Inflammatory bowel disease

For the Spring Postgraduate Course session on inflammatory bowel disease (IBD), we were fortunate to secure four of the best educators on IBD in the American Gastroenterological Association.

William Sandborn, MD, of the University of California, San Diego, led the session with an overview of the immunomodulators and biologics that are employed for the treatment of Crohn’s disease and ulcerative colitis in 2016, including the thiopurines, methotrexate, calcineurin inhibitors, anti–tumor necrosis factor (TNF) agents, anti-integrins, and upcoming therapies such as ustekinumab (anti-interleukins 12 and 23) and tofacitinib (Janus kinase antagonist).

The evidence base for thiopurine monotherapy in IBD is weaker than we had once assumed, and the combination of infliximab and azathioprine remains the gold standard in efficacy with respect to steroid-free remission. Methotrexate remains a reasonable option as an immunomodulator, especially for patients who can’t tolerate thiopurines or who are risk averse. Cyclosporine has a niche indication for the treatment of acute severe colitis, and is at least equivalent to infliximab for that indication.

We have a total of four anti-TNF agents approved for the treatment of moderate to severe Crohn’s disease and ulcerative colitis, including infliximab, adalimumab, certolizumab pegol (Crohn’s only), and golimumab (ulcerative colitis only). The infliximab biosimilar CT-P13 is approved for IBD in several countries. The anti-integrin, vedolizumab, is approved for both moderate to severe ulcerative colitis and Crohn’s disease. Ustekinumab was shown to be more effective than placebo in inducing clinical response and remission in moderate to severe Crohn’s disease patients who were either refractory/intolerant to or naive to anti-TNF therapy. Tofacitinib was recently shown in two trials to be more effective than placebo in inducing clinical remission and mucosal healing in patients with moderate to severe ulcerative colitis.

Maria Abreu, MD, from the University of Miami highlighted the fact that although our current therapies are far more effective than previous ones, they can be problematic, and dose adjustment is often needed. We should tailor our treatment plan based on our assessment of the patient’s risk for intestinal complications or surgery – patients with multiple risk factors such as young age at diagnosis, extensive involvement, deep ulcers, previous surgeries, or penetrating/stricturing behavior at baseline should be treated more aggressively, perhaps with a top-down approach. In general, biologics will be more effective when used in combination with immunomodulators. Monotherapy can be considered in patients with low inflammatory burden, few risk factors for more severe disease, or in those at high risk for complications from combination therapy.

At least one way in which concomitant immunomodulator therapy exerts its beneficial effect is by increasing trough levels of the biologic. One recent study of the relationship between adalimumab levels and endoscopic inflammation suggested that the median adalimumab trough level associated with mucosal healing was 13.5 mcg/mL. Patients with low drug levels and no or low levels of anti-drug antibodies should undergo dose escalation. Those with absent drug levels and high levels of antibodies should switch to a different agent. If the drug level is considered adequate and yet inflammation is still present, consideration should be given to switching to a biologic with a different mechanism of action. In some patients with low levels of antibodies who are on monotherapy, there may be a role for adding an immunomodulator in an attempt to suppress antibody formation. The importance of vedolizumab and ustekinumab as biologics with different mechanisms of action was also highlighted. An exciting class of biologics currently under development is the anti–IL-23 class, including drugs such as risankizumab and MEDI-2070.

David T. Rubin, MD, from the University of Chicago reviewed the various complications associated with IBD and its therapies. Disease-related complications include clinical flares, bowel obstruction, fistula/abscess formation, intestinal cancer, the need for surgery (sometimes more than one), and extraintestinal manifestations. More accurate diagnosis and earlier effective therapies may help to reduce the risk of these complications. Certain infections such as herpes zoster, pneumonia, and Clostridium difficile infection appear to occur more commonly in IBD patients. The TREAT registry showed that the use of corticosteroids is associated with an increased risk of serious infections and mortality, and the use of infliximab is associated with an increased risk of serious infection. C. difficile infection in particular can be problematic, and should be treated aggressively. Thiopurines appear to increase the risk of lymphoma and nonmelanoma skin cancer. Lymphoma risk quickly reverts to baseline after thiopurines are discontinued. Overall, no increased risk of cancer can be demonstrated among patients on anti-TNF therapy, and patients with a history of cancer do not have an increased risk of recurrent or new cancers on anti-TNF therapy. There may be an association between anti-TNF use and melanoma, although this bears further study.

Miguel Regueiro, MD, from the University of Pittsburgh wrapped up the session with a talk on managing postoperative IBD patients. Although the ileal pouch–anal anastomosis (IPAA) broadened access to proctocolectomy, it is associated with several disorders, including pelvic sepsis, pouchitis, Crohn’s disease of the ileoanal pouch, cuffitis, and irritable pouch syndrome. At least 50% of IPAA patients will develop at least one episode of pouchitis. Most patients will respond to ciprofloxacin or metronidazole, but a small percentage will develop chronic pouchitis. Ileocecal resection for the complications of Crohn’s disease generally results in immediate improvements in quality of life, but unfortunately, most patients will develop endoscopic and eventually clinical recurrence. At 6-12 months after surgery, a Rutgeerts score of i2 or higher (at least five aphthous lesions in the neoterminal ileum) is associated with a high risk of clinical recurrence, and this finding can be used as a trigger for escalation of therapy.

Infliximab was associated with a markedly decreased risk of endoscopic recurrence in a small investigator-initiated trial, and subsequent studies have strongly suggested that infliximab and adalimumab reduce the risk of recurrence. Although the primary endpoint of clinical recurrence was not met in the large multicenter PREVENT trial, infliximab was shown to significantly decrease endoscopic recurrence. The POCER study showed that a slightly less proactive approach of watchful waiting in lower-risk patients and making decisions about therapy at the 6-month colonoscopy was a reasonable one. The risk factors one must consider in stratifying postop patients include early age at surgery, short time between diagnosis and surgery, cigarette smoking, penetrating disease behavior, and a history of previous resections.

Dr. Loftus is professor of medicine in the division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He has consulted for and has received research support from Janssen, UCB, Takeda, and AbbVie.

This is a summary provided by the moderator of one of the spring postgraduate course sessions held at DDW 2016.

For the Spring Postgraduate Course session on inflammatory bowel disease (IBD), we were fortunate to secure four of the best educators on IBD in the American Gastroenterological Association.

William Sandborn, MD, of the University of California, San Diego, led the session with an overview of the immunomodulators and biologics that are employed for the treatment of Crohn’s disease and ulcerative colitis in 2016, including the thiopurines, methotrexate, calcineurin inhibitors, anti–tumor necrosis factor (TNF) agents, anti-integrins, and upcoming therapies such as ustekinumab (anti-interleukins 12 and 23) and tofacitinib (Janus kinase antagonist).

The evidence base for thiopurine monotherapy in IBD is weaker than we had once assumed, and the combination of infliximab and azathioprine remains the gold standard in efficacy with respect to steroid-free remission. Methotrexate remains a reasonable option as an immunomodulator, especially for patients who can’t tolerate thiopurines or who are risk averse. Cyclosporine has a niche indication for the treatment of acute severe colitis, and is at least equivalent to infliximab for that indication.

We have a total of four anti-TNF agents approved for the treatment of moderate to severe Crohn’s disease and ulcerative colitis, including infliximab, adalimumab, certolizumab pegol (Crohn’s only), and golimumab (ulcerative colitis only). The infliximab biosimilar CT-P13 is approved for IBD in several countries. The anti-integrin, vedolizumab, is approved for both moderate to severe ulcerative colitis and Crohn’s disease. Ustekinumab was shown to be more effective than placebo in inducing clinical response and remission in moderate to severe Crohn’s disease patients who were either refractory/intolerant to or naive to anti-TNF therapy. Tofacitinib was recently shown in two trials to be more effective than placebo in inducing clinical remission and mucosal healing in patients with moderate to severe ulcerative colitis.

Maria Abreu, MD, from the University of Miami highlighted the fact that although our current therapies are far more effective than previous ones, they can be problematic, and dose adjustment is often needed. We should tailor our treatment plan based on our assessment of the patient’s risk for intestinal complications or surgery – patients with multiple risk factors such as young age at diagnosis, extensive involvement, deep ulcers, previous surgeries, or penetrating/stricturing behavior at baseline should be treated more aggressively, perhaps with a top-down approach. In general, biologics will be more effective when used in combination with immunomodulators. Monotherapy can be considered in patients with low inflammatory burden, few risk factors for more severe disease, or in those at high risk for complications from combination therapy.

At least one way in which concomitant immunomodulator therapy exerts its beneficial effect is by increasing trough levels of the biologic. One recent study of the relationship between adalimumab levels and endoscopic inflammation suggested that the median adalimumab trough level associated with mucosal healing was 13.5 mcg/mL. Patients with low drug levels and no or low levels of anti-drug antibodies should undergo dose escalation. Those with absent drug levels and high levels of antibodies should switch to a different agent. If the drug level is considered adequate and yet inflammation is still present, consideration should be given to switching to a biologic with a different mechanism of action. In some patients with low levels of antibodies who are on monotherapy, there may be a role for adding an immunomodulator in an attempt to suppress antibody formation. The importance of vedolizumab and ustekinumab as biologics with different mechanisms of action was also highlighted. An exciting class of biologics currently under development is the anti–IL-23 class, including drugs such as risankizumab and MEDI-2070.

David T. Rubin, MD, from the University of Chicago reviewed the various complications associated with IBD and its therapies. Disease-related complications include clinical flares, bowel obstruction, fistula/abscess formation, intestinal cancer, the need for surgery (sometimes more than one), and extraintestinal manifestations. More accurate diagnosis and earlier effective therapies may help to reduce the risk of these complications. Certain infections such as herpes zoster, pneumonia, and Clostridium difficile infection appear to occur more commonly in IBD patients. The TREAT registry showed that the use of corticosteroids is associated with an increased risk of serious infections and mortality, and the use of infliximab is associated with an increased risk of serious infection. C. difficile infection in particular can be problematic, and should be treated aggressively. Thiopurines appear to increase the risk of lymphoma and nonmelanoma skin cancer. Lymphoma risk quickly reverts to baseline after thiopurines are discontinued. Overall, no increased risk of cancer can be demonstrated among patients on anti-TNF therapy, and patients with a history of cancer do not have an increased risk of recurrent or new cancers on anti-TNF therapy. There may be an association between anti-TNF use and melanoma, although this bears further study.

Miguel Regueiro, MD, from the University of Pittsburgh wrapped up the session with a talk on managing postoperative IBD patients. Although the ileal pouch–anal anastomosis (IPAA) broadened access to proctocolectomy, it is associated with several disorders, including pelvic sepsis, pouchitis, Crohn’s disease of the ileoanal pouch, cuffitis, and irritable pouch syndrome. At least 50% of IPAA patients will develop at least one episode of pouchitis. Most patients will respond to ciprofloxacin or metronidazole, but a small percentage will develop chronic pouchitis. Ileocecal resection for the complications of Crohn’s disease generally results in immediate improvements in quality of life, but unfortunately, most patients will develop endoscopic and eventually clinical recurrence. At 6-12 months after surgery, a Rutgeerts score of i2 or higher (at least five aphthous lesions in the neoterminal ileum) is associated with a high risk of clinical recurrence, and this finding can be used as a trigger for escalation of therapy.

Infliximab was associated with a markedly decreased risk of endoscopic recurrence in a small investigator-initiated trial, and subsequent studies have strongly suggested that infliximab and adalimumab reduce the risk of recurrence. Although the primary endpoint of clinical recurrence was not met in the large multicenter PREVENT trial, infliximab was shown to significantly decrease endoscopic recurrence. The POCER study showed that a slightly less proactive approach of watchful waiting in lower-risk patients and making decisions about therapy at the 6-month colonoscopy was a reasonable one. The risk factors one must consider in stratifying postop patients include early age at surgery, short time between diagnosis and surgery, cigarette smoking, penetrating disease behavior, and a history of previous resections.

Dr. Loftus is professor of medicine in the division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He has consulted for and has received research support from Janssen, UCB, Takeda, and AbbVie.

This is a summary provided by the moderator of one of the spring postgraduate course sessions held at DDW 2016.

For the Spring Postgraduate Course session on inflammatory bowel disease (IBD), we were fortunate to secure four of the best educators on IBD in the American Gastroenterological Association.

William Sandborn, MD, of the University of California, San Diego, led the session with an overview of the immunomodulators and biologics that are employed for the treatment of Crohn’s disease and ulcerative colitis in 2016, including the thiopurines, methotrexate, calcineurin inhibitors, anti–tumor necrosis factor (TNF) agents, anti-integrins, and upcoming therapies such as ustekinumab (anti-interleukins 12 and 23) and tofacitinib (Janus kinase antagonist).

The evidence base for thiopurine monotherapy in IBD is weaker than we had once assumed, and the combination of infliximab and azathioprine remains the gold standard in efficacy with respect to steroid-free remission. Methotrexate remains a reasonable option as an immunomodulator, especially for patients who can’t tolerate thiopurines or who are risk averse. Cyclosporine has a niche indication for the treatment of acute severe colitis, and is at least equivalent to infliximab for that indication.

We have a total of four anti-TNF agents approved for the treatment of moderate to severe Crohn’s disease and ulcerative colitis, including infliximab, adalimumab, certolizumab pegol (Crohn’s only), and golimumab (ulcerative colitis only). The infliximab biosimilar CT-P13 is approved for IBD in several countries. The anti-integrin, vedolizumab, is approved for both moderate to severe ulcerative colitis and Crohn’s disease. Ustekinumab was shown to be more effective than placebo in inducing clinical response and remission in moderate to severe Crohn’s disease patients who were either refractory/intolerant to or naive to anti-TNF therapy. Tofacitinib was recently shown in two trials to be more effective than placebo in inducing clinical remission and mucosal healing in patients with moderate to severe ulcerative colitis.

Maria Abreu, MD, from the University of Miami highlighted the fact that although our current therapies are far more effective than previous ones, they can be problematic, and dose adjustment is often needed. We should tailor our treatment plan based on our assessment of the patient’s risk for intestinal complications or surgery – patients with multiple risk factors such as young age at diagnosis, extensive involvement, deep ulcers, previous surgeries, or penetrating/stricturing behavior at baseline should be treated more aggressively, perhaps with a top-down approach. In general, biologics will be more effective when used in combination with immunomodulators. Monotherapy can be considered in patients with low inflammatory burden, few risk factors for more severe disease, or in those at high risk for complications from combination therapy.

At least one way in which concomitant immunomodulator therapy exerts its beneficial effect is by increasing trough levels of the biologic. One recent study of the relationship between adalimumab levels and endoscopic inflammation suggested that the median adalimumab trough level associated with mucosal healing was 13.5 mcg/mL. Patients with low drug levels and no or low levels of anti-drug antibodies should undergo dose escalation. Those with absent drug levels and high levels of antibodies should switch to a different agent. If the drug level is considered adequate and yet inflammation is still present, consideration should be given to switching to a biologic with a different mechanism of action. In some patients with low levels of antibodies who are on monotherapy, there may be a role for adding an immunomodulator in an attempt to suppress antibody formation. The importance of vedolizumab and ustekinumab as biologics with different mechanisms of action was also highlighted. An exciting class of biologics currently under development is the anti–IL-23 class, including drugs such as risankizumab and MEDI-2070.

David T. Rubin, MD, from the University of Chicago reviewed the various complications associated with IBD and its therapies. Disease-related complications include clinical flares, bowel obstruction, fistula/abscess formation, intestinal cancer, the need for surgery (sometimes more than one), and extraintestinal manifestations. More accurate diagnosis and earlier effective therapies may help to reduce the risk of these complications. Certain infections such as herpes zoster, pneumonia, and Clostridium difficile infection appear to occur more commonly in IBD patients. The TREAT registry showed that the use of corticosteroids is associated with an increased risk of serious infections and mortality, and the use of infliximab is associated with an increased risk of serious infection. C. difficile infection in particular can be problematic, and should be treated aggressively. Thiopurines appear to increase the risk of lymphoma and nonmelanoma skin cancer. Lymphoma risk quickly reverts to baseline after thiopurines are discontinued. Overall, no increased risk of cancer can be demonstrated among patients on anti-TNF therapy, and patients with a history of cancer do not have an increased risk of recurrent or new cancers on anti-TNF therapy. There may be an association between anti-TNF use and melanoma, although this bears further study.

Miguel Regueiro, MD, from the University of Pittsburgh wrapped up the session with a talk on managing postoperative IBD patients. Although the ileal pouch–anal anastomosis (IPAA) broadened access to proctocolectomy, it is associated with several disorders, including pelvic sepsis, pouchitis, Crohn’s disease of the ileoanal pouch, cuffitis, and irritable pouch syndrome. At least 50% of IPAA patients will develop at least one episode of pouchitis. Most patients will respond to ciprofloxacin or metronidazole, but a small percentage will develop chronic pouchitis. Ileocecal resection for the complications of Crohn’s disease generally results in immediate improvements in quality of life, but unfortunately, most patients will develop endoscopic and eventually clinical recurrence. At 6-12 months after surgery, a Rutgeerts score of i2 or higher (at least five aphthous lesions in the neoterminal ileum) is associated with a high risk of clinical recurrence, and this finding can be used as a trigger for escalation of therapy.

Infliximab was associated with a markedly decreased risk of endoscopic recurrence in a small investigator-initiated trial, and subsequent studies have strongly suggested that infliximab and adalimumab reduce the risk of recurrence. Although the primary endpoint of clinical recurrence was not met in the large multicenter PREVENT trial, infliximab was shown to significantly decrease endoscopic recurrence. The POCER study showed that a slightly less proactive approach of watchful waiting in lower-risk patients and making decisions about therapy at the 6-month colonoscopy was a reasonable one. The risk factors one must consider in stratifying postop patients include early age at surgery, short time between diagnosis and surgery, cigarette smoking, penetrating disease behavior, and a history of previous resections.

Dr. Loftus is professor of medicine in the division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He has consulted for and has received research support from Janssen, UCB, Takeda, and AbbVie.

This is a summary provided by the moderator of one of the spring postgraduate course sessions held at DDW 2016.