TBD Meeting (5815-13)

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.