a single relapse, and extrapolated it to patients with multiple relapses,” Dr. Doernberg, medical director of adult antimicrobial stewardship at UCSF Medical Center, said at the UCSF Annual Advances in Internal Medicine meeting.
In a recent analysis, researchers collected real-world data on implementation of fidaxomicin for CDI patients at seven hospitals in the United Kingdom (Eur J Clin Microbiol Infect Dis. 2016 Feb;35[2]:251-9). In two hospitals where fidaxomicin was used as the first-line treatment for all primary and recurrent episodes, the recurrence rate reduced from 10.6% to 3.1% and from 16.3% to 3.1%, with a significant difference in 28-day mortality, from 18.2% to 3.1%; (P less than .05) and 17.3% to 6.3% (P less than .05). In the remaining five hospitals that used fidaxomicin in selected patients only, the changes in recurrence rates and mortality were less marked.
Other studies have found that fidaxomicin has a similar cure rate, compared with vancomycin (around 88%) but a lower recurrence rate (13%-15%, compared with 25%-27%, respectively; see N Engl J Med. 2011 Feb 3;364[5]:422-31). However, the general cost for a course is significantly more, compared with metronidazole and vancomycin, making fidaxomicin less cost effective as a first-line agent in most cases (Clin Infect Dis. 2013 Aug 15; 57[4]:555-61).
“Our guidelines recommend it in patients who have a very high risk for relapse who would not be candidates for fecal transplant down the line, which generally means immunocompromised patients,” Dr. Doernberg said.
Additional considerations when treating CDI include stopping unnecessary antibiotics, shortening the antibiotic course, narrowing the antibiotic spectrum, and stopping acid-suppressive medication when possible, especially proton pump inhibitors. “Do no use anti-peristaltic agents until acute symptoms of CDI improve,” she said.
Dr. Doernberg disclosed that she is a consultant for Actelion. She has also conducted prior research studies with Cerexa, Cubist, and Merck.
SAN FRANCISCO– The role of fidaxomicin for treating mild to moderate Clostridium difficile infection is still finding its way, according to Sarah Doernberg, MD.
For now, fidaxomicin, a narrow spectrum macrocyclic antibiotic, may be appropriate for those at high risk for relapse and/or those requiring concomitant antibiotics – but its high price tag may be prohibitive.
“I think a lot of centers have taken the fidaxomicin data, which were based on patients with initial infection or a single relapse, and extrapolated it to patients with multiple relapses,” Dr. Doernberg, medical director of adult antimicrobial stewardship at UCSF Medical Center, said at the UCSF Annual Advances in Internal Medicine meeting.
In a recent analysis, researchers collected real-world data on implementation of fidaxomicin for CDI patients at seven hospitals in the United Kingdom (Eur J Clin Microbiol Infect Dis. 2016 Feb;35[2]:251-9). In two hospitals where fidaxomicin was used as the first-line treatment for all primary and recurrent episodes, the recurrence rate reduced from 10.6% to 3.1% and from 16.3% to 3.1%, with a significant difference in 28-day mortality, from 18.2% to 3.1%; (P less than .05) and 17.3% to 6.3% (P less than .05). In the remaining five hospitals that used fidaxomicin in selected patients only, the changes in recurrence rates and mortality were less marked.
Other studies have found that fidaxomicin has a similar cure rate, compared with vancomycin (around 88%) but a lower recurrence rate (13%-15%, compared with 25%-27%, respectively; see N Engl J Med. 2011 Feb 3;364[5]:422-31). However, the general cost for a course is significantly more, compared with metronidazole and vancomycin, making fidaxomicin less cost effective as a first-line agent in most cases (Clin Infect Dis. 2013 Aug 15; 57[4]:555-61).
“Our guidelines recommend it in patients who have a very high risk for relapse who would not be candidates for fecal transplant down the line, which generally means immunocompromised patients,” Dr. Doernberg said.
Additional considerations when treating CDI include stopping unnecessary antibiotics, shortening the antibiotic course, narrowing the antibiotic spectrum, and stopping acid-suppressive medication when possible, especially proton pump inhibitors. “Do no use anti-peristaltic agents until acute symptoms of CDI improve,” she said.
Dr. Doernberg disclosed that she is a consultant for Actelion. She has also conducted prior research studies with Cerexa, Cubist, and Merck.
AT THE ANNUAL ADVANCES IN INTERNAL MEDICINE
AGA Guideline: Therapeutic drug monitoring in IBD
Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).
Therapeutic drug monitoring can help guide whether to ramp up a dose (if the trough level is below the threshold) or switch therapy (if the trough level is above the threshold) when patients are not responding adequately to maintenance treatment. A nonresponder with optimal trough concentrations might need to switch drug classes, the guideline noted. A patient with low trough levels and no antidrug antibodies is probably experiencing rapid drug clearance in the setting of high inflammation. A patient with low or undetectable trough levels and high antidrug antibody titers has developed neutralizing antidrug antibodies. However, trough concentrations can vary for many other reasons, ranging from disease severity and inflammation to body mass index and sex. Therefore, target levels also vary and can be challenging to set.
The AGA makes no recommendation about routine, proactive TDM in patients with quiescent IBD who are on anti-TNF agents. While proactive TDM can shed light on endoscopic response and drug clearance, it might also trigger a premature switch of therapies; this is particularly likely because physicians have sparse data on either target trough levels for asymptomatic patients or the clinical significance of “low-titer” antidrug antibodies. The optimal frequency of proactive TDM also remains unclear.
Pending better data, the AGA recommended checking infliximab or adalimumab trough levels as close to the next dose as possible – that is, within 24 hours. Drug trough levels are consistent across commercial assays, but antidrug antibody titers are not, and there are no uniform thresholds for clinically relevant antidrug antibody titers. “Therefore, it may be beneficial to utilize the same assay when checking for trough concentration and antidrug antibodies,” the guideline stated.
For patients on a thiopurine, routine testing of thiopurine methyltransferase (TPMT) enzyme or genotype is recommended to guide dosing. In three pooled studies comprising 1,145 patients, only two patients were homozygous; further, rates of hematologic adverse events, clinical remission, and treatment discontinuation did not differ based on TPMT testing itself. However, using TPMT testing to guide dosing was associated with an 89% decrease in the risk of hematologic adverse events among patients who had a homozygous genotype or had low or absent TPMT enzymatic activity. “While this risk may be mitigated by routine laboratory CBC checking, adherence to regular monitoring in clinical practice is suboptimal,” the guideline stated. “It is important to continue to perform routine lab monitoring [of] CBC and liver enzymes after starting a thiopurine, regardless of the TPMT testing results.”
The AGA also conditionally supported reactive monitoring of thiopurine metabolites to guide treatment changes if patients develop breakthrough symptoms or treatment-related adverse effects. For active IBD symptoms in spite of thiopurine monotherapy, a target 6-thioguanine (6-TGN) cutoff between 230 and 450 pmol per 8 x 108 RBC is recommended. Again, supporting evidence is of “very low quality” – in a retrospective, observational study, patients who received treatment according to a TDM algorithm were five times more likely to respond to a change in therapy (relative risk, 5.2). The guideline recommended against monitoring thiopurine metabolites in quiescent IBD. Studies did not support this practice, compared with standard dosing, although no study of thiopurine metabolites included patients on thiopurine/anti-TNF combination therapy, the guideline’s authors noted.
The guideline includes clinical-decision support tools on when to perform TDM and how to interpret results when patients are taking an anti-TNF agent or a thiopurine. The guideline does not cover vedolizumab or ustekinumab because data are sparse. Other knowledge gaps include when best to measure trough concentrations; whether empiric dose escalation or TDM is preferred if response to induction is suboptimal; how target trough concentrations vary based on disease phenotype, disease state, or treatment goals; which levels and durations of antidrug antibody titers are clinically significant; and whether to suppress antidrug antibodies before changing therapy. Future studies should compare routine proactive and reactive TDM, investigate how often to perform proactive TDM, and characterize TDM of newly approved biologic agents, the guideline concluded.
The authors of the guideline document disclosed no conflicts related to the guideline topic.
Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).
Therapeutic drug monitoring can help guide whether to ramp up a dose (if the trough level is below the threshold) or switch therapy (if the trough level is above the threshold) when patients are not responding adequately to maintenance treatment. A nonresponder with optimal trough concentrations might need to switch drug classes, the guideline noted. A patient with low trough levels and no antidrug antibodies is probably experiencing rapid drug clearance in the setting of high inflammation. A patient with low or undetectable trough levels and high antidrug antibody titers has developed neutralizing antidrug antibodies. However, trough concentrations can vary for many other reasons, ranging from disease severity and inflammation to body mass index and sex. Therefore, target levels also vary and can be challenging to set.
The AGA makes no recommendation about routine, proactive TDM in patients with quiescent IBD who are on anti-TNF agents. While proactive TDM can shed light on endoscopic response and drug clearance, it might also trigger a premature switch of therapies; this is particularly likely because physicians have sparse data on either target trough levels for asymptomatic patients or the clinical significance of “low-titer” antidrug antibodies. The optimal frequency of proactive TDM also remains unclear.
Pending better data, the AGA recommended checking infliximab or adalimumab trough levels as close to the next dose as possible – that is, within 24 hours. Drug trough levels are consistent across commercial assays, but antidrug antibody titers are not, and there are no uniform thresholds for clinically relevant antidrug antibody titers. “Therefore, it may be beneficial to utilize the same assay when checking for trough concentration and antidrug antibodies,” the guideline stated.
For patients on a thiopurine, routine testing of thiopurine methyltransferase (TPMT) enzyme or genotype is recommended to guide dosing. In three pooled studies comprising 1,145 patients, only two patients were homozygous; further, rates of hematologic adverse events, clinical remission, and treatment discontinuation did not differ based on TPMT testing itself. However, using TPMT testing to guide dosing was associated with an 89% decrease in the risk of hematologic adverse events among patients who had a homozygous genotype or had low or absent TPMT enzymatic activity. “While this risk may be mitigated by routine laboratory CBC checking, adherence to regular monitoring in clinical practice is suboptimal,” the guideline stated. “It is important to continue to perform routine lab monitoring [of] CBC and liver enzymes after starting a thiopurine, regardless of the TPMT testing results.”
The AGA also conditionally supported reactive monitoring of thiopurine metabolites to guide treatment changes if patients develop breakthrough symptoms or treatment-related adverse effects. For active IBD symptoms in spite of thiopurine monotherapy, a target 6-thioguanine (6-TGN) cutoff between 230 and 450 pmol per 8 x 108 RBC is recommended. Again, supporting evidence is of “very low quality” – in a retrospective, observational study, patients who received treatment according to a TDM algorithm were five times more likely to respond to a change in therapy (relative risk, 5.2). The guideline recommended against monitoring thiopurine metabolites in quiescent IBD. Studies did not support this practice, compared with standard dosing, although no study of thiopurine metabolites included patients on thiopurine/anti-TNF combination therapy, the guideline’s authors noted.
The guideline includes clinical-decision support tools on when to perform TDM and how to interpret results when patients are taking an anti-TNF agent or a thiopurine. The guideline does not cover vedolizumab or ustekinumab because data are sparse. Other knowledge gaps include when best to measure trough concentrations; whether empiric dose escalation or TDM is preferred if response to induction is suboptimal; how target trough concentrations vary based on disease phenotype, disease state, or treatment goals; which levels and durations of antidrug antibody titers are clinically significant; and whether to suppress antidrug antibodies before changing therapy. Future studies should compare routine proactive and reactive TDM, investigate how often to perform proactive TDM, and characterize TDM of newly approved biologic agents, the guideline concluded.
The authors of the guideline document disclosed no conflicts related to the guideline topic.
Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).
Therapeutic drug monitoring can help guide whether to ramp up a dose (if the trough level is below the threshold) or switch therapy (if the trough level is above the threshold) when patients are not responding adequately to maintenance treatment. A nonresponder with optimal trough concentrations might need to switch drug classes, the guideline noted. A patient with low trough levels and no antidrug antibodies is probably experiencing rapid drug clearance in the setting of high inflammation. A patient with low or undetectable trough levels and high antidrug antibody titers has developed neutralizing antidrug antibodies. However, trough concentrations can vary for many other reasons, ranging from disease severity and inflammation to body mass index and sex. Therefore, target levels also vary and can be challenging to set.
The AGA makes no recommendation about routine, proactive TDM in patients with quiescent IBD who are on anti-TNF agents. While proactive TDM can shed light on endoscopic response and drug clearance, it might also trigger a premature switch of therapies; this is particularly likely because physicians have sparse data on either target trough levels for asymptomatic patients or the clinical significance of “low-titer” antidrug antibodies. The optimal frequency of proactive TDM also remains unclear.
Pending better data, the AGA recommended checking infliximab or adalimumab trough levels as close to the next dose as possible – that is, within 24 hours. Drug trough levels are consistent across commercial assays, but antidrug antibody titers are not, and there are no uniform thresholds for clinically relevant antidrug antibody titers. “Therefore, it may be beneficial to utilize the same assay when checking for trough concentration and antidrug antibodies,” the guideline stated.
For patients on a thiopurine, routine testing of thiopurine methyltransferase (TPMT) enzyme or genotype is recommended to guide dosing. In three pooled studies comprising 1,145 patients, only two patients were homozygous; further, rates of hematologic adverse events, clinical remission, and treatment discontinuation did not differ based on TPMT testing itself. However, using TPMT testing to guide dosing was associated with an 89% decrease in the risk of hematologic adverse events among patients who had a homozygous genotype or had low or absent TPMT enzymatic activity. “While this risk may be mitigated by routine laboratory CBC checking, adherence to regular monitoring in clinical practice is suboptimal,” the guideline stated. “It is important to continue to perform routine lab monitoring [of] CBC and liver enzymes after starting a thiopurine, regardless of the TPMT testing results.”
The AGA also conditionally supported reactive monitoring of thiopurine metabolites to guide treatment changes if patients develop breakthrough symptoms or treatment-related adverse effects. For active IBD symptoms in spite of thiopurine monotherapy, a target 6-thioguanine (6-TGN) cutoff between 230 and 450 pmol per 8 x 108 RBC is recommended. Again, supporting evidence is of “very low quality” – in a retrospective, observational study, patients who received treatment according to a TDM algorithm were five times more likely to respond to a change in therapy (relative risk, 5.2). The guideline recommended against monitoring thiopurine metabolites in quiescent IBD. Studies did not support this practice, compared with standard dosing, although no study of thiopurine metabolites included patients on thiopurine/anti-TNF combination therapy, the guideline’s authors noted.
The guideline includes clinical-decision support tools on when to perform TDM and how to interpret results when patients are taking an anti-TNF agent or a thiopurine. The guideline does not cover vedolizumab or ustekinumab because data are sparse. Other knowledge gaps include when best to measure trough concentrations; whether empiric dose escalation or TDM is preferred if response to induction is suboptimal; how target trough concentrations vary based on disease phenotype, disease state, or treatment goals; which levels and durations of antidrug antibody titers are clinically significant; and whether to suppress antidrug antibodies before changing therapy. Future studies should compare routine proactive and reactive TDM, investigate how often to perform proactive TDM, and characterize TDM of newly approved biologic agents, the guideline concluded.
The authors of the guideline document disclosed no conflicts related to the guideline topic.
FROM GASTROENTEROLOGY
AGA Clinical Practice Update: Opioids in gastroenterology
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
Physicians should consistently rule out opioid therapy as the cause of gastrointestinal symptoms, states a new clinical practice update published in the September 2017 issue of Clinical Gastroenterology and Hepatology (Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.05.014).
About 4% of Americans receive long-term opioid therapy, primarily for musculoskeletal, postsurgical, or vascular pain, as well as nonsurgical abdominal pain, writes Michael Camilleri, MD, AGAF, of Mayo Clinic in Rochester, Minn., and his associates. Because opioid receptors thickly populate the gastrointestinal tract, exogenous opioids can trigger a variety of gastrointestinal symptoms. Examples include achalasia, gastroparesis, nausea, postsurgical ileus, constipation, and narcotic bowel syndrome.
In the stomach, opioid use can cause gastroparesis, early satiety, and postprandial nausea and emesis, especially in the postoperative setting. Even novel opioid agents that are less likely to cause constipation can retard gastric emptying. For example, tapentadol, a mu-opioid agonist and norepinephrine reuptake inhibitor, delays emptying to the same extent as oxycodone. Tramadol also appears to slow overall orocecal transit. Although gastroparesis itself can cause nausea and emesis, opioids also directly stimulate the chemoreceptor trigger zone in the area postrema in the floor of the fourth ventricle. Options for preventive therapy include using a prokinetic, such as metoclopramide, prochlorperazine, or a 5-hydroxytryptamine3 antagonist, especially if patients are receiving opioids for postoperative pain control.
Exogenous opioids also can cause ileus, especially after abdominal surgery. These patients are already at risk of ileus because of surgical stress from bowel handling, secretion of inflammatory mediators and endogenous opioids, and fluctuating hormone and electrolyte levels. Postoperative analgesia with mu-opioids adds to the risk of ileus by increasing fluid absorption and inhibiting colonic motility.
Both postsurgical and nonsurgical opioid use also can trigger opioid-induced constipation (OIC), in which patients have less than three spontaneous bowel movements a week, harder stools, increased straining, and a feeling of incomplete evacuation. Patients may also report nausea, emesis, and gastroesophageal reflux. Even low-dose and short-term opioid therapy can lead to OIC. Symptoms and treatment response can be assessed with the bowel function index, in which patients rate ease of defecation, completeness of bowel evacuation, and severity of constipation over the past week on a scale of 0-100. Scores of 0-29 suggest no OIC. Patients who score above 30 despite over-the-counter laxatives are candidates for stepped-up treatments, including prolonged-release naloxone and oxycodone, the intestinal secretagogue lubiprostone, or peripherally acting mu-opioid receptor antagonists (PAMORAs), such as methylnaltrexone (12 mg subcutaneously) and naloxegol (12.5 mg or 25 mg per day orally). Additionally, tapentadol controls pain at lower doses than oxycodone and is less likely to cause constipation.
Narcotic bowel syndrome typically presents as moderate to severe daily abdominal pain lasting more than 3 months in patients on long-term opioids equating to a dosage of more than 100 mg morphine daily. Typically, patients report generalized, persistent, colicky abdominal pain that does not respond to dose escalation and worsens with dose tapering. Work-up is negative for differentials such as kidney stones or bowel obstruction. One epidemiological study estimated that 4% of patients on long-term opiates develop narcotic bowel syndrome, but the true prevalence may be higher according to the experts who authored this update. Mechanisms remain unclear but may include neuroplastic changes that favor the facilitation of pain signals rather than their inhibition, inflammation of spinal glial cells through activation of toll-like receptors, abnormal function of the N-methyl-D aspartate receptor at the level of the spinal cord, and central nociceptive abnormalities related to certain psychological traits or a history of trauma.
Treating narcotic bowel syndrome requires detoxification with appropriate nonopioid therapies for pain, anxiety, and withdrawal symptoms, including the use of clonidine. “This is best handled through specialists or centers with expertise in opiate dependence,” the experts stated. Patients who are able to stay off narcotics report improvements in pain, but the recidivism rate is about 50%.
The practice update also covers opioid therapy for gastrointestinal disorders. The PAMORA alvimopan shortens time to first postoperative stool without counteracting opioid analgesia during recovery. Alvimopan also has been found to hasten recovery of gastrointestinal function in patients with postoperative ileus after bowel resection. There is no evidence for using mu-opioid agonists for pain associated with irritable bowel syndrome (IBS), but the synthetic peripheral mu-opioid receptor agonist loperamide can improve stool consistency and urgency. A typical dose is 2 mg after each loose bowel movement or 2-4 mg before eating in cases of postprandial diarrhea. The mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist eluxadoline also can potentially improve stool consistency and urgency, global IBS symptoms, IBS symptom severity score, and quality of life. However, the FDA warns against using eluxadoline in patients who do not have a gallbladder because of the risk of severe outcomes – including death – related to sphincter of Oddi spasm and pancreatitis. Eluxadoline has been linked to at least two such fatalities in cholecystectomized patients. In each case, symptoms began after a single dose.
Dr. Camilleri is funded by the National Institutes of Health. He disclosed ties to AstraZeneca and Shionogi. The two coauthors disclosed ties to Forest Research Labs, Ironwood Pharmaceuticals, Prometheus, and Salix.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Campylobacteriosis incidence rises in U.S. from 2004 to 2012
Incidence of campylobacteriosis increased significantly in the United States from 2004 to 2012, according to Aimee Geissler, PhD, and her associates.
A total of 303,520 cases of campylobacteriosis were reported during the study period, with the average incidence rate growing from 10.5 cases per 100,000 persons during 2004-2006 to 12.7 cases per 100,000 persons during 2010-2012, an increase of 21%. The median number of Camplyobacter outbreaks doubled from 28 during 2004-2006 to 56 during 2010-2012; in total, 347 outbreaks were reported. Campylobacteriosis is the nation’s most common bacterial diarrheal illness.
The study findings “underscore the importance of standardizing national surveillance for campylobacteriosis, which is important in understanding the burden of infection, better describing geographic variations and differences among species, elucidating risk factors, and targeting prevention and control measures,” the investigators concluded.
Find the full study in Clinical Infectious Diseases (2017 Jul 20. doi: 10.1093/cid/cix624).
Incidence of campylobacteriosis increased significantly in the United States from 2004 to 2012, according to Aimee Geissler, PhD, and her associates.
A total of 303,520 cases of campylobacteriosis were reported during the study period, with the average incidence rate growing from 10.5 cases per 100,000 persons during 2004-2006 to 12.7 cases per 100,000 persons during 2010-2012, an increase of 21%. The median number of Camplyobacter outbreaks doubled from 28 during 2004-2006 to 56 during 2010-2012; in total, 347 outbreaks were reported. Campylobacteriosis is the nation’s most common bacterial diarrheal illness.
The study findings “underscore the importance of standardizing national surveillance for campylobacteriosis, which is important in understanding the burden of infection, better describing geographic variations and differences among species, elucidating risk factors, and targeting prevention and control measures,” the investigators concluded.
Find the full study in Clinical Infectious Diseases (2017 Jul 20. doi: 10.1093/cid/cix624).
Incidence of campylobacteriosis increased significantly in the United States from 2004 to 2012, according to Aimee Geissler, PhD, and her associates.
A total of 303,520 cases of campylobacteriosis were reported during the study period, with the average incidence rate growing from 10.5 cases per 100,000 persons during 2004-2006 to 12.7 cases per 100,000 persons during 2010-2012, an increase of 21%. The median number of Camplyobacter outbreaks doubled from 28 during 2004-2006 to 56 during 2010-2012; in total, 347 outbreaks were reported. Campylobacteriosis is the nation’s most common bacterial diarrheal illness.
The study findings “underscore the importance of standardizing national surveillance for campylobacteriosis, which is important in understanding the burden of infection, better describing geographic variations and differences among species, elucidating risk factors, and targeting prevention and control measures,” the investigators concluded.
Find the full study in Clinical Infectious Diseases (2017 Jul 20. doi: 10.1093/cid/cix624).
FROM CLINICAL INFECTIOUS DISEASES
Inflammatory bowel disease rate higher among urban residents
Children born in urban areas are more likely to develop inflammatory bowel disease (IBD) when they grow up than are children born in rural areas, a Canadian study showed.
With rising rates of IBD in developing nations and urbanized areas, the investigators interpreted these findings as a positive step toward further understanding, and eventually eliminating, the risk of developing IBD.
The retrospective, population-based study gathered a total of 45,567 IBD patients: 6,662 living in rural residences and 38,905 living in urban residences in Nova Scotia, Ontario, Alberta, and Manitoba, Canada.
Patients in rural areas were on average older than urban patients (average age, 43 years vs. 40 years). Rural patients were also, on average, diagnosed later than were urban patients, with an average age at diagnosis of 42 years, compared with 38 years for urban residents.
The IBD incidence rate among urban patients was 33.16/100,000 (95% CI, 27.24-39.08), compared with 30.72/100,000 (95% CI, 23.81-37.64) among rural residents (Am J Gastroenterol. 2017 Jul 25. doi: 10.1038/ajg.2017.208).
Exposure to these environments while growing up was especially significant, with the lowest rate among children younger than 10 years in rural areas (incidence rate ratio, 0.58; 95% CI, 0.43-0.73), followed by adolescents between 10 and 17.9 years (IRR, 0.72; 95% CI, 0.64-0.81), according to investigators.
The incidence rate of IBD among rural children stayed consistent from birth through age 5 years, which may be evidence that development of IBD later in life is correlated with patients’ time in rural areas, the investigators reported.
Although Dr. Benchimol and his coauthors could not point to the exact reason for these results, they said factors such as diet and early exposure to animals, which may help develop useful bacteria that could help fight IBD development, are possible explanations.
“The mechanism by which rurality protects against IBD is uncertain, and may include dietary and lifestyle factors, environmental exposures, or segregation of individuals with different genetic risk profiles,” the investigators wrote. “These effects may be stronger in children because their gut microbiome is in evolution and may be vulnerable to changes in the first 2 years of life.”
This study was limited by certain classification factors, such as what constitutes an urban or rural area, which may have affected the outcomes. A lack of information on the effects of confounding factors, particularly ethnicity, genotype, phenotype, disease severity, or family history also limited this study, the investigators said.
The Janssen Future Leaders in IBD Program funded the study. Investigators reported receiving financial support from or holding leadership positions in the Canadian Institutes of Health Research, the Canadian Child Health Clinician Scientist program, and the Nova Scotia Health Research Foundation.
ezimmerman@frontlinemedcom.com
On Twitter @eaztweets
Children born in urban areas are more likely to develop inflammatory bowel disease (IBD) when they grow up than are children born in rural areas, a Canadian study showed.
With rising rates of IBD in developing nations and urbanized areas, the investigators interpreted these findings as a positive step toward further understanding, and eventually eliminating, the risk of developing IBD.
The retrospective, population-based study gathered a total of 45,567 IBD patients: 6,662 living in rural residences and 38,905 living in urban residences in Nova Scotia, Ontario, Alberta, and Manitoba, Canada.
Patients in rural areas were on average older than urban patients (average age, 43 years vs. 40 years). Rural patients were also, on average, diagnosed later than were urban patients, with an average age at diagnosis of 42 years, compared with 38 years for urban residents.
The IBD incidence rate among urban patients was 33.16/100,000 (95% CI, 27.24-39.08), compared with 30.72/100,000 (95% CI, 23.81-37.64) among rural residents (Am J Gastroenterol. 2017 Jul 25. doi: 10.1038/ajg.2017.208).
Exposure to these environments while growing up was especially significant, with the lowest rate among children younger than 10 years in rural areas (incidence rate ratio, 0.58; 95% CI, 0.43-0.73), followed by adolescents between 10 and 17.9 years (IRR, 0.72; 95% CI, 0.64-0.81), according to investigators.
The incidence rate of IBD among rural children stayed consistent from birth through age 5 years, which may be evidence that development of IBD later in life is correlated with patients’ time in rural areas, the investigators reported.
Although Dr. Benchimol and his coauthors could not point to the exact reason for these results, they said factors such as diet and early exposure to animals, which may help develop useful bacteria that could help fight IBD development, are possible explanations.
“The mechanism by which rurality protects against IBD is uncertain, and may include dietary and lifestyle factors, environmental exposures, or segregation of individuals with different genetic risk profiles,” the investigators wrote. “These effects may be stronger in children because their gut microbiome is in evolution and may be vulnerable to changes in the first 2 years of life.”
This study was limited by certain classification factors, such as what constitutes an urban or rural area, which may have affected the outcomes. A lack of information on the effects of confounding factors, particularly ethnicity, genotype, phenotype, disease severity, or family history also limited this study, the investigators said.
The Janssen Future Leaders in IBD Program funded the study. Investigators reported receiving financial support from or holding leadership positions in the Canadian Institutes of Health Research, the Canadian Child Health Clinician Scientist program, and the Nova Scotia Health Research Foundation.
ezimmerman@frontlinemedcom.com
On Twitter @eaztweets
Children born in urban areas are more likely to develop inflammatory bowel disease (IBD) when they grow up than are children born in rural areas, a Canadian study showed.
With rising rates of IBD in developing nations and urbanized areas, the investigators interpreted these findings as a positive step toward further understanding, and eventually eliminating, the risk of developing IBD.
The retrospective, population-based study gathered a total of 45,567 IBD patients: 6,662 living in rural residences and 38,905 living in urban residences in Nova Scotia, Ontario, Alberta, and Manitoba, Canada.
Patients in rural areas were on average older than urban patients (average age, 43 years vs. 40 years). Rural patients were also, on average, diagnosed later than were urban patients, with an average age at diagnosis of 42 years, compared with 38 years for urban residents.
The IBD incidence rate among urban patients was 33.16/100,000 (95% CI, 27.24-39.08), compared with 30.72/100,000 (95% CI, 23.81-37.64) among rural residents (Am J Gastroenterol. 2017 Jul 25. doi: 10.1038/ajg.2017.208).
Exposure to these environments while growing up was especially significant, with the lowest rate among children younger than 10 years in rural areas (incidence rate ratio, 0.58; 95% CI, 0.43-0.73), followed by adolescents between 10 and 17.9 years (IRR, 0.72; 95% CI, 0.64-0.81), according to investigators.
The incidence rate of IBD among rural children stayed consistent from birth through age 5 years, which may be evidence that development of IBD later in life is correlated with patients’ time in rural areas, the investigators reported.
Although Dr. Benchimol and his coauthors could not point to the exact reason for these results, they said factors such as diet and early exposure to animals, which may help develop useful bacteria that could help fight IBD development, are possible explanations.
“The mechanism by which rurality protects against IBD is uncertain, and may include dietary and lifestyle factors, environmental exposures, or segregation of individuals with different genetic risk profiles,” the investigators wrote. “These effects may be stronger in children because their gut microbiome is in evolution and may be vulnerable to changes in the first 2 years of life.”
This study was limited by certain classification factors, such as what constitutes an urban or rural area, which may have affected the outcomes. A lack of information on the effects of confounding factors, particularly ethnicity, genotype, phenotype, disease severity, or family history also limited this study, the investigators said.
The Janssen Future Leaders in IBD Program funded the study. Investigators reported receiving financial support from or holding leadership positions in the Canadian Institutes of Health Research, the Canadian Child Health Clinician Scientist program, and the Nova Scotia Health Research Foundation.
ezimmerman@frontlinemedcom.com
On Twitter @eaztweets
FROM THE AMERICAN JOURNAL OF GASTROENTEROLOGY
Key clinical point:
Major finding: The incidence of IBD among urban residents was 33.16/100,000 (95% CI, 27.24-39.08), compared with 30.72/100,000 (95% CI, 23.81-37.64) among rural residents.
Data source: A population-based, retrospective analysis of residents among four Canadian provinces between 1999 and 2010.
Disclosures: The Janssen Future Leaders in IBD Program sponsored the study. Investigators reported receiving financial support from or holding leadership positions in the Canadian Institutes of Health Research, the Canadian Child Health Clinician Scientist program, and the Nova Scotia Health Research Foundation.
VIDEO: High myristic acid intake linked to relapse in ulcerative colitis
High intake of myristic acid approximately tripled the odds of relapse in patients with ulcerative colitis (UC), compared with low intake, according to the results of a 12-month multicenter, prospective, observational study reported in the September 2017 issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.12.036).
Relapsers consumed an average of 2.2 g of this saturated fatty acid daily from sources such as palm and coconut oils, as well as dairy fats, reported Edward L. Barnes, MD, MPH, and his associates at Brigham and Women’s Hospital, Boston, on behalf of the DREAM (Diet’s Role in Exacerbations of Mesalamine Maintenance) investigators. Nonrelapsers averaged 1.4 g/day. “Our broader goal is to determine how alterations in diet can improve the care of people with IBD [inflammatory bowel disease],” the researchers wrote. “These findings can help design interventional dietary studies to determine if supplementation or avoidance of certain compounds might reduce the risk of a flare for patients with ulcerative colitis in remission.”
Dietary factors are thought to underlie relapse in ulcerative colitis, but specific culprits are poorly defined, the investigators said. Therefore, the DREAM study prospectively tracked dietary intake and flares among a homogeneous group of 412 patients with UC from 25 academic and community gastroenterology practices in the United States. Between 2007 and 2014, patients were interviewed by telephone every 3 months for 1 year or until they reported a flare, defined as a Simple Clinical Colitis Activity Index score of at least 5 or a change in disease activity that entailed a change in medication.
Source: American Gastroenterological Association
A total of 34 patients were lost to follow-up, and 45 (11% of those remaining) flared within a year of study enrollment. “When analyzed in tertiles, increasing intake of multiple fatty acids was associated with increasing odds of relapse,” the researchers wrote. Predictors of flare in the univariate analysis included high intake of myristic acid, oleic acid, eicosenoic acid, palmitelaidic acid, total translinoleic acid, saturated fat, monounsaturated fat, and omega-3 fatty acids. These predictors also included moderate or high intake of alpha-linolenic acid. Only high intake of myristic acid maintained a significant dose-response relationship in the multivariable analysis (odds ratio, 3.0; 95% confidence interval, 1.2-7.7; P = .02 for high vs. low intake). Moderate intake of alpha-linolenic acid predicted flare (OR, 5.5; CI, 95%, 1.6-19.3; P = .001) in the multivariable analysis, but high intake did not (OR, 1.3; CI, 95%, 0.3-7.0; P = .4). “Other foods previously implicated in flares of UC, such as processed meat, alcohol, and foods high in sulfur, were not associated with an increased risk of flare,” the researchers wrote.
Study participants were generally in their mid- to late 40s, white, and not current smokers. More than half were male. Most had proctitis or left-sided colitis, not pancolitis. Relapsers averaged 2.4 flares in the 18 months before enrollment (standard deviation, 1.9), compared with 1.8 flares for nonrelapsers (SD, 2.4; P = .003).
This observational study not only was subject to unmeasured confounding, but also excluded many types of patients. Among those excluded were anyone with a history of allergy to salicylates, aminosalicylates, or mesalamine tablets. Also excluded were those who had recent exposure to NSAIDs, oral or parenteral antibiotics, antidiarrheals, antispasmodics, immunosuppressives, biologics, or corticosteroids (except budesonide). Requiring monotherapy with an aminosalicylate might limit the generalizability of the findings, the investigators noted. Patients also were on variable doses of aminosalicylates, and higher doses might have helped inhibit flares.
Actavis and the National Institutes of Health provided funding. The investigators reported having no relevant financial conflicts.
Patients with inflammatory bowel disease commonly ask their physicians if dietary modifications can be made to control their disease. Despite the interest from patients, we have limited data to provide informed recommendations.
These results provide additional information to better guide our discussions with patients regarding diet and disease activity. However, the overall body of information remains sparse, and we should reinforce that dietary manipulation is an adjunct measure, at best, to our current medical therapies.
Rajesh Rasik Shah, MD, is an assistant professor of internal medicine and gastroenterology at Baylor College of Medicine, Houston. He has no conflicts of interest.
Patients with inflammatory bowel disease commonly ask their physicians if dietary modifications can be made to control their disease. Despite the interest from patients, we have limited data to provide informed recommendations.
These results provide additional information to better guide our discussions with patients regarding diet and disease activity. However, the overall body of information remains sparse, and we should reinforce that dietary manipulation is an adjunct measure, at best, to our current medical therapies.
Rajesh Rasik Shah, MD, is an assistant professor of internal medicine and gastroenterology at Baylor College of Medicine, Houston. He has no conflicts of interest.
Patients with inflammatory bowel disease commonly ask their physicians if dietary modifications can be made to control their disease. Despite the interest from patients, we have limited data to provide informed recommendations.
These results provide additional information to better guide our discussions with patients regarding diet and disease activity. However, the overall body of information remains sparse, and we should reinforce that dietary manipulation is an adjunct measure, at best, to our current medical therapies.
Rajesh Rasik Shah, MD, is an assistant professor of internal medicine and gastroenterology at Baylor College of Medicine, Houston. He has no conflicts of interest.
High intake of myristic acid approximately tripled the odds of relapse in patients with ulcerative colitis (UC), compared with low intake, according to the results of a 12-month multicenter, prospective, observational study reported in the September 2017 issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.12.036).
Relapsers consumed an average of 2.2 g of this saturated fatty acid daily from sources such as palm and coconut oils, as well as dairy fats, reported Edward L. Barnes, MD, MPH, and his associates at Brigham and Women’s Hospital, Boston, on behalf of the DREAM (Diet’s Role in Exacerbations of Mesalamine Maintenance) investigators. Nonrelapsers averaged 1.4 g/day. “Our broader goal is to determine how alterations in diet can improve the care of people with IBD [inflammatory bowel disease],” the researchers wrote. “These findings can help design interventional dietary studies to determine if supplementation or avoidance of certain compounds might reduce the risk of a flare for patients with ulcerative colitis in remission.”
Dietary factors are thought to underlie relapse in ulcerative colitis, but specific culprits are poorly defined, the investigators said. Therefore, the DREAM study prospectively tracked dietary intake and flares among a homogeneous group of 412 patients with UC from 25 academic and community gastroenterology practices in the United States. Between 2007 and 2014, patients were interviewed by telephone every 3 months for 1 year or until they reported a flare, defined as a Simple Clinical Colitis Activity Index score of at least 5 or a change in disease activity that entailed a change in medication.
Source: American Gastroenterological Association
A total of 34 patients were lost to follow-up, and 45 (11% of those remaining) flared within a year of study enrollment. “When analyzed in tertiles, increasing intake of multiple fatty acids was associated with increasing odds of relapse,” the researchers wrote. Predictors of flare in the univariate analysis included high intake of myristic acid, oleic acid, eicosenoic acid, palmitelaidic acid, total translinoleic acid, saturated fat, monounsaturated fat, and omega-3 fatty acids. These predictors also included moderate or high intake of alpha-linolenic acid. Only high intake of myristic acid maintained a significant dose-response relationship in the multivariable analysis (odds ratio, 3.0; 95% confidence interval, 1.2-7.7; P = .02 for high vs. low intake). Moderate intake of alpha-linolenic acid predicted flare (OR, 5.5; CI, 95%, 1.6-19.3; P = .001) in the multivariable analysis, but high intake did not (OR, 1.3; CI, 95%, 0.3-7.0; P = .4). “Other foods previously implicated in flares of UC, such as processed meat, alcohol, and foods high in sulfur, were not associated with an increased risk of flare,” the researchers wrote.
Study participants were generally in their mid- to late 40s, white, and not current smokers. More than half were male. Most had proctitis or left-sided colitis, not pancolitis. Relapsers averaged 2.4 flares in the 18 months before enrollment (standard deviation, 1.9), compared with 1.8 flares for nonrelapsers (SD, 2.4; P = .003).
This observational study not only was subject to unmeasured confounding, but also excluded many types of patients. Among those excluded were anyone with a history of allergy to salicylates, aminosalicylates, or mesalamine tablets. Also excluded were those who had recent exposure to NSAIDs, oral or parenteral antibiotics, antidiarrheals, antispasmodics, immunosuppressives, biologics, or corticosteroids (except budesonide). Requiring monotherapy with an aminosalicylate might limit the generalizability of the findings, the investigators noted. Patients also were on variable doses of aminosalicylates, and higher doses might have helped inhibit flares.
Actavis and the National Institutes of Health provided funding. The investigators reported having no relevant financial conflicts.
High intake of myristic acid approximately tripled the odds of relapse in patients with ulcerative colitis (UC), compared with low intake, according to the results of a 12-month multicenter, prospective, observational study reported in the September 2017 issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.12.036).
Relapsers consumed an average of 2.2 g of this saturated fatty acid daily from sources such as palm and coconut oils, as well as dairy fats, reported Edward L. Barnes, MD, MPH, and his associates at Brigham and Women’s Hospital, Boston, on behalf of the DREAM (Diet’s Role in Exacerbations of Mesalamine Maintenance) investigators. Nonrelapsers averaged 1.4 g/day. “Our broader goal is to determine how alterations in diet can improve the care of people with IBD [inflammatory bowel disease],” the researchers wrote. “These findings can help design interventional dietary studies to determine if supplementation or avoidance of certain compounds might reduce the risk of a flare for patients with ulcerative colitis in remission.”
Dietary factors are thought to underlie relapse in ulcerative colitis, but specific culprits are poorly defined, the investigators said. Therefore, the DREAM study prospectively tracked dietary intake and flares among a homogeneous group of 412 patients with UC from 25 academic and community gastroenterology practices in the United States. Between 2007 and 2014, patients were interviewed by telephone every 3 months for 1 year or until they reported a flare, defined as a Simple Clinical Colitis Activity Index score of at least 5 or a change in disease activity that entailed a change in medication.
Source: American Gastroenterological Association
A total of 34 patients were lost to follow-up, and 45 (11% of those remaining) flared within a year of study enrollment. “When analyzed in tertiles, increasing intake of multiple fatty acids was associated with increasing odds of relapse,” the researchers wrote. Predictors of flare in the univariate analysis included high intake of myristic acid, oleic acid, eicosenoic acid, palmitelaidic acid, total translinoleic acid, saturated fat, monounsaturated fat, and omega-3 fatty acids. These predictors also included moderate or high intake of alpha-linolenic acid. Only high intake of myristic acid maintained a significant dose-response relationship in the multivariable analysis (odds ratio, 3.0; 95% confidence interval, 1.2-7.7; P = .02 for high vs. low intake). Moderate intake of alpha-linolenic acid predicted flare (OR, 5.5; CI, 95%, 1.6-19.3; P = .001) in the multivariable analysis, but high intake did not (OR, 1.3; CI, 95%, 0.3-7.0; P = .4). “Other foods previously implicated in flares of UC, such as processed meat, alcohol, and foods high in sulfur, were not associated with an increased risk of flare,” the researchers wrote.
Study participants were generally in their mid- to late 40s, white, and not current smokers. More than half were male. Most had proctitis or left-sided colitis, not pancolitis. Relapsers averaged 2.4 flares in the 18 months before enrollment (standard deviation, 1.9), compared with 1.8 flares for nonrelapsers (SD, 2.4; P = .003).
This observational study not only was subject to unmeasured confounding, but also excluded many types of patients. Among those excluded were anyone with a history of allergy to salicylates, aminosalicylates, or mesalamine tablets. Also excluded were those who had recent exposure to NSAIDs, oral or parenteral antibiotics, antidiarrheals, antispasmodics, immunosuppressives, biologics, or corticosteroids (except budesonide). Requiring monotherapy with an aminosalicylate might limit the generalizability of the findings, the investigators noted. Patients also were on variable doses of aminosalicylates, and higher doses might have helped inhibit flares.
Actavis and the National Institutes of Health provided funding. The investigators reported having no relevant financial conflicts.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: High intake of myristic acid tripled the odds of relapse in patients with ulcerative colitis.
Major finding: Protein, processed meat, alcohol, and sulfur intake were not linked to UC relapse.
Data source: A multicenter prospective study of 412 patients with UC.
Disclosures: Actavis and the National Institutes of Health provided funding. The investigators reported having no relevant financial conflicts.
Developments in celiac disease and wheat-sensitivity disorders
Celiac disease remained a rare disease until this century. “When I went to medical school, people from Ireland, the Netherlands, and other Northern Europeans had celiac disease. The prevalence of celiac disease has increased in the United States and worldwide.
Advances have been made in the understanding of celiac disease pathogenesis over the past few decades regarding the host genotype, currently restricted to the HLA genes, the delivery mode of gluten, type of feeding, time of feeding, and possibly antibiotics modulating the microbiome. The DQ2 genes are necessary but are insufficient to explain the development of celiac disease. About 40% of the burden of celiac disease is related to the HLA-DQ2.2, 2.5, and 8 genes. In spite of many genomewide association studies, no key molecules have been identified that play a significant role in causing the disease to date.
The association of enteric infections and celiac disease may explain why genetically susceptible individuals that are exposed to gluten from childhood do not all develop the disease in early childhood. The average age of diagnosis of celiac disease in modern times is the mid-40s, and the individuals have been eating gluten all their lives, so it’s not clear why and when people develop celiac disease. It has been postulated that enteric infection could modulate the immune system, cause breaches in the mucosal barrier, and alters of the microbiome, thus triggering the disease. A study recently published in Science supports the role of reovirus as a trigger for celiac disease and results from the TEDDY study group published in Clinical Gastroenterology and Hepatology suggest that rotavirus vaccination could reduce celiac disease autoimmunity in susceptible children.
While the mechanisms underlying nonceliac gluten sensitivity or wheat sensitivity are still unclear, the terms “encompass individuals who report symptoms or alterations in health that are related to perceived gluten or wheat ingestion.” These symptoms could stem from fructose or fructans in wheat starch (FODMAPs), which could lead to symptoms similar to irritable bowel syndrome or other functional GI disorders. North American data show that more and more people without a diagnosis of celiac disease are consuming gluten-free products. Researchers have postulated that the pathophysiology of these conditions could include activation of the innate immune system, increased permeability, mucosal inflammation, basophil and eosinophil activation, antigliadin antibody elevation, and wheat amyloid trypsin inhibitors, but data have been inconsistent. The recommendation for diagnosing nonceliac gluten or wheat sensitivity is a double-blind placebo-controlled gluten trial to assess gluten-induced symptoms after excluding celiac disease or wheat allergy, but this testing is rarely available in North America. A recent study published in Clinical Gastroenterology and Hepatology demonstrated the limitations of this testing. The gluten-free diet is now very popular, but some drawbacks have emerged. These include an increased risk for cardiovascular disorders linked to the diet according to a recent study published in BMJ, and increased levels of heavy metals in urine and blood found in insecticide used on rice, according to a recent study published in Epidemiology. Further studies are needed to corroborate these recall diet studies.
Dr. Crowe is a clinical professor of medicine in the department of gastroenterology, University of California, San Diego. She reports financial relationships with UpToDate, Ferring, and Otsuka. She made her comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
Celiac disease remained a rare disease until this century. “When I went to medical school, people from Ireland, the Netherlands, and other Northern Europeans had celiac disease. The prevalence of celiac disease has increased in the United States and worldwide.
Advances have been made in the understanding of celiac disease pathogenesis over the past few decades regarding the host genotype, currently restricted to the HLA genes, the delivery mode of gluten, type of feeding, time of feeding, and possibly antibiotics modulating the microbiome. The DQ2 genes are necessary but are insufficient to explain the development of celiac disease. About 40% of the burden of celiac disease is related to the HLA-DQ2.2, 2.5, and 8 genes. In spite of many genomewide association studies, no key molecules have been identified that play a significant role in causing the disease to date.
The association of enteric infections and celiac disease may explain why genetically susceptible individuals that are exposed to gluten from childhood do not all develop the disease in early childhood. The average age of diagnosis of celiac disease in modern times is the mid-40s, and the individuals have been eating gluten all their lives, so it’s not clear why and when people develop celiac disease. It has been postulated that enteric infection could modulate the immune system, cause breaches in the mucosal barrier, and alters of the microbiome, thus triggering the disease. A study recently published in Science supports the role of reovirus as a trigger for celiac disease and results from the TEDDY study group published in Clinical Gastroenterology and Hepatology suggest that rotavirus vaccination could reduce celiac disease autoimmunity in susceptible children.
While the mechanisms underlying nonceliac gluten sensitivity or wheat sensitivity are still unclear, the terms “encompass individuals who report symptoms or alterations in health that are related to perceived gluten or wheat ingestion.” These symptoms could stem from fructose or fructans in wheat starch (FODMAPs), which could lead to symptoms similar to irritable bowel syndrome or other functional GI disorders. North American data show that more and more people without a diagnosis of celiac disease are consuming gluten-free products. Researchers have postulated that the pathophysiology of these conditions could include activation of the innate immune system, increased permeability, mucosal inflammation, basophil and eosinophil activation, antigliadin antibody elevation, and wheat amyloid trypsin inhibitors, but data have been inconsistent. The recommendation for diagnosing nonceliac gluten or wheat sensitivity is a double-blind placebo-controlled gluten trial to assess gluten-induced symptoms after excluding celiac disease or wheat allergy, but this testing is rarely available in North America. A recent study published in Clinical Gastroenterology and Hepatology demonstrated the limitations of this testing. The gluten-free diet is now very popular, but some drawbacks have emerged. These include an increased risk for cardiovascular disorders linked to the diet according to a recent study published in BMJ, and increased levels of heavy metals in urine and blood found in insecticide used on rice, according to a recent study published in Epidemiology. Further studies are needed to corroborate these recall diet studies.
Dr. Crowe is a clinical professor of medicine in the department of gastroenterology, University of California, San Diego. She reports financial relationships with UpToDate, Ferring, and Otsuka. She made her comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
Celiac disease remained a rare disease until this century. “When I went to medical school, people from Ireland, the Netherlands, and other Northern Europeans had celiac disease. The prevalence of celiac disease has increased in the United States and worldwide.
Advances have been made in the understanding of celiac disease pathogenesis over the past few decades regarding the host genotype, currently restricted to the HLA genes, the delivery mode of gluten, type of feeding, time of feeding, and possibly antibiotics modulating the microbiome. The DQ2 genes are necessary but are insufficient to explain the development of celiac disease. About 40% of the burden of celiac disease is related to the HLA-DQ2.2, 2.5, and 8 genes. In spite of many genomewide association studies, no key molecules have been identified that play a significant role in causing the disease to date.
The association of enteric infections and celiac disease may explain why genetically susceptible individuals that are exposed to gluten from childhood do not all develop the disease in early childhood. The average age of diagnosis of celiac disease in modern times is the mid-40s, and the individuals have been eating gluten all their lives, so it’s not clear why and when people develop celiac disease. It has been postulated that enteric infection could modulate the immune system, cause breaches in the mucosal barrier, and alters of the microbiome, thus triggering the disease. A study recently published in Science supports the role of reovirus as a trigger for celiac disease and results from the TEDDY study group published in Clinical Gastroenterology and Hepatology suggest that rotavirus vaccination could reduce celiac disease autoimmunity in susceptible children.
While the mechanisms underlying nonceliac gluten sensitivity or wheat sensitivity are still unclear, the terms “encompass individuals who report symptoms or alterations in health that are related to perceived gluten or wheat ingestion.” These symptoms could stem from fructose or fructans in wheat starch (FODMAPs), which could lead to symptoms similar to irritable bowel syndrome or other functional GI disorders. North American data show that more and more people without a diagnosis of celiac disease are consuming gluten-free products. Researchers have postulated that the pathophysiology of these conditions could include activation of the innate immune system, increased permeability, mucosal inflammation, basophil and eosinophil activation, antigliadin antibody elevation, and wheat amyloid trypsin inhibitors, but data have been inconsistent. The recommendation for diagnosing nonceliac gluten or wheat sensitivity is a double-blind placebo-controlled gluten trial to assess gluten-induced symptoms after excluding celiac disease or wheat allergy, but this testing is rarely available in North America. A recent study published in Clinical Gastroenterology and Hepatology demonstrated the limitations of this testing. The gluten-free diet is now very popular, but some drawbacks have emerged. These include an increased risk for cardiovascular disorders linked to the diet according to a recent study published in BMJ, and increased levels of heavy metals in urine and blood found in insecticide used on rice, according to a recent study published in Epidemiology. Further studies are needed to corroborate these recall diet studies.
Dr. Crowe is a clinical professor of medicine in the department of gastroenterology, University of California, San Diego. She reports financial relationships with UpToDate, Ferring, and Otsuka. She made her comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
Multiply recurrent C. difficile infection is on the rise
A retrospective cohort study of Clostridium difficile infection (CDI), the most common health care–associated infection, found that multiply recurrent CDI (mrCDI) is increasing in incidence, disproportionately to the overall increase in CDI.
Researchers from the University of Pennsylvania, Philadelphia, worked with a database of more than 38 million individuals with private health insurance between January 2001 and December 2012.
Cases of CDI and mrCDI in the study population were determined through ICD-9 diagnosis codes, and prescriptions for treatment. To meet the definition of mrCDI, there had to be at least three courses of treatment lasting at least 14 days each.
In the study population, 45,341 persons developed CDI, of whom 1,669 had mrCDI. The median age was 46 years, and 58.9% were female. Between 2001 and 2012, CDI incidence increased by 42.7% (P = .004), while mrCDI incidence increased by 188.8% (P less than .001).
With increases in CDI and mrCDI incidence, and with the effectiveness of standard antibiotic treatment decreasing with each recurrence, “demand for new antimicrobial therapies and FMT [fecal microbiota transplantation] can be expected to increase considerably in the coming years,” wrote Gene K. Ma, MD, and his coauthors.
As for FMT, the researchers noted that its likely greater demand in the future (as suggested by their study results) highlights the importance of establishing the long-term safety of the procedure (Ann Intern Med. 2017 Jul. doi: 10.7326/M16-2733).
The retrospective cohort study was based on administrative data rather than laboratory data, Sameer D. Saini, MD, MS, and Akbar K. Waljee, MD, noted in an editorial accompanying the study. Further, with Medicare patients excluded from the study (because Medicare data were not available for the full time period studied for private insurance data), the data may not be of relevance to patients older than age 65 years.
But the general conclusion that both CDI and mrCDI are on the rise is a crucial matter. “We must first have a better understanding of mrCDI, its scope and epidemiology, and its associated risk factors. The study by Ma and colleagues begins this important work. A better understanding of the epidemiology of mrCDI is a critical first step toward developing a sound strategy to address this growing public health challenge.”
Dr. Saini and Dr. Waljee are with the VA Ann Arbor (Michigan) Center for Clinical Management. Their editorial accompanied the study in Annals of Internal Medicine (2017 Jul. doi: 10.7326/M17-1565).
The retrospective cohort study was based on administrative data rather than laboratory data, Sameer D. Saini, MD, MS, and Akbar K. Waljee, MD, noted in an editorial accompanying the study. Further, with Medicare patients excluded from the study (because Medicare data were not available for the full time period studied for private insurance data), the data may not be of relevance to patients older than age 65 years.
But the general conclusion that both CDI and mrCDI are on the rise is a crucial matter. “We must first have a better understanding of mrCDI, its scope and epidemiology, and its associated risk factors. The study by Ma and colleagues begins this important work. A better understanding of the epidemiology of mrCDI is a critical first step toward developing a sound strategy to address this growing public health challenge.”
Dr. Saini and Dr. Waljee are with the VA Ann Arbor (Michigan) Center for Clinical Management. Their editorial accompanied the study in Annals of Internal Medicine (2017 Jul. doi: 10.7326/M17-1565).
The retrospective cohort study was based on administrative data rather than laboratory data, Sameer D. Saini, MD, MS, and Akbar K. Waljee, MD, noted in an editorial accompanying the study. Further, with Medicare patients excluded from the study (because Medicare data were not available for the full time period studied for private insurance data), the data may not be of relevance to patients older than age 65 years.
But the general conclusion that both CDI and mrCDI are on the rise is a crucial matter. “We must first have a better understanding of mrCDI, its scope and epidemiology, and its associated risk factors. The study by Ma and colleagues begins this important work. A better understanding of the epidemiology of mrCDI is a critical first step toward developing a sound strategy to address this growing public health challenge.”
Dr. Saini and Dr. Waljee are with the VA Ann Arbor (Michigan) Center for Clinical Management. Their editorial accompanied the study in Annals of Internal Medicine (2017 Jul. doi: 10.7326/M17-1565).
A retrospective cohort study of Clostridium difficile infection (CDI), the most common health care–associated infection, found that multiply recurrent CDI (mrCDI) is increasing in incidence, disproportionately to the overall increase in CDI.
Researchers from the University of Pennsylvania, Philadelphia, worked with a database of more than 38 million individuals with private health insurance between January 2001 and December 2012.
Cases of CDI and mrCDI in the study population were determined through ICD-9 diagnosis codes, and prescriptions for treatment. To meet the definition of mrCDI, there had to be at least three courses of treatment lasting at least 14 days each.
In the study population, 45,341 persons developed CDI, of whom 1,669 had mrCDI. The median age was 46 years, and 58.9% were female. Between 2001 and 2012, CDI incidence increased by 42.7% (P = .004), while mrCDI incidence increased by 188.8% (P less than .001).
With increases in CDI and mrCDI incidence, and with the effectiveness of standard antibiotic treatment decreasing with each recurrence, “demand for new antimicrobial therapies and FMT [fecal microbiota transplantation] can be expected to increase considerably in the coming years,” wrote Gene K. Ma, MD, and his coauthors.
As for FMT, the researchers noted that its likely greater demand in the future (as suggested by their study results) highlights the importance of establishing the long-term safety of the procedure (Ann Intern Med. 2017 Jul. doi: 10.7326/M16-2733).
A retrospective cohort study of Clostridium difficile infection (CDI), the most common health care–associated infection, found that multiply recurrent CDI (mrCDI) is increasing in incidence, disproportionately to the overall increase in CDI.
Researchers from the University of Pennsylvania, Philadelphia, worked with a database of more than 38 million individuals with private health insurance between January 2001 and December 2012.
Cases of CDI and mrCDI in the study population were determined through ICD-9 diagnosis codes, and prescriptions for treatment. To meet the definition of mrCDI, there had to be at least three courses of treatment lasting at least 14 days each.
In the study population, 45,341 persons developed CDI, of whom 1,669 had mrCDI. The median age was 46 years, and 58.9% were female. Between 2001 and 2012, CDI incidence increased by 42.7% (P = .004), while mrCDI incidence increased by 188.8% (P less than .001).
With increases in CDI and mrCDI incidence, and with the effectiveness of standard antibiotic treatment decreasing with each recurrence, “demand for new antimicrobial therapies and FMT [fecal microbiota transplantation] can be expected to increase considerably in the coming years,” wrote Gene K. Ma, MD, and his coauthors.
As for FMT, the researchers noted that its likely greater demand in the future (as suggested by their study results) highlights the importance of establishing the long-term safety of the procedure (Ann Intern Med. 2017 Jul. doi: 10.7326/M16-2733).
FROM ANNALS OF INTERNAL MEDICINE
Loop ileostomy tops colectomy for IBD rescue
SEATTLE – Diverting loop ileostomies save patients with inflammatory bowel disease (IBD) with severe colitis from rushed total abdominal colectomies, buying time for patient optimization before surgery, and perhaps even saving colons, according to a report from the University of California, Los Angeles.
Urgent colectomy is the standard of care, but it’s a big operation when patients aren’t doing well. Immunosuppression, malnutrition, and other problems lead to high rates of complications.
In 2013, UCLA physicians decided to try rescue diverting loop ileostomies (DLIs), a relatively quick, minimally invasive option to temporarily divert the fecal stream, instead. The idea is to give the colon a chance to heal and the patient another shot at medical management and recovery before definitive surgery. There’s even a chance of colon salvage.
The approach has been working well at UCLA. Investigators previously reported good results for their first eight patients. They presented updated results for the series – now up to 34 patients – at the annual meeting of the American Society of Colon and Rectal Surgeons.
So far, DLI allowed 91% of patients (31/34) to avoid urgent total colectomies. It’s “a safe alternative. Patients undergoing DLI have acceptably low complication rates and most are afforded time for medical and nutritional optimization prior to proceeding with their definitive surgical care,” said presenter Tara Russell, MD, a UCLA surgery resident.
“Currently, [almost every] patient presenting with acute colitis who we aren’t able to get to the point of discharge with medical optimization” is now offered rescue DLI at the university, and patients have been eager for a chance at avoiding total colectomy. The only patients who are not offered DLI are those with, for instance, fulminant toxic megacolon, Dr. Russell said.
The DLI approach failed in just 2 of the 18 ulcerative colitis patients and 1 of the 16 Crohn’s patients in the series. All three went on to emergent total colectomies 11-53 days after the procedure.
The majority of DLI patients tolerated oral intake by postop day 1, and the median time to resuming a regular diet was 2 days. Most people were discharged within a day or 2 of diversion, and a few took longer to achieve medical rescue. Almost 90% had an improvement in nutritional status, and over 80% went on to elective laparoscopic definitive procedures or colon salvage.
Two patients had postop wound infections, “but there were no other complications” with DLI, Dr. Russell said.
All DLIs were performed with a single-incision laparoscopic approach and took an average of about a half hour. Most of the diversions were in the right lower abdominal quadrant.
The mean age of the patients was 36 years, with a range of 16-81 years. Just over half were men. Of 21 patients who met systemic inflammatory response syndrome criteria at the time of operation, 13 (62%) resolved within 24 hours of DLI.
SEATTLE – Diverting loop ileostomies save patients with inflammatory bowel disease (IBD) with severe colitis from rushed total abdominal colectomies, buying time for patient optimization before surgery, and perhaps even saving colons, according to a report from the University of California, Los Angeles.
Urgent colectomy is the standard of care, but it’s a big operation when patients aren’t doing well. Immunosuppression, malnutrition, and other problems lead to high rates of complications.
In 2013, UCLA physicians decided to try rescue diverting loop ileostomies (DLIs), a relatively quick, minimally invasive option to temporarily divert the fecal stream, instead. The idea is to give the colon a chance to heal and the patient another shot at medical management and recovery before definitive surgery. There’s even a chance of colon salvage.
The approach has been working well at UCLA. Investigators previously reported good results for their first eight patients. They presented updated results for the series – now up to 34 patients – at the annual meeting of the American Society of Colon and Rectal Surgeons.
So far, DLI allowed 91% of patients (31/34) to avoid urgent total colectomies. It’s “a safe alternative. Patients undergoing DLI have acceptably low complication rates and most are afforded time for medical and nutritional optimization prior to proceeding with their definitive surgical care,” said presenter Tara Russell, MD, a UCLA surgery resident.
“Currently, [almost every] patient presenting with acute colitis who we aren’t able to get to the point of discharge with medical optimization” is now offered rescue DLI at the university, and patients have been eager for a chance at avoiding total colectomy. The only patients who are not offered DLI are those with, for instance, fulminant toxic megacolon, Dr. Russell said.
The DLI approach failed in just 2 of the 18 ulcerative colitis patients and 1 of the 16 Crohn’s patients in the series. All three went on to emergent total colectomies 11-53 days after the procedure.
The majority of DLI patients tolerated oral intake by postop day 1, and the median time to resuming a regular diet was 2 days. Most people were discharged within a day or 2 of diversion, and a few took longer to achieve medical rescue. Almost 90% had an improvement in nutritional status, and over 80% went on to elective laparoscopic definitive procedures or colon salvage.
Two patients had postop wound infections, “but there were no other complications” with DLI, Dr. Russell said.
All DLIs were performed with a single-incision laparoscopic approach and took an average of about a half hour. Most of the diversions were in the right lower abdominal quadrant.
The mean age of the patients was 36 years, with a range of 16-81 years. Just over half were men. Of 21 patients who met systemic inflammatory response syndrome criteria at the time of operation, 13 (62%) resolved within 24 hours of DLI.
SEATTLE – Diverting loop ileostomies save patients with inflammatory bowel disease (IBD) with severe colitis from rushed total abdominal colectomies, buying time for patient optimization before surgery, and perhaps even saving colons, according to a report from the University of California, Los Angeles.
Urgent colectomy is the standard of care, but it’s a big operation when patients aren’t doing well. Immunosuppression, malnutrition, and other problems lead to high rates of complications.
In 2013, UCLA physicians decided to try rescue diverting loop ileostomies (DLIs), a relatively quick, minimally invasive option to temporarily divert the fecal stream, instead. The idea is to give the colon a chance to heal and the patient another shot at medical management and recovery before definitive surgery. There’s even a chance of colon salvage.
The approach has been working well at UCLA. Investigators previously reported good results for their first eight patients. They presented updated results for the series – now up to 34 patients – at the annual meeting of the American Society of Colon and Rectal Surgeons.
So far, DLI allowed 91% of patients (31/34) to avoid urgent total colectomies. It’s “a safe alternative. Patients undergoing DLI have acceptably low complication rates and most are afforded time for medical and nutritional optimization prior to proceeding with their definitive surgical care,” said presenter Tara Russell, MD, a UCLA surgery resident.
“Currently, [almost every] patient presenting with acute colitis who we aren’t able to get to the point of discharge with medical optimization” is now offered rescue DLI at the university, and patients have been eager for a chance at avoiding total colectomy. The only patients who are not offered DLI are those with, for instance, fulminant toxic megacolon, Dr. Russell said.
The DLI approach failed in just 2 of the 18 ulcerative colitis patients and 1 of the 16 Crohn’s patients in the series. All three went on to emergent total colectomies 11-53 days after the procedure.
The majority of DLI patients tolerated oral intake by postop day 1, and the median time to resuming a regular diet was 2 days. Most people were discharged within a day or 2 of diversion, and a few took longer to achieve medical rescue. Almost 90% had an improvement in nutritional status, and over 80% went on to elective laparoscopic definitive procedures or colon salvage.
Two patients had postop wound infections, “but there were no other complications” with DLI, Dr. Russell said.
All DLIs were performed with a single-incision laparoscopic approach and took an average of about a half hour. Most of the diversions were in the right lower abdominal quadrant.
The mean age of the patients was 36 years, with a range of 16-81 years. Just over half were men. Of 21 patients who met systemic inflammatory response syndrome criteria at the time of operation, 13 (62%) resolved within 24 hours of DLI.
AT ASCRS 2017
Key clinical point:
Major finding: DLI allowed 91% of patients (31/34) to avoid urgent total colectomies.
Data source: A report on 34 patients with severe, acute inflammatory bowel disease colitis.
Disclosures: The presenter had no disclosures.