IBD & Intestinal Disorders

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – Current and previous use of thiopurines, biologics, and combination therapies are all independent risk factors for skin cancer, according to expert analysis given at a conference on inflammatory bowel diseases.

Although population-based cohort studies have shown that the baseline risk for nonmelanoma skin cancer in IBD has risen more than a third since the preimmunomodulator era, regardless of the mode of treatment, "Cutaneous side effects of immunomodulators and biologics are a rising concern in clinical practice," said Dr. Jean-Frederic Colombel of the Icahn School of Medicine at Mount Sinai in New York. "Patients with Crohn’s disease in particular have shown a twofold increased risk for nonmelanoma skin cancer, outside of any kind of immunomodulator or biologic therapy."

Thiopurine use has been associated with a twofold increased risk of nonmelanoma skin cancer that persists even after withdrawal from the medication, although there is not an increased risk for melanoma, according to Dr. Colombel.

In a comparative analysis of studies published primarily since 2011, he noted an epidemiologic study with an A level of evidence for nearly 10,000 IBD patients undergoing thiopurine treatment that had an increased risk for NMSC with an odds ratio of approximately 2.2 (95% CI, 1.24-3.81).

"What is very important to note is that the risk of nonmelanoma skin cancer persists even after the antimetabolite has been stopped," said Dr. Colombel, referring to data from the CESAME study that indicated, regardless of age, past and current thiopurine use was associated with higher incidence rates of NMSC.

To date, other immunomodulators have not been associated with NMSC, said Dr. Colombel. "What we are observing is quite specific to azathioprine."

Thiopurines are not considered a risk factor for melanoma, said Dr. Colombel. He cited a study of records from a health care claims database for the period between 1997 and 2009. In the study, 209 melanoma cases were matched with 823 controls. Exposure to thiopurines was associated with an OR of 1.1 for melanoma. In that same study, patients exposed to biologics were found to have an increased risk of melanoma, although the risk was higher in patients with Crohn’s disease than those with ulcerative colitis (OR, 1.94 vs. 1.73).

Biologics may also increase the risk of NMSC, although currently the data are "controversial" said Dr. Colombel. "The results are more difficult to interpret."

The risk for NMSC in IBD patients exposed to biologics was evaluated in three studies published between 2010 and 2013. One study indicated no significant increased risk for either past or current biologic use (OR 1.14, 95% CI 0.95-1.36).

Another study indicated a twofold increased risk for patients who’d withdrawn from biologic therapy (OR 2.07, 95% CI 1.28-3.33) and who had persistent use (OR 2.18, 95% CI, 1.07-4.46).

A third study showed a 2.3 increased NMSC risk (95% CI, 1.44-3.47).

In a meta-analysis published in 2013, the pooled relative risk for melanoma in IBD patients exposed to biologics was not shown to be significant (RR, 1.10).

Combination therapy has been found to increase the risk of NMSC nearly fourfold, said Dr. Colombel.

Even though more data are needed, Dr. Colombel said that all patients who are scheduled to start immunosuppression should be informed of the potential for dermatologic complications. "Personally, I am now sending all my patients to a dermatologist for a baseline evaluation," he said.

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Colombel reported many disclosures, including Abbott Laboratories, Bristol-Myers Squibb, Genentech, Inc., Pfizer Inc. and sanofi-aventis, among others.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – Refractory celiac disease is often the result of patients having either received an incorrect diagnosis, or their noncompliance, according to Dr. Joseph Murray of the Mayo Clinic in Rochester, Minn.

"When faced with such a patient, it’s important to reconfirm the original diagnosis," said Dr. Murray, who made his remarks during a clinical track presentation at a conference on inflammatory bowel.

In cases in which the diagnosis can be confirmed and the patient is compliant, discovering if there are other conditions, and whether to intervene and how, are the important next steps, according to Dr. Murray.

When patients present with symptoms of nonresponsive celiac disease, besides taking the patient’s history, which should include whether the patient has any first-degree family members with "true" celiac disease, not just family members who have chosen to stop eating gluten, "I will always ask for the original biopsies," said Dr. Murray.

In addition, original serology tests, if they were done, can confirm whether there are celiac-specific antibodies. "Gliadin antibodies are not celiac specific," said Dr. Murray. "You can get gliadin antibodies in virtually every other disorder that affects the intestines, so they are pretty much worthless." Better specificity comes from tissue transglutaminase or endomysial antibodies, he said at the meeting diseases sponsored by the Crohn’s & Colitis Foundation of America.

Human leukocyte antigen genotyping, and whether the patient had a clinically obvious response to a gluten-free diet also will help the clinician puzzle out if the original diagnosis was correct, according to Dr. Murray. Worth noting is whether the patient has dermatitis herpetiformis, "That’s pathognomonic for celiac disease," said Dr. Murray.

For example, in the case of a 90-year-old woman whose biopsy 10 years before had been interpreted as presumptive celiac disease and who had had an initial response to a gluten-free diet, had symptoms that persisted for a decade because she’d contracted tropical sprue from annual visits to Indonesia that were not noted in her original patient history. Treated properly, her symptoms abated entirely, according to Dr. Murray. "She wasn’t exactly happy about her 10 years of living gluten free," he said.

Dangers of noncompliance

As for patients who claim to follow a gluten-free diet, "That’s not true most of the time," said Dr. Murray. "A positive serology test in a patient who’s been following a gluten-free diet for a year or more means they’re not just getting a little gluten. They’re getting a lot of gluten." It can either be advertent or inadvertently, he said.

However, serology is insensitive for lower levels of gluten contamination, but a gram of gluten, roughly one-half a slice of bread per day, can be detected, according to Dr. Murray.

If noncompliance is the reason for the refractory condition, patients are at greater risk for increased mortality, osteoporosis, lymphomas, and other cancers, and psychological effects such as depression. "Eliminating the gluten may take time. Often we have to use behavioral counselors to help," said Dr. Murray.

Also key is to stay in touch with the patient. "Follow-up in patients with celiac disease is abysmal," Dr. Murray said, "It’s almost like once the disease is diagnosed, it’s forgotten about medically."

"The complicating thing about celiac disease can be that autoimmune disorders and like disorders hang out together," said Dr. Murray. "Complications of celiac disease also can occur in multiples."

Bacterial overgrowth, microscopic colitis, lymphoma, and systemic sclerosis associated–dysmotility are all concurrent conditions Dr. Murray reported seeing in his own practice when treating refractory celiac disease.

Because lactose intolerance is also common in celiac disease, Dr. Murray said he will often advises patients to avoid dairy for a year, and then gradually add that back into the diet with good results. "Often, that will work, so I don’t even test for lactose intolerance initially," he said.

Despite all the possible etiologies for nonresponsive celiac disease, gluten exposure was found in more than a third of cases, while "true refractory celiac disease really makes up only about 10% or 11% of these nonresponsive patients," said Dr. Murray, referring to a study on the topic (Clin. Gastroenterol. Hepatol. 2007;5:445-50).

Patients with celiac disease also can have multifocal strictures in the proximal duodenum that reach the jejunum, "but rarely affect the ileum," according to Dr. Murray.

Possible lymphomas

"The first thing that I think about when I see a really sick patient previously diagnosed with celiac disease several years before is, ‘Does the patient have lymphoma?’" said Dr. Murray. Ulcerative jejunoileitis typically indicates that lymphoma is imminent, although shallower ulcers are often linked to the use of NSAIDs, he said.

Giant cavitating lymphadenopathy, while rare, is also a consideration, according to Dr. Murray. "A premalignant type of disorder, sometimes will respond to immunosuppressives, but often can presage the development of lymphoma," he said.

True refractory celiac disease involves symptomatic malabsorption, severe enteropathy, and a primary or secondary nonresponse to a gluten-free diet. "By definition, there should be no lymphoma," said Dr. Murray.

Refractory celiac disease is either characterized as type 1, which has a normal T-cell population and responds well to immunosuppression, or as type 2 with clonal T cells.

Dr. Murray said he often uses topical budesonide to treat type 1 patients, with good results, since there is about a 90% recovery rate in this patient population. Type 2 is the most pernicious, with nearly half of patients dying within 5 years of diagnosis, either from malignant or infectious complications, according to Dr. Murray. "Type 2 refractory disease is not a trivial disease," he said.

Although most adults with celiac disease don’t heal, many are asymptomatic; however, this does not mean a patient’s risk of mortality from the disease has improved. Patients are also at greater risk for malignant complications. (Am. J. Gastroenterol. 2010;105:1412-20 [doi:10.1038/ajg.2010.10]).

"We really don’t know what we should do about those asymptomatic patients," said Dr. Murray. He noted that, "Failure to heal is not entirely benign, but it’s not refractory celiac disease," said Dr. Murray.

Dr. Murray stated that he had no disclosures.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – Refractory celiac disease is often the result of patients having either received an incorrect diagnosis, or their noncompliance, according to Dr. Joseph Murray of the Mayo Clinic in Rochester, Minn.

"When faced with such a patient, it’s important to reconfirm the original diagnosis," said Dr. Murray, who made his remarks during a clinical track presentation at a conference on inflammatory bowel.

In cases in which the diagnosis can be confirmed and the patient is compliant, discovering if there are other conditions, and whether to intervene and how, are the important next steps, according to Dr. Murray.

When patients present with symptoms of nonresponsive celiac disease, besides taking the patient’s history, which should include whether the patient has any first-degree family members with "true" celiac disease, not just family members who have chosen to stop eating gluten, "I will always ask for the original biopsies," said Dr. Murray.

In addition, original serology tests, if they were done, can confirm whether there are celiac-specific antibodies. "Gliadin antibodies are not celiac specific," said Dr. Murray. "You can get gliadin antibodies in virtually every other disorder that affects the intestines, so they are pretty much worthless." Better specificity comes from tissue transglutaminase or endomysial antibodies, he said at the meeting diseases sponsored by the Crohn’s & Colitis Foundation of America.

Human leukocyte antigen genotyping, and whether the patient had a clinically obvious response to a gluten-free diet also will help the clinician puzzle out if the original diagnosis was correct, according to Dr. Murray. Worth noting is whether the patient has dermatitis herpetiformis, "That’s pathognomonic for celiac disease," said Dr. Murray.

For example, in the case of a 90-year-old woman whose biopsy 10 years before had been interpreted as presumptive celiac disease and who had had an initial response to a gluten-free diet, had symptoms that persisted for a decade because she’d contracted tropical sprue from annual visits to Indonesia that were not noted in her original patient history. Treated properly, her symptoms abated entirely, according to Dr. Murray. "She wasn’t exactly happy about her 10 years of living gluten free," he said.

Dangers of noncompliance

As for patients who claim to follow a gluten-free diet, "That’s not true most of the time," said Dr. Murray. "A positive serology test in a patient who’s been following a gluten-free diet for a year or more means they’re not just getting a little gluten. They’re getting a lot of gluten." It can either be advertent or inadvertently, he said.

However, serology is insensitive for lower levels of gluten contamination, but a gram of gluten, roughly one-half a slice of bread per day, can be detected, according to Dr. Murray.

If noncompliance is the reason for the refractory condition, patients are at greater risk for increased mortality, osteoporosis, lymphomas, and other cancers, and psychological effects such as depression. "Eliminating the gluten may take time. Often we have to use behavioral counselors to help," said Dr. Murray.

Also key is to stay in touch with the patient. "Follow-up in patients with celiac disease is abysmal," Dr. Murray said, "It’s almost like once the disease is diagnosed, it’s forgotten about medically."

"The complicating thing about celiac disease can be that autoimmune disorders and like disorders hang out together," said Dr. Murray. "Complications of celiac disease also can occur in multiples."

Bacterial overgrowth, microscopic colitis, lymphoma, and systemic sclerosis associated–dysmotility are all concurrent conditions Dr. Murray reported seeing in his own practice when treating refractory celiac disease.

Because lactose intolerance is also common in celiac disease, Dr. Murray said he will often advises patients to avoid dairy for a year, and then gradually add that back into the diet with good results. "Often, that will work, so I don’t even test for lactose intolerance initially," he said.

Despite all the possible etiologies for nonresponsive celiac disease, gluten exposure was found in more than a third of cases, while "true refractory celiac disease really makes up only about 10% or 11% of these nonresponsive patients," said Dr. Murray, referring to a study on the topic (Clin. Gastroenterol. Hepatol. 2007;5:445-50).

Patients with celiac disease also can have multifocal strictures in the proximal duodenum that reach the jejunum, "but rarely affect the ileum," according to Dr. Murray.

Possible lymphomas

"The first thing that I think about when I see a really sick patient previously diagnosed with celiac disease several years before is, ‘Does the patient have lymphoma?’" said Dr. Murray. Ulcerative jejunoileitis typically indicates that lymphoma is imminent, although shallower ulcers are often linked to the use of NSAIDs, he said.

Giant cavitating lymphadenopathy, while rare, is also a consideration, according to Dr. Murray. "A premalignant type of disorder, sometimes will respond to immunosuppressives, but often can presage the development of lymphoma," he said.

True refractory celiac disease involves symptomatic malabsorption, severe enteropathy, and a primary or secondary nonresponse to a gluten-free diet. "By definition, there should be no lymphoma," said Dr. Murray.

Refractory celiac disease is either characterized as type 1, which has a normal T-cell population and responds well to immunosuppression, or as type 2 with clonal T cells.

Dr. Murray said he often uses topical budesonide to treat type 1 patients, with good results, since there is about a 90% recovery rate in this patient population. Type 2 is the most pernicious, with nearly half of patients dying within 5 years of diagnosis, either from malignant or infectious complications, according to Dr. Murray. "Type 2 refractory disease is not a trivial disease," he said.

Although most adults with celiac disease don’t heal, many are asymptomatic; however, this does not mean a patient’s risk of mortality from the disease has improved. Patients are also at greater risk for malignant complications. (Am. J. Gastroenterol. 2010;105:1412-20 [doi:10.1038/ajg.2010.10]).

"We really don’t know what we should do about those asymptomatic patients," said Dr. Murray. He noted that, "Failure to heal is not entirely benign, but it’s not refractory celiac disease," said Dr. Murray.

Dr. Murray stated that he had no disclosures.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – Refractory celiac disease is often the result of patients having either received an incorrect diagnosis, or their noncompliance, according to Dr. Joseph Murray of the Mayo Clinic in Rochester, Minn.

"When faced with such a patient, it’s important to reconfirm the original diagnosis," said Dr. Murray, who made his remarks during a clinical track presentation at a conference on inflammatory bowel.

In cases in which the diagnosis can be confirmed and the patient is compliant, discovering if there are other conditions, and whether to intervene and how, are the important next steps, according to Dr. Murray.

When patients present with symptoms of nonresponsive celiac disease, besides taking the patient’s history, which should include whether the patient has any first-degree family members with "true" celiac disease, not just family members who have chosen to stop eating gluten, "I will always ask for the original biopsies," said Dr. Murray.

In addition, original serology tests, if they were done, can confirm whether there are celiac-specific antibodies. "Gliadin antibodies are not celiac specific," said Dr. Murray. "You can get gliadin antibodies in virtually every other disorder that affects the intestines, so they are pretty much worthless." Better specificity comes from tissue transglutaminase or endomysial antibodies, he said at the meeting diseases sponsored by the Crohn’s & Colitis Foundation of America.

Human leukocyte antigen genotyping, and whether the patient had a clinically obvious response to a gluten-free diet also will help the clinician puzzle out if the original diagnosis was correct, according to Dr. Murray. Worth noting is whether the patient has dermatitis herpetiformis, "That’s pathognomonic for celiac disease," said Dr. Murray.

For example, in the case of a 90-year-old woman whose biopsy 10 years before had been interpreted as presumptive celiac disease and who had had an initial response to a gluten-free diet, had symptoms that persisted for a decade because she’d contracted tropical sprue from annual visits to Indonesia that were not noted in her original patient history. Treated properly, her symptoms abated entirely, according to Dr. Murray. "She wasn’t exactly happy about her 10 years of living gluten free," he said.

Dangers of noncompliance

As for patients who claim to follow a gluten-free diet, "That’s not true most of the time," said Dr. Murray. "A positive serology test in a patient who’s been following a gluten-free diet for a year or more means they’re not just getting a little gluten. They’re getting a lot of gluten." It can either be advertent or inadvertently, he said.

However, serology is insensitive for lower levels of gluten contamination, but a gram of gluten, roughly one-half a slice of bread per day, can be detected, according to Dr. Murray.

If noncompliance is the reason for the refractory condition, patients are at greater risk for increased mortality, osteoporosis, lymphomas, and other cancers, and psychological effects such as depression. "Eliminating the gluten may take time. Often we have to use behavioral counselors to help," said Dr. Murray.

Also key is to stay in touch with the patient. "Follow-up in patients with celiac disease is abysmal," Dr. Murray said, "It’s almost like once the disease is diagnosed, it’s forgotten about medically."

"The complicating thing about celiac disease can be that autoimmune disorders and like disorders hang out together," said Dr. Murray. "Complications of celiac disease also can occur in multiples."

Bacterial overgrowth, microscopic colitis, lymphoma, and systemic sclerosis associated–dysmotility are all concurrent conditions Dr. Murray reported seeing in his own practice when treating refractory celiac disease.

Because lactose intolerance is also common in celiac disease, Dr. Murray said he will often advises patients to avoid dairy for a year, and then gradually add that back into the diet with good results. "Often, that will work, so I don’t even test for lactose intolerance initially," he said.

Despite all the possible etiologies for nonresponsive celiac disease, gluten exposure was found in more than a third of cases, while "true refractory celiac disease really makes up only about 10% or 11% of these nonresponsive patients," said Dr. Murray, referring to a study on the topic (Clin. Gastroenterol. Hepatol. 2007;5:445-50).

Patients with celiac disease also can have multifocal strictures in the proximal duodenum that reach the jejunum, "but rarely affect the ileum," according to Dr. Murray.

Possible lymphomas

"The first thing that I think about when I see a really sick patient previously diagnosed with celiac disease several years before is, ‘Does the patient have lymphoma?’" said Dr. Murray. Ulcerative jejunoileitis typically indicates that lymphoma is imminent, although shallower ulcers are often linked to the use of NSAIDs, he said.

Giant cavitating lymphadenopathy, while rare, is also a consideration, according to Dr. Murray. "A premalignant type of disorder, sometimes will respond to immunosuppressives, but often can presage the development of lymphoma," he said.

True refractory celiac disease involves symptomatic malabsorption, severe enteropathy, and a primary or secondary nonresponse to a gluten-free diet. "By definition, there should be no lymphoma," said Dr. Murray.

Refractory celiac disease is either characterized as type 1, which has a normal T-cell population and responds well to immunosuppression, or as type 2 with clonal T cells.

Dr. Murray said he often uses topical budesonide to treat type 1 patients, with good results, since there is about a 90% recovery rate in this patient population. Type 2 is the most pernicious, with nearly half of patients dying within 5 years of diagnosis, either from malignant or infectious complications, according to Dr. Murray. "Type 2 refractory disease is not a trivial disease," he said.

Although most adults with celiac disease don’t heal, many are asymptomatic; however, this does not mean a patient’s risk of mortality from the disease has improved. Patients are also at greater risk for malignant complications. (Am. J. Gastroenterol. 2010;105:1412-20 [doi:10.1038/ajg.2010.10]).

"We really don’t know what we should do about those asymptomatic patients," said Dr. Murray. He noted that, "Failure to heal is not entirely benign, but it’s not refractory celiac disease," said Dr. Murray.

Dr. Murray stated that he had no disclosures.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – The benefits of short-term trial immunosuppressive therapy outweigh the risks in inflammatory bowel disease, but certain patient populations require more vigilance than others, Dr. James D. Lewis said at the 2013 Advances in IBD meeting.

"We can probably all agree that thiopurines increase the risk of lymphoma," said Dr. Lewis, of the University of Pennsylvania, Philadelphia, at the conference on inflammatory bowel diseases. "But I’ve gone from ‘probably’ to ‘possibly’ when it comes to using anti-TNF [anti–tumor necrosis factor] therapy. I believe that a short trial of biologics therapy can really inform the risk-benefit balance, moving the conversation from ‘it might make a patient better’ to either it did or it didn’t."

In young males and the elderly, the benefit of combination therapy might not prove worth the risks of the treatment, said Dr. Lewis, "but in the middle ground, I think we have a sweet spot."

Overall, unless ineffective treatment is justifiable for other reasons such as the prevention of antibody formation, it should be discontinued, he said.

Results from the CESAME study, published in 2009, reinforce previously published data, indicating the risk of lymphoma is up to five times higher in IBD patients exposed to thiopurines than in the general population (Lancet 2009;374:1617-25).

"The most important data from CESAME, however, was that patients who discontinued thiopurines had a lymphoma incidence rate that went back to that of the general population," Dr. Lewis said at the meeting, sponsored by the Crohn’s & Colitis Foundation of America.

The link between lymphoma and anti-TNF treatment is harder to establish in IBD patients, because many in this cohort also have been exposed to thiopurines as part of combination therapies, he said.

Combination therapy is possibly associated with a higher risk of lymphoma than thiopurine monotherapy, and it has been shown to lead to a higher incidence rate than biologics monotherapy, said Dr. Lewis.

If you counsel patients that there is a 1 in 2,000 risk of lymphoma per year, he said, but it takes only a quarter of a year to figure out if the drugs are going to work, then the short-term risk is 1.25 per 10,000 that an additional lymphoma would develop because of that 3-month treatment. "And if you stop the treatment, presumably that risk goes away."

The risk-to-benefit ratio would therefore be favorable for most patients who took thiopurines versus those who did not, he said. "The caveat being, the older you get, the more marginal that risk-benefit balance becomes, probably because as you age, your baseline risk for lymphoma is going up."

Regarding the risk of hepatosplenic T-cell lymphoma in patients exposed to immunosuppressive therapy, Dr. Lewis said that when he pooled the risk in person-years from two studies, he "did some back-of-the-envelope calculations and found that in males, the risk might be on the order of 11 in 100,000 person-years of thiopurine exposure."

That means the number needed to harm is about 9,000 patients, which when combined with the possible risk of developing other lymphomas, the number needed to harm is about 6,000 young males for 1 lymphoma death per year, according to Dr. Lewis.

"But I want to caution you that I am almost sure this is an overestimate of the risk, because if this is true, then it means in young males treated with thiopurines who get lymphoma, a third of them would be hepatosplenic lymphomas, and that seems unlikely," he said.

The ultimate magnitude of risk for adding thiopurine therapy for patients, particularly young males, is on par with that of the risk of death from annual use of automobiles, which Dr. Lewis said was approximately 1 in 9,090.

Since "a substantial proportion" of lymphomas associated with immunosuppression are related to the Epstein-Barr virus, according to Dr. Lewis, aside from minimizing unnecessary treatment, which can be hard to define, clinicians might consider discontinuing just thiopurine therapy, or all therapy in the setting of long-term remission. "I’m not endorsing that," he said. "I am saying that is a question for you to consider."

Other considerations include determining the minimum dose of thiopurine or methotrexate necessary to augment the effectiveness of anti-TNF treatment, as well as whether methotrexate is as effective as thiopurines without having an increased lymphoma risk, although only "indirect evidence" currently exists. "It would be nice to see a head-to-head comparison of those," he said.

As for using Epstein-Barr virus serology to help stratify risk, Dr. Lewis said that currently there are no guidelines for it in IBD, and he does not have a set rule to recommend it.

Dr. Lewis disclosed that he consults for AbbVie, Janssen, Prometheus, and Millennium and has received research funding from Centocor and Takeda.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – The benefits of short-term trial immunosuppressive therapy outweigh the risks in inflammatory bowel disease, but certain patient populations require more vigilance than others, Dr. James D. Lewis said at the 2013 Advances in IBD meeting.

"We can probably all agree that thiopurines increase the risk of lymphoma," said Dr. Lewis, of the University of Pennsylvania, Philadelphia, at the conference on inflammatory bowel diseases. "But I’ve gone from ‘probably’ to ‘possibly’ when it comes to using anti-TNF [anti–tumor necrosis factor] therapy. I believe that a short trial of biologics therapy can really inform the risk-benefit balance, moving the conversation from ‘it might make a patient better’ to either it did or it didn’t."

In young males and the elderly, the benefit of combination therapy might not prove worth the risks of the treatment, said Dr. Lewis, "but in the middle ground, I think we have a sweet spot."

Overall, unless ineffective treatment is justifiable for other reasons such as the prevention of antibody formation, it should be discontinued, he said.

Results from the CESAME study, published in 2009, reinforce previously published data, indicating the risk of lymphoma is up to five times higher in IBD patients exposed to thiopurines than in the general population (Lancet 2009;374:1617-25).

"The most important data from CESAME, however, was that patients who discontinued thiopurines had a lymphoma incidence rate that went back to that of the general population," Dr. Lewis said at the meeting, sponsored by the Crohn’s & Colitis Foundation of America.

The link between lymphoma and anti-TNF treatment is harder to establish in IBD patients, because many in this cohort also have been exposed to thiopurines as part of combination therapies, he said.

Combination therapy is possibly associated with a higher risk of lymphoma than thiopurine monotherapy, and it has been shown to lead to a higher incidence rate than biologics monotherapy, said Dr. Lewis.

If you counsel patients that there is a 1 in 2,000 risk of lymphoma per year, he said, but it takes only a quarter of a year to figure out if the drugs are going to work, then the short-term risk is 1.25 per 10,000 that an additional lymphoma would develop because of that 3-month treatment. "And if you stop the treatment, presumably that risk goes away."

The risk-to-benefit ratio would therefore be favorable for most patients who took thiopurines versus those who did not, he said. "The caveat being, the older you get, the more marginal that risk-benefit balance becomes, probably because as you age, your baseline risk for lymphoma is going up."

Regarding the risk of hepatosplenic T-cell lymphoma in patients exposed to immunosuppressive therapy, Dr. Lewis said that when he pooled the risk in person-years from two studies, he "did some back-of-the-envelope calculations and found that in males, the risk might be on the order of 11 in 100,000 person-years of thiopurine exposure."

That means the number needed to harm is about 9,000 patients, which when combined with the possible risk of developing other lymphomas, the number needed to harm is about 6,000 young males for 1 lymphoma death per year, according to Dr. Lewis.

"But I want to caution you that I am almost sure this is an overestimate of the risk, because if this is true, then it means in young males treated with thiopurines who get lymphoma, a third of them would be hepatosplenic lymphomas, and that seems unlikely," he said.

The ultimate magnitude of risk for adding thiopurine therapy for patients, particularly young males, is on par with that of the risk of death from annual use of automobiles, which Dr. Lewis said was approximately 1 in 9,090.

Since "a substantial proportion" of lymphomas associated with immunosuppression are related to the Epstein-Barr virus, according to Dr. Lewis, aside from minimizing unnecessary treatment, which can be hard to define, clinicians might consider discontinuing just thiopurine therapy, or all therapy in the setting of long-term remission. "I’m not endorsing that," he said. "I am saying that is a question for you to consider."

Other considerations include determining the minimum dose of thiopurine or methotrexate necessary to augment the effectiveness of anti-TNF treatment, as well as whether methotrexate is as effective as thiopurines without having an increased lymphoma risk, although only "indirect evidence" currently exists. "It would be nice to see a head-to-head comparison of those," he said.

As for using Epstein-Barr virus serology to help stratify risk, Dr. Lewis said that currently there are no guidelines for it in IBD, and he does not have a set rule to recommend it.

Dr. Lewis disclosed that he consults for AbbVie, Janssen, Prometheus, and Millennium and has received research funding from Centocor and Takeda.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – The benefits of short-term trial immunosuppressive therapy outweigh the risks in inflammatory bowel disease, but certain patient populations require more vigilance than others, Dr. James D. Lewis said at the 2013 Advances in IBD meeting.

"We can probably all agree that thiopurines increase the risk of lymphoma," said Dr. Lewis, of the University of Pennsylvania, Philadelphia, at the conference on inflammatory bowel diseases. "But I’ve gone from ‘probably’ to ‘possibly’ when it comes to using anti-TNF [anti–tumor necrosis factor] therapy. I believe that a short trial of biologics therapy can really inform the risk-benefit balance, moving the conversation from ‘it might make a patient better’ to either it did or it didn’t."

In young males and the elderly, the benefit of combination therapy might not prove worth the risks of the treatment, said Dr. Lewis, "but in the middle ground, I think we have a sweet spot."

Overall, unless ineffective treatment is justifiable for other reasons such as the prevention of antibody formation, it should be discontinued, he said.

Results from the CESAME study, published in 2009, reinforce previously published data, indicating the risk of lymphoma is up to five times higher in IBD patients exposed to thiopurines than in the general population (Lancet 2009;374:1617-25).

"The most important data from CESAME, however, was that patients who discontinued thiopurines had a lymphoma incidence rate that went back to that of the general population," Dr. Lewis said at the meeting, sponsored by the Crohn’s & Colitis Foundation of America.

The link between lymphoma and anti-TNF treatment is harder to establish in IBD patients, because many in this cohort also have been exposed to thiopurines as part of combination therapies, he said.

Combination therapy is possibly associated with a higher risk of lymphoma than thiopurine monotherapy, and it has been shown to lead to a higher incidence rate than biologics monotherapy, said Dr. Lewis.

If you counsel patients that there is a 1 in 2,000 risk of lymphoma per year, he said, but it takes only a quarter of a year to figure out if the drugs are going to work, then the short-term risk is 1.25 per 10,000 that an additional lymphoma would develop because of that 3-month treatment. "And if you stop the treatment, presumably that risk goes away."

The risk-to-benefit ratio would therefore be favorable for most patients who took thiopurines versus those who did not, he said. "The caveat being, the older you get, the more marginal that risk-benefit balance becomes, probably because as you age, your baseline risk for lymphoma is going up."

Regarding the risk of hepatosplenic T-cell lymphoma in patients exposed to immunosuppressive therapy, Dr. Lewis said that when he pooled the risk in person-years from two studies, he "did some back-of-the-envelope calculations and found that in males, the risk might be on the order of 11 in 100,000 person-years of thiopurine exposure."

That means the number needed to harm is about 9,000 patients, which when combined with the possible risk of developing other lymphomas, the number needed to harm is about 6,000 young males for 1 lymphoma death per year, according to Dr. Lewis.

"But I want to caution you that I am almost sure this is an overestimate of the risk, because if this is true, then it means in young males treated with thiopurines who get lymphoma, a third of them would be hepatosplenic lymphomas, and that seems unlikely," he said.

The ultimate magnitude of risk for adding thiopurine therapy for patients, particularly young males, is on par with that of the risk of death from annual use of automobiles, which Dr. Lewis said was approximately 1 in 9,090.

Since "a substantial proportion" of lymphomas associated with immunosuppression are related to the Epstein-Barr virus, according to Dr. Lewis, aside from minimizing unnecessary treatment, which can be hard to define, clinicians might consider discontinuing just thiopurine therapy, or all therapy in the setting of long-term remission. "I’m not endorsing that," he said. "I am saying that is a question for you to consider."

Other considerations include determining the minimum dose of thiopurine or methotrexate necessary to augment the effectiveness of anti-TNF treatment, as well as whether methotrexate is as effective as thiopurines without having an increased lymphoma risk, although only "indirect evidence" currently exists. "It would be nice to see a head-to-head comparison of those," he said.

As for using Epstein-Barr virus serology to help stratify risk, Dr. Lewis said that currently there are no guidelines for it in IBD, and he does not have a set rule to recommend it.

Dr. Lewis disclosed that he consults for AbbVie, Janssen, Prometheus, and Millennium and has received research funding from Centocor and Takeda.

wmcknight@frontlinemedcom.com

HOLLYWOOD, FLA. – Patients on angiotensin-receptor blocking therapy who present with severe gastrointestinal symptoms may be experiencing drug-induced enteropathy, Dr. Joseph A. Murray said at the 2013 Advances in IBD meeting.

He discovered the connection in a retrospective analysis of patients after treating two women with collagenous celiac disease whose patient history included olmesartan therapy. "Until a few years ago, I’d never heard of such a thing," he said. "But for a condition like collagenous sprue, which is exceptionally rare, that really got my attention."

Olmesartan was implicated in 14 out of 32 cases of refractory idiopathic sprue treated by Dr. Murray at the Mayo Clinic in Rochester, Minn., between 2008 and 2011. "It’s very much less common for other ARBs [angiotensin-receptor blockers] such as valsartan and irbesartan to have a spruelike effect on patients," Dr. Murray said of his clinical experience.

Since he noted the connection, he has successfully treated 22 additional such cases: When all patients were taken off the ARB, their symptoms – particularly their severe diarrhea – resolved, and the patients required no further therapy. They also were all able to return to a diet that contained gluten.

Autoimmune- vs. drug-induced enteropathy

Drug- and autoimmune-induced enteropathy have similar presentations, including severe chronic diarrhea; villous atrophy and collagen deposition with or without intraepithelial lymphocytes; and negative tissue transglutaminase antibodies and endomysial antibodies.

In drug-induced enteropathy, however, laboratory findings will always be seronegative for celiac disease and there will be no response to a gluten-free diet.

Patients taking olmesartan who previously were diagnosed with celiac disease should be retested, as should patients not currently taking olmesertan but who were on the drug at the time they were diagnosed.

In patients with severe diarrhea, olmesartan should be suspected, Dr. Murray said. Diarrhea in drug-induced cases is severe and protracted, with patients experiencing as many as 42 bowel movements a day. Acute renal failure and the need for parenteral nutrition are also possible with this condition, he said.

Clinical presentation

Of the 22 patients (median age, 70 years) treated for drug-induced enteropathy, 13 were women and 21 were non-Hispanic white. Twelve had one or more multiple electrolyte abnormalities, 14 had normocytic normochromic anemia, and 10 were severely hypoalbuminemic.

The amount of ARB prescribed to patients varied from 10 to 40 mg. "Patients had been on olmesartan for at least a year, and even as long as 3 years, before the symptoms started, which often did so abruptly, without explanation."

Prior treatments that had failed in these patients included a gluten-free diet, systemic steroids or budesonide, antidiarrheal agents, pancreatic enzymes, bile acid sequestrants, metronidazole, azathioprine, and octreotide.

In all of the 17 patients who had follow-up biopsies, the villi recovered. Anecdotal reports of four patients who were rechallenged with olmesartan included a full return of the illness, regardless of the period of time that had elapsed.

Possible mechanisms

"We think it’s a cell-mediated immune response, not the classic, ‘I take medication, I get hypersensistivity’ response," Dr. Murray said.

ARBs inhibit transforming growth factor (TGF)-beta, and TGF-beta "is key for regulating the immune response in the gut," he said. However, because TGF-beta also drives collagen formation, that there would be a high number of collagenous sprue cases casts doubt on this as a clear mechanism, he said.

Another possibility Dr. Murray and his associates tested, but rejected, is that a bioactivating hydrolase enzyme activates olmesartan given as a prodrug, in the epithelial tissue of the intestine and liver, creating polymorphisms.

The role of angiotensin receptors in the gut and on lymphocytes has not yet been explained, although there is some similarity to celiac disease where "lots of regulatory T cells in patients "simply don’t work," Dr. Murray said. "We know that these are CD8-positive T cells, so they are cytotoxic, and there are plenty of FOXP3 cells present, and they don’t change when you take them off the drug."

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Murray had no relevant disclosures.

HOLLYWOOD, FLA. – Patients on angiotensin-receptor blocking therapy who present with severe gastrointestinal symptoms may be experiencing drug-induced enteropathy, Dr. Joseph A. Murray said at the 2013 Advances in IBD meeting.

He discovered the connection in a retrospective analysis of patients after treating two women with collagenous celiac disease whose patient history included olmesartan therapy. "Until a few years ago, I’d never heard of such a thing," he said. "But for a condition like collagenous sprue, which is exceptionally rare, that really got my attention."

Olmesartan was implicated in 14 out of 32 cases of refractory idiopathic sprue treated by Dr. Murray at the Mayo Clinic in Rochester, Minn., between 2008 and 2011. "It’s very much less common for other ARBs [angiotensin-receptor blockers] such as valsartan and irbesartan to have a spruelike effect on patients," Dr. Murray said of his clinical experience.

Since he noted the connection, he has successfully treated 22 additional such cases: When all patients were taken off the ARB, their symptoms – particularly their severe diarrhea – resolved, and the patients required no further therapy. They also were all able to return to a diet that contained gluten.

Autoimmune- vs. drug-induced enteropathy

Drug- and autoimmune-induced enteropathy have similar presentations, including severe chronic diarrhea; villous atrophy and collagen deposition with or without intraepithelial lymphocytes; and negative tissue transglutaminase antibodies and endomysial antibodies.

In drug-induced enteropathy, however, laboratory findings will always be seronegative for celiac disease and there will be no response to a gluten-free diet.

Patients taking olmesartan who previously were diagnosed with celiac disease should be retested, as should patients not currently taking olmesertan but who were on the drug at the time they were diagnosed.

In patients with severe diarrhea, olmesartan should be suspected, Dr. Murray said. Diarrhea in drug-induced cases is severe and protracted, with patients experiencing as many as 42 bowel movements a day. Acute renal failure and the need for parenteral nutrition are also possible with this condition, he said.

Clinical presentation

Of the 22 patients (median age, 70 years) treated for drug-induced enteropathy, 13 were women and 21 were non-Hispanic white. Twelve had one or more multiple electrolyte abnormalities, 14 had normocytic normochromic anemia, and 10 were severely hypoalbuminemic.

The amount of ARB prescribed to patients varied from 10 to 40 mg. "Patients had been on olmesartan for at least a year, and even as long as 3 years, before the symptoms started, which often did so abruptly, without explanation."

Prior treatments that had failed in these patients included a gluten-free diet, systemic steroids or budesonide, antidiarrheal agents, pancreatic enzymes, bile acid sequestrants, metronidazole, azathioprine, and octreotide.

In all of the 17 patients who had follow-up biopsies, the villi recovered. Anecdotal reports of four patients who were rechallenged with olmesartan included a full return of the illness, regardless of the period of time that had elapsed.

Possible mechanisms

"We think it’s a cell-mediated immune response, not the classic, ‘I take medication, I get hypersensistivity’ response," Dr. Murray said.

ARBs inhibit transforming growth factor (TGF)-beta, and TGF-beta "is key for regulating the immune response in the gut," he said. However, because TGF-beta also drives collagen formation, that there would be a high number of collagenous sprue cases casts doubt on this as a clear mechanism, he said.

Another possibility Dr. Murray and his associates tested, but rejected, is that a bioactivating hydrolase enzyme activates olmesartan given as a prodrug, in the epithelial tissue of the intestine and liver, creating polymorphisms.

The role of angiotensin receptors in the gut and on lymphocytes has not yet been explained, although there is some similarity to celiac disease where "lots of regulatory T cells in patients "simply don’t work," Dr. Murray said. "We know that these are CD8-positive T cells, so they are cytotoxic, and there are plenty of FOXP3 cells present, and they don’t change when you take them off the drug."

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Murray had no relevant disclosures.

HOLLYWOOD, FLA. – Patients on angiotensin-receptor blocking therapy who present with severe gastrointestinal symptoms may be experiencing drug-induced enteropathy, Dr. Joseph A. Murray said at the 2013 Advances in IBD meeting.

He discovered the connection in a retrospective analysis of patients after treating two women with collagenous celiac disease whose patient history included olmesartan therapy. "Until a few years ago, I’d never heard of such a thing," he said. "But for a condition like collagenous sprue, which is exceptionally rare, that really got my attention."

Olmesartan was implicated in 14 out of 32 cases of refractory idiopathic sprue treated by Dr. Murray at the Mayo Clinic in Rochester, Minn., between 2008 and 2011. "It’s very much less common for other ARBs [angiotensin-receptor blockers] such as valsartan and irbesartan to have a spruelike effect on patients," Dr. Murray said of his clinical experience.

Since he noted the connection, he has successfully treated 22 additional such cases: When all patients were taken off the ARB, their symptoms – particularly their severe diarrhea – resolved, and the patients required no further therapy. They also were all able to return to a diet that contained gluten.

Autoimmune- vs. drug-induced enteropathy

Drug- and autoimmune-induced enteropathy have similar presentations, including severe chronic diarrhea; villous atrophy and collagen deposition with or without intraepithelial lymphocytes; and negative tissue transglutaminase antibodies and endomysial antibodies.

In drug-induced enteropathy, however, laboratory findings will always be seronegative for celiac disease and there will be no response to a gluten-free diet.

Patients taking olmesartan who previously were diagnosed with celiac disease should be retested, as should patients not currently taking olmesertan but who were on the drug at the time they were diagnosed.

In patients with severe diarrhea, olmesartan should be suspected, Dr. Murray said. Diarrhea in drug-induced cases is severe and protracted, with patients experiencing as many as 42 bowel movements a day. Acute renal failure and the need for parenteral nutrition are also possible with this condition, he said.

Clinical presentation

Of the 22 patients (median age, 70 years) treated for drug-induced enteropathy, 13 were women and 21 were non-Hispanic white. Twelve had one or more multiple electrolyte abnormalities, 14 had normocytic normochromic anemia, and 10 were severely hypoalbuminemic.

The amount of ARB prescribed to patients varied from 10 to 40 mg. "Patients had been on olmesartan for at least a year, and even as long as 3 years, before the symptoms started, which often did so abruptly, without explanation."

Prior treatments that had failed in these patients included a gluten-free diet, systemic steroids or budesonide, antidiarrheal agents, pancreatic enzymes, bile acid sequestrants, metronidazole, azathioprine, and octreotide.

In all of the 17 patients who had follow-up biopsies, the villi recovered. Anecdotal reports of four patients who were rechallenged with olmesartan included a full return of the illness, regardless of the period of time that had elapsed.

Possible mechanisms

"We think it’s a cell-mediated immune response, not the classic, ‘I take medication, I get hypersensistivity’ response," Dr. Murray said.

ARBs inhibit transforming growth factor (TGF)-beta, and TGF-beta "is key for regulating the immune response in the gut," he said. However, because TGF-beta also drives collagen formation, that there would be a high number of collagenous sprue cases casts doubt on this as a clear mechanism, he said.

Another possibility Dr. Murray and his associates tested, but rejected, is that a bioactivating hydrolase enzyme activates olmesartan given as a prodrug, in the epithelial tissue of the intestine and liver, creating polymorphisms.

The role of angiotensin receptors in the gut and on lymphocytes has not yet been explained, although there is some similarity to celiac disease where "lots of regulatory T cells in patients "simply don’t work," Dr. Murray said. "We know that these are CD8-positive T cells, so they are cytotoxic, and there are plenty of FOXP3 cells present, and they don’t change when you take them off the drug."

The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Murray had no relevant disclosures.

Two large U.S.-based studies have found the risk of intussusception, a rare type of bowel obstruction in infants, to be elevated after rotavirus vaccination.

Concerns about intussusception risk date back to 1999, when a tetravalent rotavirus vaccine was withdrawn by its manufacturer after being shown to be associated with between 1 and 2 excess cases per 10,000 infants vaccinated.

Findings from clinical trials of newer pentavalent and monovalent vaccines, introduced in 2006 and 2008, respectively, showed no such excess intussusception risk. However, recent studies from Australia, Mexico, and Brazil have indicated that excess risk is associated with these newer vaccines as well, though to a far lesser degree than with the earlier vaccine.

The first of the new studies, published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoal1303164), offers evidence for a slight but statistically significant increase in intussusception risk associated with use of Merck’s pentavalent vaccine, RV5 (RotaTeq).

CDC/Dr. Erskine Palmer

For their research, Katherine Yih, Ph.D., of Harvard Medical School and the Harvard Pilgrim Health Care Institute, Boston, and her associates looked at data from more than 1.2 million doses of RV5. The Food and Drug Administration (FDA) sponsored the study, and data were derived from health plans included in the FDA’s Mini-Sentinel surveillance program.

Using data from 507,874 first doses and 1,277,556 total doses of RV5, Dr. Yih’s team found an excess risk of 1.5 cases per 100,000 within 21 days after the first dose (95% confidence interval, 0.2-3.2), with no further increases in risk seen after the second or third dose. This represents about one tenth of the excess risk seen with the first-generation vaccine.

Dr. Yih and her associates also looked at data from 103,098 doses of a monovalent vaccine, GlaxoSmithKline’s RV1 (Rotarix). Risk was seen as increased after the second dose. However, this study was insufficiently powered to demonstrate a statistically significant risk in association with the monovalent vaccine.

The team acknowledged that some missing chart information reduced the power and precision of their study.

A separate study, also published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1311708), looked at data from 207,955 doses of the monovalent vaccine, identifying intussusception cases recorded within 7 days after a first or second dose.

The investigators, led by Eric Weintraub, of the Centers for Disease Control and Prevention (CDC) in Atlanta, found 5.3 excess cases over expected background rates per 100,000 infants vaccinated with two doses. The authors acknowledged that their findings of elevated risk could be due to chance, given the small number of cases seen in the study.

In the same study, Mr. Weintraub and his colleagues found no increase in risk associated with the pentavalent vaccine, for which there were data on 1,301,810 doses. However, they noted, the confidence intervals for this finding were wide.

The data used in Mr. Weintraub and colleagues’ study came from the Vaccine Safety Datalink surveillance program run by the CDC. The CDC program collects data from health care plans different from those used in the FDA’s program.

Mr. Weintraub and his associates acknowledged that other studies, including that of Dr. Yih and colleagues, had shown elevated risk associated with the pentavalent vaccine. The difference in results, the investigators wrote, might be attributable to different study methodologies, uncontrolled confounding, and varying background rates of intussusception in the study populations.

Mr. Weintraub’s study was funded by the CDC. Three of his coauthors reported commercial grant support from GlaxoSmithKline, Inviragen, Merck, and other companies. One of Dr. Yih’s coauthors disclosed being an employee and stockholder of Aetna, which participates in the Mini-Sentinel program.

Two large U.S.-based studies have found the risk of intussusception, a rare type of bowel obstruction in infants, to be elevated after rotavirus vaccination.

Concerns about intussusception risk date back to 1999, when a tetravalent rotavirus vaccine was withdrawn by its manufacturer after being shown to be associated with between 1 and 2 excess cases per 10,000 infants vaccinated.

Findings from clinical trials of newer pentavalent and monovalent vaccines, introduced in 2006 and 2008, respectively, showed no such excess intussusception risk. However, recent studies from Australia, Mexico, and Brazil have indicated that excess risk is associated with these newer vaccines as well, though to a far lesser degree than with the earlier vaccine.

The first of the new studies, published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoal1303164), offers evidence for a slight but statistically significant increase in intussusception risk associated with use of Merck’s pentavalent vaccine, RV5 (RotaTeq).

CDC/Dr. Erskine Palmer

For their research, Katherine Yih, Ph.D., of Harvard Medical School and the Harvard Pilgrim Health Care Institute, Boston, and her associates looked at data from more than 1.2 million doses of RV5. The Food and Drug Administration (FDA) sponsored the study, and data were derived from health plans included in the FDA’s Mini-Sentinel surveillance program.

Using data from 507,874 first doses and 1,277,556 total doses of RV5, Dr. Yih’s team found an excess risk of 1.5 cases per 100,000 within 21 days after the first dose (95% confidence interval, 0.2-3.2), with no further increases in risk seen after the second or third dose. This represents about one tenth of the excess risk seen with the first-generation vaccine.

Dr. Yih and her associates also looked at data from 103,098 doses of a monovalent vaccine, GlaxoSmithKline’s RV1 (Rotarix). Risk was seen as increased after the second dose. However, this study was insufficiently powered to demonstrate a statistically significant risk in association with the monovalent vaccine.

The team acknowledged that some missing chart information reduced the power and precision of their study.

A separate study, also published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1311708), looked at data from 207,955 doses of the monovalent vaccine, identifying intussusception cases recorded within 7 days after a first or second dose.

The investigators, led by Eric Weintraub, of the Centers for Disease Control and Prevention (CDC) in Atlanta, found 5.3 excess cases over expected background rates per 100,000 infants vaccinated with two doses. The authors acknowledged that their findings of elevated risk could be due to chance, given the small number of cases seen in the study.

In the same study, Mr. Weintraub and his colleagues found no increase in risk associated with the pentavalent vaccine, for which there were data on 1,301,810 doses. However, they noted, the confidence intervals for this finding were wide.

The data used in Mr. Weintraub and colleagues’ study came from the Vaccine Safety Datalink surveillance program run by the CDC. The CDC program collects data from health care plans different from those used in the FDA’s program.

Mr. Weintraub and his associates acknowledged that other studies, including that of Dr. Yih and colleagues, had shown elevated risk associated with the pentavalent vaccine. The difference in results, the investigators wrote, might be attributable to different study methodologies, uncontrolled confounding, and varying background rates of intussusception in the study populations.

Mr. Weintraub’s study was funded by the CDC. Three of his coauthors reported commercial grant support from GlaxoSmithKline, Inviragen, Merck, and other companies. One of Dr. Yih’s coauthors disclosed being an employee and stockholder of Aetna, which participates in the Mini-Sentinel program.

Two large U.S.-based studies have found the risk of intussusception, a rare type of bowel obstruction in infants, to be elevated after rotavirus vaccination.

Concerns about intussusception risk date back to 1999, when a tetravalent rotavirus vaccine was withdrawn by its manufacturer after being shown to be associated with between 1 and 2 excess cases per 10,000 infants vaccinated.

Findings from clinical trials of newer pentavalent and monovalent vaccines, introduced in 2006 and 2008, respectively, showed no such excess intussusception risk. However, recent studies from Australia, Mexico, and Brazil have indicated that excess risk is associated with these newer vaccines as well, though to a far lesser degree than with the earlier vaccine.

The first of the new studies, published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoal1303164), offers evidence for a slight but statistically significant increase in intussusception risk associated with use of Merck’s pentavalent vaccine, RV5 (RotaTeq).

CDC/Dr. Erskine Palmer

For their research, Katherine Yih, Ph.D., of Harvard Medical School and the Harvard Pilgrim Health Care Institute, Boston, and her associates looked at data from more than 1.2 million doses of RV5. The Food and Drug Administration (FDA) sponsored the study, and data were derived from health plans included in the FDA’s Mini-Sentinel surveillance program.

Using data from 507,874 first doses and 1,277,556 total doses of RV5, Dr. Yih’s team found an excess risk of 1.5 cases per 100,000 within 21 days after the first dose (95% confidence interval, 0.2-3.2), with no further increases in risk seen after the second or third dose. This represents about one tenth of the excess risk seen with the first-generation vaccine.

Dr. Yih and her associates also looked at data from 103,098 doses of a monovalent vaccine, GlaxoSmithKline’s RV1 (Rotarix). Risk was seen as increased after the second dose. However, this study was insufficiently powered to demonstrate a statistically significant risk in association with the monovalent vaccine.

The team acknowledged that some missing chart information reduced the power and precision of their study.

A separate study, also published online Jan. 14 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1311708), looked at data from 207,955 doses of the monovalent vaccine, identifying intussusception cases recorded within 7 days after a first or second dose.

The investigators, led by Eric Weintraub, of the Centers for Disease Control and Prevention (CDC) in Atlanta, found 5.3 excess cases over expected background rates per 100,000 infants vaccinated with two doses. The authors acknowledged that their findings of elevated risk could be due to chance, given the small number of cases seen in the study.

In the same study, Mr. Weintraub and his colleagues found no increase in risk associated with the pentavalent vaccine, for which there were data on 1,301,810 doses. However, they noted, the confidence intervals for this finding were wide.

The data used in Mr. Weintraub and colleagues’ study came from the Vaccine Safety Datalink surveillance program run by the CDC. The CDC program collects data from health care plans different from those used in the FDA’s program.

Mr. Weintraub and his associates acknowledged that other studies, including that of Dr. Yih and colleagues, had shown elevated risk associated with the pentavalent vaccine. The difference in results, the investigators wrote, might be attributable to different study methodologies, uncontrolled confounding, and varying background rates of intussusception in the study populations.

Mr. Weintraub’s study was funded by the CDC. Three of his coauthors reported commercial grant support from GlaxoSmithKline, Inviragen, Merck, and other companies. One of Dr. Yih’s coauthors disclosed being an employee and stockholder of Aetna, which participates in the Mini-Sentinel program.

A skin patch vaccine designed to prevent traveler’s diarrhea was shown ineffective in a phase III trial published in Lancet Infectious Diseases.

The patch contained Escherichia coli heat-labile toxin. "Future vaccines against traveler’s diarrhea might need to include several antigens against various diarrheal pathogens, and might need to be able to generate mucosal and higher systemic immunity," concluded the investigators, led by Dr. Ronald Behrens of the Hospital for Tropical Diseases in London.

The subjects, healthy adults around 30 years old, were from Germany and the United Kingdom; 821 got a skin patch that contained 37.5 mcg heat-labile toxin and that they wore on their shoulder for 6 hours; 823 got a placebo patch. Both groups got a second patch on the opposite shoulder 2 weeks later (Lancet Infect. Dis. 2013 [doi:10.1016/S1473-3099(13)70297-4]).

Subjects then traveled to either Mexico or Guatemala for at least a week. They recorded their stool output in a diarrhea diary and provided samples for pathogen identification; 30 (3.7%; 95% confidence interval 2.5-5.2) in the heat-labile toxin-patch group and 46 (5.6%; 95% CI 4.1-7.4) in the placebo group were treated for moderate or severe enterotoxigenic E. coli (ETEC) diarrhea, passing four or more unformed stools in 24 hours.

Vaccine efficacy was 34.6%, (95% CI –2.2-58.9; P = .0621), with no statistical difference in the incidence of ETEC diarrhea between the two groups. "The vaccine did seem to provide a small amount of protection against heat-labile toxin-positive ETEC," but not against other forms of ETEC and diarrhea caused by other pathogens. Using a single antigen vaccine "might not be realistic," the investigators said.

The all-cause diarrhea incidence was 17.1% in the vaccine group and 15.2% in the placebo group. Even "a 100% effective ETEC vaccine would still have had only about 50% vaccine efficacy for moderate-to-severe all-cause diarrhea," they noted.

The vaccine was immunogenic; 84% of the treated subjects, but just 13% of placebo patients, converted to LT-specific serum immunoglobulin G; 41% (vs. 2% in the placebo group) seroconverted to anti-LT IgA, but "serum IgG and IgA titers were not associated with vaccine efficacy, suggesting that such titers cannot be used as a correlate of protection," the investigators said.

The number of ETEC cases was lower than expected, as well, which "might have reduced the precision of our findings," they said.

More than 90% of patients had local reactions to the LT patch, including redness, rash, pruritus, pain, edema, and hyperpigmentation. Vaccine-induced hyperpigmentation persisted at 6-month follow-up in about 20% of study subjects. About 56% of those given placebo had local patch reactions, but none had hyperpigmentation at 6 months.

"The LT component in the patch probably caused this vigorous dermal immune response in nearly all vaccine recipients," said the investigators, who also noted that other ETEC vaccines in development "have not yet shown clinically important benefits."

The study was funded by Intercell USA, makers of the vaccine. One of the 17 investigators is an Intercell employee, and study funding paid part of the other investigators’ salaries. Three investigators reported other financial relationships with Intercell, Salix Pharmaceuticals, or Norgine Pharmaceuticals.

aotto@frontlinemedcom.com

A skin patch vaccine designed to prevent traveler’s diarrhea was shown ineffective in a phase III trial published in Lancet Infectious Diseases.

The patch contained Escherichia coli heat-labile toxin. "Future vaccines against traveler’s diarrhea might need to include several antigens against various diarrheal pathogens, and might need to be able to generate mucosal and higher systemic immunity," concluded the investigators, led by Dr. Ronald Behrens of the Hospital for Tropical Diseases in London.

The subjects, healthy adults around 30 years old, were from Germany and the United Kingdom; 821 got a skin patch that contained 37.5 mcg heat-labile toxin and that they wore on their shoulder for 6 hours; 823 got a placebo patch. Both groups got a second patch on the opposite shoulder 2 weeks later (Lancet Infect. Dis. 2013 [doi:10.1016/S1473-3099(13)70297-4]).

Subjects then traveled to either Mexico or Guatemala for at least a week. They recorded their stool output in a diarrhea diary and provided samples for pathogen identification; 30 (3.7%; 95% confidence interval 2.5-5.2) in the heat-labile toxin-patch group and 46 (5.6%; 95% CI 4.1-7.4) in the placebo group were treated for moderate or severe enterotoxigenic E. coli (ETEC) diarrhea, passing four or more unformed stools in 24 hours.

Vaccine efficacy was 34.6%, (95% CI –2.2-58.9; P = .0621), with no statistical difference in the incidence of ETEC diarrhea between the two groups. "The vaccine did seem to provide a small amount of protection against heat-labile toxin-positive ETEC," but not against other forms of ETEC and diarrhea caused by other pathogens. Using a single antigen vaccine "might not be realistic," the investigators said.

The all-cause diarrhea incidence was 17.1% in the vaccine group and 15.2% in the placebo group. Even "a 100% effective ETEC vaccine would still have had only about 50% vaccine efficacy for moderate-to-severe all-cause diarrhea," they noted.

The vaccine was immunogenic; 84% of the treated subjects, but just 13% of placebo patients, converted to LT-specific serum immunoglobulin G; 41% (vs. 2% in the placebo group) seroconverted to anti-LT IgA, but "serum IgG and IgA titers were not associated with vaccine efficacy, suggesting that such titers cannot be used as a correlate of protection," the investigators said.

The number of ETEC cases was lower than expected, as well, which "might have reduced the precision of our findings," they said.

More than 90% of patients had local reactions to the LT patch, including redness, rash, pruritus, pain, edema, and hyperpigmentation. Vaccine-induced hyperpigmentation persisted at 6-month follow-up in about 20% of study subjects. About 56% of those given placebo had local patch reactions, but none had hyperpigmentation at 6 months.

"The LT component in the patch probably caused this vigorous dermal immune response in nearly all vaccine recipients," said the investigators, who also noted that other ETEC vaccines in development "have not yet shown clinically important benefits."

The study was funded by Intercell USA, makers of the vaccine. One of the 17 investigators is an Intercell employee, and study funding paid part of the other investigators’ salaries. Three investigators reported other financial relationships with Intercell, Salix Pharmaceuticals, or Norgine Pharmaceuticals.

aotto@frontlinemedcom.com

A skin patch vaccine designed to prevent traveler’s diarrhea was shown ineffective in a phase III trial published in Lancet Infectious Diseases.

The patch contained Escherichia coli heat-labile toxin. "Future vaccines against traveler’s diarrhea might need to include several antigens against various diarrheal pathogens, and might need to be able to generate mucosal and higher systemic immunity," concluded the investigators, led by Dr. Ronald Behrens of the Hospital for Tropical Diseases in London.

The subjects, healthy adults around 30 years old, were from Germany and the United Kingdom; 821 got a skin patch that contained 37.5 mcg heat-labile toxin and that they wore on their shoulder for 6 hours; 823 got a placebo patch. Both groups got a second patch on the opposite shoulder 2 weeks later (Lancet Infect. Dis. 2013 [doi:10.1016/S1473-3099(13)70297-4]).

Subjects then traveled to either Mexico or Guatemala for at least a week. They recorded their stool output in a diarrhea diary and provided samples for pathogen identification; 30 (3.7%; 95% confidence interval 2.5-5.2) in the heat-labile toxin-patch group and 46 (5.6%; 95% CI 4.1-7.4) in the placebo group were treated for moderate or severe enterotoxigenic E. coli (ETEC) diarrhea, passing four or more unformed stools in 24 hours.

Vaccine efficacy was 34.6%, (95% CI –2.2-58.9; P = .0621), with no statistical difference in the incidence of ETEC diarrhea between the two groups. "The vaccine did seem to provide a small amount of protection against heat-labile toxin-positive ETEC," but not against other forms of ETEC and diarrhea caused by other pathogens. Using a single antigen vaccine "might not be realistic," the investigators said.

The all-cause diarrhea incidence was 17.1% in the vaccine group and 15.2% in the placebo group. Even "a 100% effective ETEC vaccine would still have had only about 50% vaccine efficacy for moderate-to-severe all-cause diarrhea," they noted.

The vaccine was immunogenic; 84% of the treated subjects, but just 13% of placebo patients, converted to LT-specific serum immunoglobulin G; 41% (vs. 2% in the placebo group) seroconverted to anti-LT IgA, but "serum IgG and IgA titers were not associated with vaccine efficacy, suggesting that such titers cannot be used as a correlate of protection," the investigators said.

The number of ETEC cases was lower than expected, as well, which "might have reduced the precision of our findings," they said.

More than 90% of patients had local reactions to the LT patch, including redness, rash, pruritus, pain, edema, and hyperpigmentation. Vaccine-induced hyperpigmentation persisted at 6-month follow-up in about 20% of study subjects. About 56% of those given placebo had local patch reactions, but none had hyperpigmentation at 6 months.

"The LT component in the patch probably caused this vigorous dermal immune response in nearly all vaccine recipients," said the investigators, who also noted that other ETEC vaccines in development "have not yet shown clinically important benefits."

The study was funded by Intercell USA, makers of the vaccine. One of the 17 investigators is an Intercell employee, and study funding paid part of the other investigators’ salaries. Three investigators reported other financial relationships with Intercell, Salix Pharmaceuticals, or Norgine Pharmaceuticals.

aotto@frontlinemedcom.com

HOLLYWOOD, FLA. – Exposure to antibiotics other than penicillins, in particular metronidazole and quinolones, was associated with new-onset Crohn’s disease, based on a meta-analysis of observational and case-control studies presented by Dr. Ryan Ungaro at a conference on inflammatory bowel diseases.

"Exposure to antibiotics may somehow contribute to alterations in the microbiome and result in dysbiosis, which is known to be part of the pathogenesis that leads to IBD," said Dr. Ungaro, of the Icahn School of Medicine at Mount Sinai, New York. Alternatively, antibiotic exposures might just be surrogate markers for an infectious trigger that is actually associated with IBD. The analysis did not detect a link between antibiotic exposure and ulcerative colitis.

Whitney McKnight/Frontline Medical News

Dr. Ungaro and his colleagues performed a meta-analysis of 11 studies that included the records of 7,208 patients who had been newly diagnosed with IBD after antibiotic exposure; 3,937 had Crohn’s disease, 3,207 had ulcerative colitis, and 64 had unclassified IBD. Nine of the studies accounted for the potential confounding of diagnostic delay, with a range of 4 months to 4 years.

All classes of antibiotics except penicillin were implicated in new-onset IBD, with an odds ratio (OR) of 1.55 for the overall risk of new-onset IBD after antibiotic exposure. Three studies provided data on the use of metronidazole, which proved to have the highest associated risk for new cases of IBD with a pooled OR of 5.01 (P = .005). Quinolones were accounted for in three of the studies and carried the next-highest associated risk, an OR of 1.79 (P = .040).

When stratified by age, the OR for new IBD diagnosis in adults was 1.43 and in children was 1.89. The OR for a new diagnosis of Crohn’s disease was 1.56 in adults and 2.7 in children.

The conference was sponsored by the Crohn’s & Colitis Foundation of America.

Dr. Ungaro did not have any relevant disclosures.

HOLLYWOOD, FLA. – Exposure to antibiotics other than penicillins, in particular metronidazole and quinolones, was associated with new-onset Crohn’s disease, based on a meta-analysis of observational and case-control studies presented by Dr. Ryan Ungaro at a conference on inflammatory bowel diseases.

"Exposure to antibiotics may somehow contribute to alterations in the microbiome and result in dysbiosis, which is known to be part of the pathogenesis that leads to IBD," said Dr. Ungaro, of the Icahn School of Medicine at Mount Sinai, New York. Alternatively, antibiotic exposures might just be surrogate markers for an infectious trigger that is actually associated with IBD. The analysis did not detect a link between antibiotic exposure and ulcerative colitis.

Whitney McKnight/Frontline Medical News

Dr. Ungaro and his colleagues performed a meta-analysis of 11 studies that included the records of 7,208 patients who had been newly diagnosed with IBD after antibiotic exposure; 3,937 had Crohn’s disease, 3,207 had ulcerative colitis, and 64 had unclassified IBD. Nine of the studies accounted for the potential confounding of diagnostic delay, with a range of 4 months to 4 years.

All classes of antibiotics except penicillin were implicated in new-onset IBD, with an odds ratio (OR) of 1.55 for the overall risk of new-onset IBD after antibiotic exposure. Three studies provided data on the use of metronidazole, which proved to have the highest associated risk for new cases of IBD with a pooled OR of 5.01 (P = .005). Quinolones were accounted for in three of the studies and carried the next-highest associated risk, an OR of 1.79 (P = .040).

When stratified by age, the OR for new IBD diagnosis in adults was 1.43 and in children was 1.89. The OR for a new diagnosis of Crohn’s disease was 1.56 in adults and 2.7 in children.

The conference was sponsored by the Crohn’s & Colitis Foundation of America.

Dr. Ungaro did not have any relevant disclosures.

HOLLYWOOD, FLA. – Exposure to antibiotics other than penicillins, in particular metronidazole and quinolones, was associated with new-onset Crohn’s disease, based on a meta-analysis of observational and case-control studies presented by Dr. Ryan Ungaro at a conference on inflammatory bowel diseases.

"Exposure to antibiotics may somehow contribute to alterations in the microbiome and result in dysbiosis, which is known to be part of the pathogenesis that leads to IBD," said Dr. Ungaro, of the Icahn School of Medicine at Mount Sinai, New York. Alternatively, antibiotic exposures might just be surrogate markers for an infectious trigger that is actually associated with IBD. The analysis did not detect a link between antibiotic exposure and ulcerative colitis.

Whitney McKnight/Frontline Medical News

Dr. Ungaro and his colleagues performed a meta-analysis of 11 studies that included the records of 7,208 patients who had been newly diagnosed with IBD after antibiotic exposure; 3,937 had Crohn’s disease, 3,207 had ulcerative colitis, and 64 had unclassified IBD. Nine of the studies accounted for the potential confounding of diagnostic delay, with a range of 4 months to 4 years.

All classes of antibiotics except penicillin were implicated in new-onset IBD, with an odds ratio (OR) of 1.55 for the overall risk of new-onset IBD after antibiotic exposure. Three studies provided data on the use of metronidazole, which proved to have the highest associated risk for new cases of IBD with a pooled OR of 5.01 (P = .005). Quinolones were accounted for in three of the studies and carried the next-highest associated risk, an OR of 1.79 (P = .040).

When stratified by age, the OR for new IBD diagnosis in adults was 1.43 and in children was 1.89. The OR for a new diagnosis of Crohn’s disease was 1.56 in adults and 2.7 in children.

The conference was sponsored by the Crohn’s & Colitis Foundation of America.

Dr. Ungaro did not have any relevant disclosures.

Diets low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols reduced functional gastrointestinal symptoms in patients with irritable bowel syndrome.

The finding, published by Dr. Emma P. Halmos in the January issue of Gastroenterology (2013; [doi:10.1053/j.gastro.2013.09.046]), confirms that the diet’s "growing popularity" is warranted, and supports its use as a first-line therapy for IBS.

Dr. Halmos of Monash University, in Box Hill, Australia, and her colleagues looked at 30 patients with IBS and 8 healthy controls.

At baseline, all patients recorded their normal, daily dietary intake in a food diary for 1 week, as well as IBS symptoms.

Patients were then randomized to receive either 21 days’ worth of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), meaning less than or equal to 5 grams per sitting of these ingredients, or food representing a typical Australian diet.

For example, instead of a breakfast of "wheat biscuit–type cereal with 1/2 cup lactose-free milk, two slices wheat toast," the low-FODMAP adherents were given one cup corn flakes with 1/2 cup lactose-free milk and two slices of spelt toast.

Almost all food was provided, including three main meals and three snacks daily.

Next, there was a washout period during which each participant resumed their usual diet and then crossed-over to the alternate, which was not begun until the symptoms had returned to the same level as baseline.

Patients were prohibited from taking any other therapies for IBS during the study period, nor were they permitted to take any pharmacologic agents to alter their symptoms, including laxatives or antidiarrheals.

At baseline, the mean overall gastrointestinal symptoms score for IBS patients was 36.0 mm on the Visual Analogue Scale.

By the final 14 days of the intervention, IBS patients on the low-FODMAP diet reported a mean overall symptom score of 22.8 mm (P less than .001, compared with baseline).

That was in contrast to the 44.9 mm among IBS patients on the typical Australian diet (P less than .001, compared with baseline), with the difference between the two scores also reaching statistical significance (P less than .001).

Moreover, 21 of 30 IBS patients reported improvements of 10 mm or more on the low-FODMAP diet, wrote the authors.

Healthy controls, meanwhile, had very low scores at baseline (17.8 mm), and there was no change in symptoms on the low-FODMAP or typical Australian diets.

The authors also assessed adherence, as recorded in food diaries. IBS patients were adherent for a median 41 of the 42 days of the combined diets, and healthy controls were adherent for the entire 42 days.

Additionally, "If adherence for at least 17 days of the 21 days of controlled diet (greater than 81% of the days) was arbitrarily considered compliant, then all participants were adherent to the typical Australian diet, and 80% of IBS participants (24 of 30) and 100% of healthy controls were adherent to the low-FODMAP diet," wrote the authors.

According to the authors, one of the strengths of this study was in comparing the low-FODMAP diet with a typical Australian diet, as opposed to an intentionally very-high FODMAP regimen, as earlier studies have done.

They added that providing almost all food to participants facilitated a high degree of adherence.

However, "In life, the low-FODMAP diet is dietitian taught. Dietary restriction would have more varying degrees of compliance and depend on the patients’ degree of understanding, food choices, and motivation for altering dietary habits, as well as the dietitians’ advice on level of FODMAP restriction required," they wrote.

Dr. Halmos disclosed that two coauthors have previously published books on food intolerances and a low-FODMAP diet. They wrote that the study was supported by the National Health and Medical Research Council of Australia, the Les and Eva Erdi Foundation, and by a scholarship from Monash University.

Diets low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols reduced functional gastrointestinal symptoms in patients with irritable bowel syndrome.

The finding, published by Dr. Emma P. Halmos in the January issue of Gastroenterology (2013; [doi:10.1053/j.gastro.2013.09.046]), confirms that the diet’s "growing popularity" is warranted, and supports its use as a first-line therapy for IBS.

Dr. Halmos of Monash University, in Box Hill, Australia, and her colleagues looked at 30 patients with IBS and 8 healthy controls.

At baseline, all patients recorded their normal, daily dietary intake in a food diary for 1 week, as well as IBS symptoms.

Patients were then randomized to receive either 21 days’ worth of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), meaning less than or equal to 5 grams per sitting of these ingredients, or food representing a typical Australian diet.

For example, instead of a breakfast of "wheat biscuit–type cereal with 1/2 cup lactose-free milk, two slices wheat toast," the low-FODMAP adherents were given one cup corn flakes with 1/2 cup lactose-free milk and two slices of spelt toast.

Almost all food was provided, including three main meals and three snacks daily.

Next, there was a washout period during which each participant resumed their usual diet and then crossed-over to the alternate, which was not begun until the symptoms had returned to the same level as baseline.

Patients were prohibited from taking any other therapies for IBS during the study period, nor were they permitted to take any pharmacologic agents to alter their symptoms, including laxatives or antidiarrheals.

At baseline, the mean overall gastrointestinal symptoms score for IBS patients was 36.0 mm on the Visual Analogue Scale.

By the final 14 days of the intervention, IBS patients on the low-FODMAP diet reported a mean overall symptom score of 22.8 mm (P less than .001, compared with baseline).

That was in contrast to the 44.9 mm among IBS patients on the typical Australian diet (P less than .001, compared with baseline), with the difference between the two scores also reaching statistical significance (P less than .001).

Moreover, 21 of 30 IBS patients reported improvements of 10 mm or more on the low-FODMAP diet, wrote the authors.

Healthy controls, meanwhile, had very low scores at baseline (17.8 mm), and there was no change in symptoms on the low-FODMAP or typical Australian diets.

The authors also assessed adherence, as recorded in food diaries. IBS patients were adherent for a median 41 of the 42 days of the combined diets, and healthy controls were adherent for the entire 42 days.

Additionally, "If adherence for at least 17 days of the 21 days of controlled diet (greater than 81% of the days) was arbitrarily considered compliant, then all participants were adherent to the typical Australian diet, and 80% of IBS participants (24 of 30) and 100% of healthy controls were adherent to the low-FODMAP diet," wrote the authors.

According to the authors, one of the strengths of this study was in comparing the low-FODMAP diet with a typical Australian diet, as opposed to an intentionally very-high FODMAP regimen, as earlier studies have done.

They added that providing almost all food to participants facilitated a high degree of adherence.

However, "In life, the low-FODMAP diet is dietitian taught. Dietary restriction would have more varying degrees of compliance and depend on the patients’ degree of understanding, food choices, and motivation for altering dietary habits, as well as the dietitians’ advice on level of FODMAP restriction required," they wrote.

Dr. Halmos disclosed that two coauthors have previously published books on food intolerances and a low-FODMAP diet. They wrote that the study was supported by the National Health and Medical Research Council of Australia, the Les and Eva Erdi Foundation, and by a scholarship from Monash University.

Diets low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols reduced functional gastrointestinal symptoms in patients with irritable bowel syndrome.

The finding, published by Dr. Emma P. Halmos in the January issue of Gastroenterology (2013; [doi:10.1053/j.gastro.2013.09.046]), confirms that the diet’s "growing popularity" is warranted, and supports its use as a first-line therapy for IBS.

Dr. Halmos of Monash University, in Box Hill, Australia, and her colleagues looked at 30 patients with IBS and 8 healthy controls.

At baseline, all patients recorded their normal, daily dietary intake in a food diary for 1 week, as well as IBS symptoms.

Patients were then randomized to receive either 21 days’ worth of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), meaning less than or equal to 5 grams per sitting of these ingredients, or food representing a typical Australian diet.

For example, instead of a breakfast of "wheat biscuit–type cereal with 1/2 cup lactose-free milk, two slices wheat toast," the low-FODMAP adherents were given one cup corn flakes with 1/2 cup lactose-free milk and two slices of spelt toast.

Almost all food was provided, including three main meals and three snacks daily.

Next, there was a washout period during which each participant resumed their usual diet and then crossed-over to the alternate, which was not begun until the symptoms had returned to the same level as baseline.

Patients were prohibited from taking any other therapies for IBS during the study period, nor were they permitted to take any pharmacologic agents to alter their symptoms, including laxatives or antidiarrheals.

At baseline, the mean overall gastrointestinal symptoms score for IBS patients was 36.0 mm on the Visual Analogue Scale.

By the final 14 days of the intervention, IBS patients on the low-FODMAP diet reported a mean overall symptom score of 22.8 mm (P less than .001, compared with baseline).

That was in contrast to the 44.9 mm among IBS patients on the typical Australian diet (P less than .001, compared with baseline), with the difference between the two scores also reaching statistical significance (P less than .001).

Moreover, 21 of 30 IBS patients reported improvements of 10 mm or more on the low-FODMAP diet, wrote the authors.

Healthy controls, meanwhile, had very low scores at baseline (17.8 mm), and there was no change in symptoms on the low-FODMAP or typical Australian diets.

The authors also assessed adherence, as recorded in food diaries. IBS patients were adherent for a median 41 of the 42 days of the combined diets, and healthy controls were adherent for the entire 42 days.

Additionally, "If adherence for at least 17 days of the 21 days of controlled diet (greater than 81% of the days) was arbitrarily considered compliant, then all participants were adherent to the typical Australian diet, and 80% of IBS participants (24 of 30) and 100% of healthy controls were adherent to the low-FODMAP diet," wrote the authors.

According to the authors, one of the strengths of this study was in comparing the low-FODMAP diet with a typical Australian diet, as opposed to an intentionally very-high FODMAP regimen, as earlier studies have done.

They added that providing almost all food to participants facilitated a high degree of adherence.

However, "In life, the low-FODMAP diet is dietitian taught. Dietary restriction would have more varying degrees of compliance and depend on the patients’ degree of understanding, food choices, and motivation for altering dietary habits, as well as the dietitians’ advice on level of FODMAP restriction required," they wrote.

Dr. Halmos disclosed that two coauthors have previously published books on food intolerances and a low-FODMAP diet. They wrote that the study was supported by the National Health and Medical Research Council of Australia, the Les and Eva Erdi Foundation, and by a scholarship from Monash University.

Subcutaneous golimumab induces and maintains clinical response in ulcerative colitis, according to two studies in the January issue of Gastroenterology.

In the first, Dr. William J. Sandborn of the University of California San Diego, and his colleagues, looked at 1,064 patients enrolled in the PURSUIT-SC study (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous), an integrated phase II and phase III study of subcutaneous golimumab.

Golimumab, developed by Janssen Pharmaceutical Companies of Johnson & Johnson – the sponsor of both studies in this month’s Gastroenterology – is a fully human monoclonal antibody to tumor necrosis factor–alpha.

All patients had an established diagnosis of UC and moderate to severe disease activity, defined as a Mayo score of 6-12, with an endoscopic subscore of at least 2.

Additionally, all patients had previously tried and failed oral 5-aminosalicylates, oral corticosteroids, azathioprine (AZA), and/or 6-mercaptopurine. Alternatively, they were simply unable to wean off corticosteroids.

Patients enrolled in the phase II, dose-finding portion of the study were randomized to subcutaneous injections of placebo or one of three different golimumab doses at weeks 0 and 2: 100/50 mg (i.e., 100 mg at week 0 and 50 mg at week 2), 200/100 mg, or 400/200 mg, respectively (n = 169).

"An additional 122 patients were enrolled while phase II data were being analyzed," wrote the authors.

"Clinical response" was defined as a decrease from baseline in the Mayo score of at least 30% and 3 or more points, accompanied by either a rectal bleeding subscore of 0 or 1, or a decrease from baseline in the rectal bleeding subscore of at least 1.

"Clinical remission" was defined as a Mayo score less than or equal to 2, with no individual subscore greater than 1.

Finally, "mucosal healing" was defined as a Mayo endoscopy subscore of 0 or 1.

The authors found that the median changes from the baseline Mayo score were –1.0, –3.0, –2.0, and –3.0 for placebo and golimumab 100/50 mg, 200/100 mg, and 400/200 mg, respectively.

Moreover, at week 6, a numerically greater proportion of patients assigned to golimumab 400/200 mg were in clinical response or remission, had mucosal healing, or had Inflammatory Bowel Disease Questionnaire (IBDQ) scores superior to that of placebo patients.

Next, after analysis of the dose-finding data, the 200/100–mg and 400/200–mg doses were selected for evaluation in phase III, a dose confirmation trial.

Overall, 774 patients participated in this portion of the trial, randomized to placebo, golimumab 200/100 mg, or 400/200 mg at weeks 0 and 2.

By week 6, significantly greater proportions of patients in the golimumab 200/100–mg and golimumab 400/200–mg groups (51.0%, and 54.9%, respectively) were in clinical response compared with patients assigned to placebo (30.3%; P less than 0.0001 for both comparisons).

"The efficacy of both golimumab induction regimens was also demonstrated for the major secondary endpoints of clinical remission, mucosal healing, and improvement from baseline in the IBDQ score, all at week 6," they added.

Looking at safety, nearly 40% of all phase III cohorts reported adverse events, most commonly headache and nasopharyngitis.

The most common serious adverse event – exacerbation of UC – was reported by 8 (1.1%) golimumab-treated and 8 (2.4%) placebo-treated patients.

A second study, also led by Dr. Sandborn, looked at whether continuous golimumab dosing would result in remission maintained to 1 year.

To that end, Dr. Sandborn next randomized the golimumab initial responders in the first study (n = 464) to placebo or injections of 50 or 100 mg golimumab every 4 weeks through 1 year.

Overall, 49.7% of patients in the 100-mg cohort maintained a clinical response through week 54, compared with 47% in the 50-mg group and 31.2% in the placebo group (P less than .001 and P = .010 for each dose versus placebo, respectively).

Remission was also seen with greater frequency among patients receiving 100 mg golimumab at both 30 and 54 weeks (27.8%) compared with placebo (15.6%; P = .004).

Finally, the proportion of patients with mucosal healing at both weeks 30 and 54 was significantly greater for patients receiving golimumab 100 mg (42.4%) compared with placebo (26.6%; P = .002). The mucosal healing rate for the 50-mg golimumab cohort was 41.7%.

Looking at safety, the authors did concede that "the proportions of patients who experienced at least one serious adverse event or discontinued because of an adverse event were greater for golimumab 100 mg compared with placebo or golimumab 50 mg."

However, "the duration of follow-up evaluation in the placebo group was notably shorter than either of the golimumab groups, and when adjusted for follow-up time, difference in the incidences of serious adverse events per 100 patient-years were less remarkable across treatment groups."

Dr. Sandborn and colleagues disclosed ties with Janssen Research and Development, which sponsored the studies. Janssen Biotech is the maker of golimumab.

Subcutaneous golimumab induces and maintains clinical response in ulcerative colitis, according to two studies in the January issue of Gastroenterology.

In the first, Dr. William J. Sandborn of the University of California San Diego, and his colleagues, looked at 1,064 patients enrolled in the PURSUIT-SC study (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous), an integrated phase II and phase III study of subcutaneous golimumab.

Golimumab, developed by Janssen Pharmaceutical Companies of Johnson & Johnson – the sponsor of both studies in this month’s Gastroenterology – is a fully human monoclonal antibody to tumor necrosis factor–alpha.

All patients had an established diagnosis of UC and moderate to severe disease activity, defined as a Mayo score of 6-12, with an endoscopic subscore of at least 2.

Additionally, all patients had previously tried and failed oral 5-aminosalicylates, oral corticosteroids, azathioprine (AZA), and/or 6-mercaptopurine. Alternatively, they were simply unable to wean off corticosteroids.

Patients enrolled in the phase II, dose-finding portion of the study were randomized to subcutaneous injections of placebo or one of three different golimumab doses at weeks 0 and 2: 100/50 mg (i.e., 100 mg at week 0 and 50 mg at week 2), 200/100 mg, or 400/200 mg, respectively (n = 169).

"An additional 122 patients were enrolled while phase II data were being analyzed," wrote the authors.

"Clinical response" was defined as a decrease from baseline in the Mayo score of at least 30% and 3 or more points, accompanied by either a rectal bleeding subscore of 0 or 1, or a decrease from baseline in the rectal bleeding subscore of at least 1.

"Clinical remission" was defined as a Mayo score less than or equal to 2, with no individual subscore greater than 1.

Finally, "mucosal healing" was defined as a Mayo endoscopy subscore of 0 or 1.

The authors found that the median changes from the baseline Mayo score were –1.0, –3.0, –2.0, and –3.0 for placebo and golimumab 100/50 mg, 200/100 mg, and 400/200 mg, respectively.

Moreover, at week 6, a numerically greater proportion of patients assigned to golimumab 400/200 mg were in clinical response or remission, had mucosal healing, or had Inflammatory Bowel Disease Questionnaire (IBDQ) scores superior to that of placebo patients.

Next, after analysis of the dose-finding data, the 200/100–mg and 400/200–mg doses were selected for evaluation in phase III, a dose confirmation trial.

Overall, 774 patients participated in this portion of the trial, randomized to placebo, golimumab 200/100 mg, or 400/200 mg at weeks 0 and 2.

By week 6, significantly greater proportions of patients in the golimumab 200/100–mg and golimumab 400/200–mg groups (51.0%, and 54.9%, respectively) were in clinical response compared with patients assigned to placebo (30.3%; P less than 0.0001 for both comparisons).

"The efficacy of both golimumab induction regimens was also demonstrated for the major secondary endpoints of clinical remission, mucosal healing, and improvement from baseline in the IBDQ score, all at week 6," they added.

Looking at safety, nearly 40% of all phase III cohorts reported adverse events, most commonly headache and nasopharyngitis.

The most common serious adverse event – exacerbation of UC – was reported by 8 (1.1%) golimumab-treated and 8 (2.4%) placebo-treated patients.

A second study, also led by Dr. Sandborn, looked at whether continuous golimumab dosing would result in remission maintained to 1 year.

To that end, Dr. Sandborn next randomized the golimumab initial responders in the first study (n = 464) to placebo or injections of 50 or 100 mg golimumab every 4 weeks through 1 year.

Overall, 49.7% of patients in the 100-mg cohort maintained a clinical response through week 54, compared with 47% in the 50-mg group and 31.2% in the placebo group (P less than .001 and P = .010 for each dose versus placebo, respectively).

Remission was also seen with greater frequency among patients receiving 100 mg golimumab at both 30 and 54 weeks (27.8%) compared with placebo (15.6%; P = .004).

Finally, the proportion of patients with mucosal healing at both weeks 30 and 54 was significantly greater for patients receiving golimumab 100 mg (42.4%) compared with placebo (26.6%; P = .002). The mucosal healing rate for the 50-mg golimumab cohort was 41.7%.

Looking at safety, the authors did concede that "the proportions of patients who experienced at least one serious adverse event or discontinued because of an adverse event were greater for golimumab 100 mg compared with placebo or golimumab 50 mg."

However, "the duration of follow-up evaluation in the placebo group was notably shorter than either of the golimumab groups, and when adjusted for follow-up time, difference in the incidences of serious adverse events per 100 patient-years were less remarkable across treatment groups."

Dr. Sandborn and colleagues disclosed ties with Janssen Research and Development, which sponsored the studies. Janssen Biotech is the maker of golimumab.

Subcutaneous golimumab induces and maintains clinical response in ulcerative colitis, according to two studies in the January issue of Gastroenterology.

In the first, Dr. William J. Sandborn of the University of California San Diego, and his colleagues, looked at 1,064 patients enrolled in the PURSUIT-SC study (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous), an integrated phase II and phase III study of subcutaneous golimumab.

Golimumab, developed by Janssen Pharmaceutical Companies of Johnson & Johnson – the sponsor of both studies in this month’s Gastroenterology – is a fully human monoclonal antibody to tumor necrosis factor–alpha.

All patients had an established diagnosis of UC and moderate to severe disease activity, defined as a Mayo score of 6-12, with an endoscopic subscore of at least 2.

Additionally, all patients had previously tried and failed oral 5-aminosalicylates, oral corticosteroids, azathioprine (AZA), and/or 6-mercaptopurine. Alternatively, they were simply unable to wean off corticosteroids.

Patients enrolled in the phase II, dose-finding portion of the study were randomized to subcutaneous injections of placebo or one of three different golimumab doses at weeks 0 and 2: 100/50 mg (i.e., 100 mg at week 0 and 50 mg at week 2), 200/100 mg, or 400/200 mg, respectively (n = 169).

"An additional 122 patients were enrolled while phase II data were being analyzed," wrote the authors.

"Clinical response" was defined as a decrease from baseline in the Mayo score of at least 30% and 3 or more points, accompanied by either a rectal bleeding subscore of 0 or 1, or a decrease from baseline in the rectal bleeding subscore of at least 1.

"Clinical remission" was defined as a Mayo score less than or equal to 2, with no individual subscore greater than 1.

Finally, "mucosal healing" was defined as a Mayo endoscopy subscore of 0 or 1.

The authors found that the median changes from the baseline Mayo score were –1.0, –3.0, –2.0, and –3.0 for placebo and golimumab 100/50 mg, 200/100 mg, and 400/200 mg, respectively.

Moreover, at week 6, a numerically greater proportion of patients assigned to golimumab 400/200 mg were in clinical response or remission, had mucosal healing, or had Inflammatory Bowel Disease Questionnaire (IBDQ) scores superior to that of placebo patients.

Next, after analysis of the dose-finding data, the 200/100–mg and 400/200–mg doses were selected for evaluation in phase III, a dose confirmation trial.

Overall, 774 patients participated in this portion of the trial, randomized to placebo, golimumab 200/100 mg, or 400/200 mg at weeks 0 and 2.

By week 6, significantly greater proportions of patients in the golimumab 200/100–mg and golimumab 400/200–mg groups (51.0%, and 54.9%, respectively) were in clinical response compared with patients assigned to placebo (30.3%; P less than 0.0001 for both comparisons).

"The efficacy of both golimumab induction regimens was also demonstrated for the major secondary endpoints of clinical remission, mucosal healing, and improvement from baseline in the IBDQ score, all at week 6," they added.

Looking at safety, nearly 40% of all phase III cohorts reported adverse events, most commonly headache and nasopharyngitis.

The most common serious adverse event – exacerbation of UC – was reported by 8 (1.1%) golimumab-treated and 8 (2.4%) placebo-treated patients.

A second study, also led by Dr. Sandborn, looked at whether continuous golimumab dosing would result in remission maintained to 1 year.

To that end, Dr. Sandborn next randomized the golimumab initial responders in the first study (n = 464) to placebo or injections of 50 or 100 mg golimumab every 4 weeks through 1 year.

Overall, 49.7% of patients in the 100-mg cohort maintained a clinical response through week 54, compared with 47% in the 50-mg group and 31.2% in the placebo group (P less than .001 and P = .010 for each dose versus placebo, respectively).

Remission was also seen with greater frequency among patients receiving 100 mg golimumab at both 30 and 54 weeks (27.8%) compared with placebo (15.6%; P = .004).

Finally, the proportion of patients with mucosal healing at both weeks 30 and 54 was significantly greater for patients receiving golimumab 100 mg (42.4%) compared with placebo (26.6%; P = .002). The mucosal healing rate for the 50-mg golimumab cohort was 41.7%.

Looking at safety, the authors did concede that "the proportions of patients who experienced at least one serious adverse event or discontinued because of an adverse event were greater for golimumab 100 mg compared with placebo or golimumab 50 mg."

However, "the duration of follow-up evaluation in the placebo group was notably shorter than either of the golimumab groups, and when adjusted for follow-up time, difference in the incidences of serious adverse events per 100 patient-years were less remarkable across treatment groups."

Dr. Sandborn and colleagues disclosed ties with Janssen Research and Development, which sponsored the studies. Janssen Biotech is the maker of golimumab.

Bisphosphonates are safe and effective for treating low bone mineral density in inflammatory bowel disease, according to a meta-analysis of 19 randomized controlled studies published in the January issue of Clinical Gastroenterology and Hepatology.

On the other hand, alternative therapies such as calcium plus vitamin D, calcitonin, and low-impact exercise demonstrated questionable efficacy, leading the authors to conclude that bisphosphonates alone "should be more aggressively considered" in this population.

Dr. John Melek of Mercy Hospital and Medical Center, Chicago, and Dr. Atsushi Sakuraba of the Inflammatory Bowel Disease Center at the University of Chicago Medicine, searched the MEDLINE and EMBASE databases as well as Google scholar, the UMIN Clinical Trials Registry, and the Cochrane Central Register for randomized controlled trials conducted between 1981 and 2011 assessing treatment for low BMD in IBD.

Overall, 11 of the 19 included studies evaluated bisphosphonates versus placebo or no treatment, while 4 looked at sodium fluoride versus placebo/no treatment, and 2 assessed calcium plus vitamin D versus placebo/no treatment.

The remaining analyses tested calcitonin versus placebo (1); low-impact exercise versus habitual physical activity (1); and bisphosphonates versus vitamin D (1) and fluoride (1). (Three studies compared multiple arms within the same study.)

Among all data on bisphosphonate efficacy, the authors found that the pooled overall effect by mixed-effect analysis revealed bisphosphonates to be significantly superior to control therapies in improving lumbar spine BMD, with a standard difference in means (SDm) of 0.51 (95% confidence interval [CI], 0.29-0.72; P less than .01).

Indeed, among the seven studies that reported improvements in the hip BMD, for example, a pooled overall effect by mixed-effect analysis showed that bisphosphonates were significantly superior to controls (both other treatments and no treatment; SDm, 0.26; 95% CI, 0.04-0.49; P = .02).

Moreover, among studies which reported the incidences of nonvertebral and vertebral fractures, the pooled ORs were 0.35 (95% CI, 0.06-1.95; P = .23) and 0.38 (95% CI, 0.15-0.96; P = .04), respectively.

Looking at adverse effects, meanwhile, the pooled odds ratio of adverse effects was a nonsignificant 1.24 (95% CI, 0.83-1.85; P = .29), "demonstrating that bisphosphonate treatment was not associated with an increased incidence of adverse effects."

Sodium fluoride, meanwhile, showed some efficacy: The four studies that assessed this treatment showed it was superior to placebo/no treatment in improving lumbar spine BMD (SDm, 1.18; 95% CI, 0.10-2.26; P = .03).

Fluoride did not, however, significantly improve hip BMD, compared with placebo, nor did it reduce the incidence of vertebral or nonvertebral fractures.

Similarly, the one study that looked at calcitonin (and assessed only children and adolescents with active or quiescent Crohn’s disease or ulcerative colitis, plus osteopenia or osteoporosis) found that this treatment was not superior to placebo in improving BMD at the lumbar spine. It did not find changes in hip BMD or the incidence of fractures.

Nor was low-impact exercise superior to control (habitual physical activity) in improving BMD at the hip or lumbar spine; fracture incidence was not assessed.

The authors conceded several limitations, the greatest of which was the presence of marked heterogeneity among studies, which necessitated use of the random-effects model or mixed-effect analysis. Indeed, much of this heterogeneity was due to the fact that some studies aimed to prevent bone loss, whereas others treated established osteopenia, they wrote.

Additionally, although many IBD patients are today treated with biologic therapies, few studies evaluated BMD regimens in IBD patients who underwent biologic treatment.

The authors disclosed no conflicts of interest related to this analysis. Dr. Sakuraba was supported by the Foreign Clinical Pharmacology Training Program of the Japanese Society of Clinical Pharmacology and Therapeutics.

Bisphosphonates are safe and effective for treating low bone mineral density in inflammatory bowel disease, according to a meta-analysis of 19 randomized controlled studies published in the January issue of Clinical Gastroenterology and Hepatology.

On the other hand, alternative therapies such as calcium plus vitamin D, calcitonin, and low-impact exercise demonstrated questionable efficacy, leading the authors to conclude that bisphosphonates alone "should be more aggressively considered" in this population.

Dr. John Melek of Mercy Hospital and Medical Center, Chicago, and Dr. Atsushi Sakuraba of the Inflammatory Bowel Disease Center at the University of Chicago Medicine, searched the MEDLINE and EMBASE databases as well as Google scholar, the UMIN Clinical Trials Registry, and the Cochrane Central Register for randomized controlled trials conducted between 1981 and 2011 assessing treatment for low BMD in IBD.

Overall, 11 of the 19 included studies evaluated bisphosphonates versus placebo or no treatment, while 4 looked at sodium fluoride versus placebo/no treatment, and 2 assessed calcium plus vitamin D versus placebo/no treatment.

The remaining analyses tested calcitonin versus placebo (1); low-impact exercise versus habitual physical activity (1); and bisphosphonates versus vitamin D (1) and fluoride (1). (Three studies compared multiple arms within the same study.)

Among all data on bisphosphonate efficacy, the authors found that the pooled overall effect by mixed-effect analysis revealed bisphosphonates to be significantly superior to control therapies in improving lumbar spine BMD, with a standard difference in means (SDm) of 0.51 (95% confidence interval [CI], 0.29-0.72; P less than .01).

Indeed, among the seven studies that reported improvements in the hip BMD, for example, a pooled overall effect by mixed-effect analysis showed that bisphosphonates were significantly superior to controls (both other treatments and no treatment; SDm, 0.26; 95% CI, 0.04-0.49; P = .02).

Moreover, among studies which reported the incidences of nonvertebral and vertebral fractures, the pooled ORs were 0.35 (95% CI, 0.06-1.95; P = .23) and 0.38 (95% CI, 0.15-0.96; P = .04), respectively.

Looking at adverse effects, meanwhile, the pooled odds ratio of adverse effects was a nonsignificant 1.24 (95% CI, 0.83-1.85; P = .29), "demonstrating that bisphosphonate treatment was not associated with an increased incidence of adverse effects."

Sodium fluoride, meanwhile, showed some efficacy: The four studies that assessed this treatment showed it was superior to placebo/no treatment in improving lumbar spine BMD (SDm, 1.18; 95% CI, 0.10-2.26; P = .03).

Fluoride did not, however, significantly improve hip BMD, compared with placebo, nor did it reduce the incidence of vertebral or nonvertebral fractures.

Similarly, the one study that looked at calcitonin (and assessed only children and adolescents with active or quiescent Crohn’s disease or ulcerative colitis, plus osteopenia or osteoporosis) found that this treatment was not superior to placebo in improving BMD at the lumbar spine. It did not find changes in hip BMD or the incidence of fractures.

Nor was low-impact exercise superior to control (habitual physical activity) in improving BMD at the hip or lumbar spine; fracture incidence was not assessed.

The authors conceded several limitations, the greatest of which was the presence of marked heterogeneity among studies, which necessitated use of the random-effects model or mixed-effect analysis. Indeed, much of this heterogeneity was due to the fact that some studies aimed to prevent bone loss, whereas others treated established osteopenia, they wrote.

Additionally, although many IBD patients are today treated with biologic therapies, few studies evaluated BMD regimens in IBD patients who underwent biologic treatment.

The authors disclosed no conflicts of interest related to this analysis. Dr. Sakuraba was supported by the Foreign Clinical Pharmacology Training Program of the Japanese Society of Clinical Pharmacology and Therapeutics.

Bisphosphonates are safe and effective for treating low bone mineral density in inflammatory bowel disease, according to a meta-analysis of 19 randomized controlled studies published in the January issue of Clinical Gastroenterology and Hepatology.

On the other hand, alternative therapies such as calcium plus vitamin D, calcitonin, and low-impact exercise demonstrated questionable efficacy, leading the authors to conclude that bisphosphonates alone "should be more aggressively considered" in this population.

Dr. John Melek of Mercy Hospital and Medical Center, Chicago, and Dr. Atsushi Sakuraba of the Inflammatory Bowel Disease Center at the University of Chicago Medicine, searched the MEDLINE and EMBASE databases as well as Google scholar, the UMIN Clinical Trials Registry, and the Cochrane Central Register for randomized controlled trials conducted between 1981 and 2011 assessing treatment for low BMD in IBD.

Overall, 11 of the 19 included studies evaluated bisphosphonates versus placebo or no treatment, while 4 looked at sodium fluoride versus placebo/no treatment, and 2 assessed calcium plus vitamin D versus placebo/no treatment.

The remaining analyses tested calcitonin versus placebo (1); low-impact exercise versus habitual physical activity (1); and bisphosphonates versus vitamin D (1) and fluoride (1). (Three studies compared multiple arms within the same study.)

Among all data on bisphosphonate efficacy, the authors found that the pooled overall effect by mixed-effect analysis revealed bisphosphonates to be significantly superior to control therapies in improving lumbar spine BMD, with a standard difference in means (SDm) of 0.51 (95% confidence interval [CI], 0.29-0.72; P less than .01).

Indeed, among the seven studies that reported improvements in the hip BMD, for example, a pooled overall effect by mixed-effect analysis showed that bisphosphonates were significantly superior to controls (both other treatments and no treatment; SDm, 0.26; 95% CI, 0.04-0.49; P = .02).

Moreover, among studies which reported the incidences of nonvertebral and vertebral fractures, the pooled ORs were 0.35 (95% CI, 0.06-1.95; P = .23) and 0.38 (95% CI, 0.15-0.96; P = .04), respectively.

Looking at adverse effects, meanwhile, the pooled odds ratio of adverse effects was a nonsignificant 1.24 (95% CI, 0.83-1.85; P = .29), "demonstrating that bisphosphonate treatment was not associated with an increased incidence of adverse effects."

Sodium fluoride, meanwhile, showed some efficacy: The four studies that assessed this treatment showed it was superior to placebo/no treatment in improving lumbar spine BMD (SDm, 1.18; 95% CI, 0.10-2.26; P = .03).

Fluoride did not, however, significantly improve hip BMD, compared with placebo, nor did it reduce the incidence of vertebral or nonvertebral fractures.

Similarly, the one study that looked at calcitonin (and assessed only children and adolescents with active or quiescent Crohn’s disease or ulcerative colitis, plus osteopenia or osteoporosis) found that this treatment was not superior to placebo in improving BMD at the lumbar spine. It did not find changes in hip BMD or the incidence of fractures.

Nor was low-impact exercise superior to control (habitual physical activity) in improving BMD at the hip or lumbar spine; fracture incidence was not assessed.

The authors conceded several limitations, the greatest of which was the presence of marked heterogeneity among studies, which necessitated use of the random-effects model or mixed-effect analysis. Indeed, much of this heterogeneity was due to the fact that some studies aimed to prevent bone loss, whereas others treated established osteopenia, they wrote.

Additionally, although many IBD patients are today treated with biologic therapies, few studies evaluated BMD regimens in IBD patients who underwent biologic treatment.

The authors disclosed no conflicts of interest related to this analysis. Dr. Sakuraba was supported by the Foreign Clinical Pharmacology Training Program of the Japanese Society of Clinical Pharmacology and Therapeutics.