Have we reached the top for therapy for IBD?

Medical therapy for the treatment of patients with inflammatory bowel disease has clearly improved the lives of patients and improved outcomes, but does not benefit all patients. Since the initial introduction of corticosteroids and mesalamine derivatives in the 1950s, medical therapy for IBD has improved significantly.

With the widespread use of antimetabolite therapy and the introduction of biologics in 1998 – infliximab, adalimumab, golimumab, certolizumab pegol, natalizumab, and finally vedolizumab – we can induce remission in steroid-dependent and steroid-refractory patients and decrease rates of surgery as well.

The goals of medical therapy have also evolved as the potency of the agents to treat patients with IBD has improved. Initially, symptom control was the desired goal of medical therapy, but soon it was recognized that this was inadequate and mucosal healing became the desired target. Now we recognize that mucosal healing is important while achieving other important endpoints – reduced hospitalization, reduction in surgery, reduced social and occupational burden, and finally doing so with improved safety and tolerability of medications.

Historically, we have used a step-up approach starting with the least effective agents and "stepping up" to more potent therapies. In this model, therapy is stepped up according to severity at presentation or failure at the prior step. We now have the ability to "profile" certain patients and treat those who will have aggressive disease with early aggressive therapy. In Crohn’s disease in particular, we are able to predict which patients will have a more virulent disease course.

Highlights of specific examples from clinical trials of current medical therapies make it very clear that there is a large unmet need for medical treatment of patients with IBD. The data presented focus on well recognized clinical studies from trials in patients with ulcerative colitis; several of these trials led to Food and Drug Administration approval.

A recent study evaluated the addition of oral mesalamine to topical mesalamine in patients with extensive ulcerative colitis, which achieved remission in 44% of patients; leaving 56% of patients with active disease.

Similarly, there were two studies evaluating patients with ulcerative colitis who received budesonide MMX (CORE I and II studies). In these studies, the rates of remission with steroid withdrawal were 17.4% and 17.9%; thus, over 80% of patients did not achieve remission.

In a recent meta-analysis the mean efficacy for azathioprine in ulcerative colitis patients was 60%. In a study using dual therapy of infliximab and azathioprine (SUCCESS trial) monotherapy with azathioprine was able to achieve remission in 24% of patients, infliximab in 22% and combination therapy in only 40% of patients; thus leaving 60% of patients not in remission.

In patients with Crohn’s disease we have similar limitations with current medical therapy. Although azathioprine has been widely used – it has recently been demonstrated to be inadequate as monotherapy for treatment of early Crohn’s disease. The rates of remission are inadequate in patients receiving infliximab (ACCENT I trial) and adalimumab (CHARM Trial) with approximately one-quarter to one-third of patients at most achieving remission. In the SONIC trial, when combination therapy with infliximab and azathioprine was used, remission with steroid-free status was achieved in 57% of patients at week 26 compared with 30% and 45%, respectively, in the azathioprine and infliximab monotherapy treatment arms.

Early aggressive therapy has been demonstrated to achieve higher rates of mucosal healing. We now recognize that it is appropriate to treat early disease, but not in all patients.

We attempt to prognosticate and treat those patients who have a poor prognosis with early aggressive therapy – specifically those patients who have fistulas, early steroid users, smo-ers, those with severe endoscopic lesions, those younger than 40, and those with extensive disease. We attempt to use combination therapy (anti-TNFs and immunomodulators) when appropriate given the added benefits: specifically, higher drug levels, fewer acute side effects, fewer infusion reactions, fewer serious infections, and also better efficacy.

Our efforts to optimize the use of treatment agents involve monitoring for antidrug antibodies and if present, switching the patient to different agents; we also monitor drug levels and when low we can increase the frequency of administration or escalate the drug dose.

We recognize that patients who have higher therapeutic trough levels within the therapeutic window are more likely to achieve clinical remission.

Several factors influence anti-TNF pharmacokinetics, including the presence of antidrug antibodies, concomitant use of immunosuppressives, low serum albumin, high baseline CRP concentration, large body size, and male gender.

Medical therapy has lessened the need for patients to undergo bowel surgery.

A recent Danish population cohort study evaluated 48,967 patients with IBD (CD, 13,185 and UC, 35,782) during 1979-2011. The 5-year cumulative probability of the first major surgery decreased from 44.7% in the early cohort (1979-1986) to 19.6% in the later cohort (2003-2011; P less than .001) for Crohn’s disease, and from 11.7% in early cohort to 7.5% in later cohort (P less than .001) for ulcerative colitis.

There are numerous drugs in development with different mechanisms of action for patients with both ulcerative colitis and Crohn’s disease. Too many IBD patients still face surgery, although there has been improvement. We are learning how to better use the medications we have and optimize therapy.

Dr. Lichtenstein is professor of medicine, department of medicine, division of gastroenterology, at the University of Pennsylvania, Philadelphia, and director of the IBD program at the university. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.

Medical therapy for the treatment of patients with inflammatory bowel disease has clearly improved the lives of patients and improved outcomes, but does not benefit all patients. Since the initial introduction of corticosteroids and mesalamine derivatives in the 1950s, medical therapy for IBD has improved significantly.

With the widespread use of antimetabolite therapy and the introduction of biologics in 1998 – infliximab, adalimumab, golimumab, certolizumab pegol, natalizumab, and finally vedolizumab – we can induce remission in steroid-dependent and steroid-refractory patients and decrease rates of surgery as well.

The goals of medical therapy have also evolved as the potency of the agents to treat patients with IBD has improved. Initially, symptom control was the desired goal of medical therapy, but soon it was recognized that this was inadequate and mucosal healing became the desired target. Now we recognize that mucosal healing is important while achieving other important endpoints – reduced hospitalization, reduction in surgery, reduced social and occupational burden, and finally doing so with improved safety and tolerability of medications.

Historically, we have used a step-up approach starting with the least effective agents and "stepping up" to more potent therapies. In this model, therapy is stepped up according to severity at presentation or failure at the prior step. We now have the ability to "profile" certain patients and treat those who will have aggressive disease with early aggressive therapy. In Crohn’s disease in particular, we are able to predict which patients will have a more virulent disease course.

Highlights of specific examples from clinical trials of current medical therapies make it very clear that there is a large unmet need for medical treatment of patients with IBD. The data presented focus on well recognized clinical studies from trials in patients with ulcerative colitis; several of these trials led to Food and Drug Administration approval.

A recent study evaluated the addition of oral mesalamine to topical mesalamine in patients with extensive ulcerative colitis, which achieved remission in 44% of patients; leaving 56% of patients with active disease.

Similarly, there were two studies evaluating patients with ulcerative colitis who received budesonide MMX (CORE I and II studies). In these studies, the rates of remission with steroid withdrawal were 17.4% and 17.9%; thus, over 80% of patients did not achieve remission.

In a recent meta-analysis the mean efficacy for azathioprine in ulcerative colitis patients was 60%. In a study using dual therapy of infliximab and azathioprine (SUCCESS trial) monotherapy with azathioprine was able to achieve remission in 24% of patients, infliximab in 22% and combination therapy in only 40% of patients; thus leaving 60% of patients not in remission.

In patients with Crohn’s disease we have similar limitations with current medical therapy. Although azathioprine has been widely used – it has recently been demonstrated to be inadequate as monotherapy for treatment of early Crohn’s disease. The rates of remission are inadequate in patients receiving infliximab (ACCENT I trial) and adalimumab (CHARM Trial) with approximately one-quarter to one-third of patients at most achieving remission. In the SONIC trial, when combination therapy with infliximab and azathioprine was used, remission with steroid-free status was achieved in 57% of patients at week 26 compared with 30% and 45%, respectively, in the azathioprine and infliximab monotherapy treatment arms.

Early aggressive therapy has been demonstrated to achieve higher rates of mucosal healing. We now recognize that it is appropriate to treat early disease, but not in all patients.

We attempt to prognosticate and treat those patients who have a poor prognosis with early aggressive therapy – specifically those patients who have fistulas, early steroid users, smo-ers, those with severe endoscopic lesions, those younger than 40, and those with extensive disease. We attempt to use combination therapy (anti-TNFs and immunomodulators) when appropriate given the added benefits: specifically, higher drug levels, fewer acute side effects, fewer infusion reactions, fewer serious infections, and also better efficacy.

Our efforts to optimize the use of treatment agents involve monitoring for antidrug antibodies and if present, switching the patient to different agents; we also monitor drug levels and when low we can increase the frequency of administration or escalate the drug dose.

We recognize that patients who have higher therapeutic trough levels within the therapeutic window are more likely to achieve clinical remission.

Several factors influence anti-TNF pharmacokinetics, including the presence of antidrug antibodies, concomitant use of immunosuppressives, low serum albumin, high baseline CRP concentration, large body size, and male gender.

Medical therapy has lessened the need for patients to undergo bowel surgery.

A recent Danish population cohort study evaluated 48,967 patients with IBD (CD, 13,185 and UC, 35,782) during 1979-2011. The 5-year cumulative probability of the first major surgery decreased from 44.7% in the early cohort (1979-1986) to 19.6% in the later cohort (2003-2011; P less than .001) for Crohn’s disease, and from 11.7% in early cohort to 7.5% in later cohort (P less than .001) for ulcerative colitis.

There are numerous drugs in development with different mechanisms of action for patients with both ulcerative colitis and Crohn’s disease. Too many IBD patients still face surgery, although there has been improvement. We are learning how to better use the medications we have and optimize therapy.

Dr. Lichtenstein is professor of medicine, department of medicine, division of gastroenterology, at the University of Pennsylvania, Philadelphia, and director of the IBD program at the university. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.

Medical therapy for the treatment of patients with inflammatory bowel disease has clearly improved the lives of patients and improved outcomes, but does not benefit all patients. Since the initial introduction of corticosteroids and mesalamine derivatives in the 1950s, medical therapy for IBD has improved significantly.

With the widespread use of antimetabolite therapy and the introduction of biologics in 1998 – infliximab, adalimumab, golimumab, certolizumab pegol, natalizumab, and finally vedolizumab – we can induce remission in steroid-dependent and steroid-refractory patients and decrease rates of surgery as well.

The goals of medical therapy have also evolved as the potency of the agents to treat patients with IBD has improved. Initially, symptom control was the desired goal of medical therapy, but soon it was recognized that this was inadequate and mucosal healing became the desired target. Now we recognize that mucosal healing is important while achieving other important endpoints – reduced hospitalization, reduction in surgery, reduced social and occupational burden, and finally doing so with improved safety and tolerability of medications.

Historically, we have used a step-up approach starting with the least effective agents and "stepping up" to more potent therapies. In this model, therapy is stepped up according to severity at presentation or failure at the prior step. We now have the ability to "profile" certain patients and treat those who will have aggressive disease with early aggressive therapy. In Crohn’s disease in particular, we are able to predict which patients will have a more virulent disease course.

Highlights of specific examples from clinical trials of current medical therapies make it very clear that there is a large unmet need for medical treatment of patients with IBD. The data presented focus on well recognized clinical studies from trials in patients with ulcerative colitis; several of these trials led to Food and Drug Administration approval.

A recent study evaluated the addition of oral mesalamine to topical mesalamine in patients with extensive ulcerative colitis, which achieved remission in 44% of patients; leaving 56% of patients with active disease.

Similarly, there were two studies evaluating patients with ulcerative colitis who received budesonide MMX (CORE I and II studies). In these studies, the rates of remission with steroid withdrawal were 17.4% and 17.9%; thus, over 80% of patients did not achieve remission.

In a recent meta-analysis the mean efficacy for azathioprine in ulcerative colitis patients was 60%. In a study using dual therapy of infliximab and azathioprine (SUCCESS trial) monotherapy with azathioprine was able to achieve remission in 24% of patients, infliximab in 22% and combination therapy in only 40% of patients; thus leaving 60% of patients not in remission.

In patients with Crohn’s disease we have similar limitations with current medical therapy. Although azathioprine has been widely used – it has recently been demonstrated to be inadequate as monotherapy for treatment of early Crohn’s disease. The rates of remission are inadequate in patients receiving infliximab (ACCENT I trial) and adalimumab (CHARM Trial) with approximately one-quarter to one-third of patients at most achieving remission. In the SONIC trial, when combination therapy with infliximab and azathioprine was used, remission with steroid-free status was achieved in 57% of patients at week 26 compared with 30% and 45%, respectively, in the azathioprine and infliximab monotherapy treatment arms.

Early aggressive therapy has been demonstrated to achieve higher rates of mucosal healing. We now recognize that it is appropriate to treat early disease, but not in all patients.

We attempt to prognosticate and treat those patients who have a poor prognosis with early aggressive therapy – specifically those patients who have fistulas, early steroid users, smo-ers, those with severe endoscopic lesions, those younger than 40, and those with extensive disease. We attempt to use combination therapy (anti-TNFs and immunomodulators) when appropriate given the added benefits: specifically, higher drug levels, fewer acute side effects, fewer infusion reactions, fewer serious infections, and also better efficacy.

Our efforts to optimize the use of treatment agents involve monitoring for antidrug antibodies and if present, switching the patient to different agents; we also monitor drug levels and when low we can increase the frequency of administration or escalate the drug dose.

We recognize that patients who have higher therapeutic trough levels within the therapeutic window are more likely to achieve clinical remission.

Several factors influence anti-TNF pharmacokinetics, including the presence of antidrug antibodies, concomitant use of immunosuppressives, low serum albumin, high baseline CRP concentration, large body size, and male gender.

Medical therapy has lessened the need for patients to undergo bowel surgery.

A recent Danish population cohort study evaluated 48,967 patients with IBD (CD, 13,185 and UC, 35,782) during 1979-2011. The 5-year cumulative probability of the first major surgery decreased from 44.7% in the early cohort (1979-1986) to 19.6% in the later cohort (2003-2011; P less than .001) for Crohn’s disease, and from 11.7% in early cohort to 7.5% in later cohort (P less than .001) for ulcerative colitis.

There are numerous drugs in development with different mechanisms of action for patients with both ulcerative colitis and Crohn’s disease. Too many IBD patients still face surgery, although there has been improvement. We are learning how to better use the medications we have and optimize therapy.

Dr. Lichtenstein is professor of medicine, department of medicine, division of gastroenterology, at the University of Pennsylvania, Philadelphia, and director of the IBD program at the university. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.