‘Game of Crohn’s ... and colitis’

 

Here is an update on the rapidly moving field of inflammatory bowel disease (IBD), from the power of the microbiome to the prediction of IBD and new ways to use established drugs.

We have had a high incidence and prevalence of IBD in the Western world, but since the 1990s, that rate has stabilized. Asian and Latin American countries, in the meantime, have witnessed a rapid rise in IBD. This observation offers opportunities to understand what changes in our environment or food supply may be contributing to this rise. It also has important economic implications since Asia, especially China, is highly populous; even small increases in the rates of affected patients represent huge increases in disease burden.

Regarding the microbiome, we now understand that, while the healthy microbiome is diverse and able to produce short-chain fatty acids, such as butyrate, the dysbiotic IBD microbiome is less diverse and characterized by expansion of proinflammatory pathobionts (such as Fusobacterium), the proliferation of sulfate-reducing bacteria, and a decrease in anti-inflammatory butyrate production.

There have now been several promising trials of fecal microbial transplant (FMT) for the treatment of ulcerative colitis (UC). The most effective strategies have involved colonic delivery of FMT, pooled donors, and repeated stool enemas to solidify the response. Following FMT, patients’ microbial diversity increases. The hope is that we can use diet as a complement to maintain the diversity and generation of beneficial metabolites, as well as deliver the therapy orally.
 

Predicting IBD

Although we have made advances in therapy, we continue to miss opportunities to prevent long-term complications. At Digestive Disease Week,^® Jean-Frederic Colombel, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, presented data on the PREDICTS study (Aliment Pharacol Ther. 2016 Jun;43[12]:1300-10), in which serum samples collected from military recruits prior to development of IBD was used to identify serologic markers that could predict those who ultimately developed Crohn’s disease but not UC.

The pediatric medical community, meanwhile, has studied an inception cohort of newly diagnosed, untreated children – the RISK cohort ( Lancet. 2017 Apr 29;389[10080]:1710-8 ) – to define some of the risk factors that predict more aggressive disease. By using biopsy tissue from the time of diagnosis, investigators could predict who would develop stricturing disease versus penetrating disease. Patients who would develop penetrating disease had up-regulation of inflammatory pathways and responded to anti–tumor necrosis factor therapy, while those who developed a stricturing phenotype had increased expression of extracellular matrix pathways and were significantly less likely to respond to anti-TNF therapy ( Lancet. 2017 Apr 29;389[10080]:1710-8 ). These studies provide a proof of concept that we might someday be able to use for personalized approaches to treating IBD.
 

 

Using new drugs, targeting new pathways

The recently published CALM study tested the hypothesis that treating to a target of no biochemical inflammation (elevated C reactive protein or fecal calprotectin) would be better than symptom-driven treatment alone. Treatment escalation for active disease included adalimumab every other week, then weekly adalimumab, and finally the addition of azathioprine. At the end of the study, patients whose medical therapy was based on both symptoms and biochemical inflammation had a higher degree of mucosal healing than did patients in the clinical management group (Lancet. 2018 Dec 23;390[10114]:2779-89).

Ustekinumab is a monoclonal antibody that targets the p40 subunit of interleukin-12 and interleukin-23 and is approved for Crohn’s disease. Various pharmaceutical companies are now developing anti-p19 antibodies, which block IL-23 only; at DDW 2018, the anti–IL-23 mirikizumab was shown to be effective in UC. We are also seeing the availability of oral medications for IBD. Just prior to DDW, tofacitinib ( N Engl J Med. 2017 May 4;376:1723-36 ), a Janus kinase (JAK) 1/3 inhibitor, which has an effect on multiple different cytokine pathways, received approval for UC. Other JAK inhibitors with different specificities are being tested in trials of UC and Crohn’s disease.
 

Dr. Abreu is a professor of medicine, a professor of microbiology and immunology, and the director of the Crohn’s & Colitis Center at the University of Miami Miller School of Medicine. She has no conflicts of interest. Dr. Abreu made her comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.

 

Here is an update on the rapidly moving field of inflammatory bowel disease (IBD), from the power of the microbiome to the prediction of IBD and new ways to use established drugs.

We have had a high incidence and prevalence of IBD in the Western world, but since the 1990s, that rate has stabilized. Asian and Latin American countries, in the meantime, have witnessed a rapid rise in IBD. This observation offers opportunities to understand what changes in our environment or food supply may be contributing to this rise. It also has important economic implications since Asia, especially China, is highly populous; even small increases in the rates of affected patients represent huge increases in disease burden.

Regarding the microbiome, we now understand that, while the healthy microbiome is diverse and able to produce short-chain fatty acids, such as butyrate, the dysbiotic IBD microbiome is less diverse and characterized by expansion of proinflammatory pathobionts (such as Fusobacterium), the proliferation of sulfate-reducing bacteria, and a decrease in anti-inflammatory butyrate production.

There have now been several promising trials of fecal microbial transplant (FMT) for the treatment of ulcerative colitis (UC). The most effective strategies have involved colonic delivery of FMT, pooled donors, and repeated stool enemas to solidify the response. Following FMT, patients’ microbial diversity increases. The hope is that we can use diet as a complement to maintain the diversity and generation of beneficial metabolites, as well as deliver the therapy orally.
 

Predicting IBD

Although we have made advances in therapy, we continue to miss opportunities to prevent long-term complications. At Digestive Disease Week,^® Jean-Frederic Colombel, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, presented data on the PREDICTS study (Aliment Pharacol Ther. 2016 Jun;43[12]:1300-10), in which serum samples collected from military recruits prior to development of IBD was used to identify serologic markers that could predict those who ultimately developed Crohn’s disease but not UC.

The pediatric medical community, meanwhile, has studied an inception cohort of newly diagnosed, untreated children – the RISK cohort ( Lancet. 2017 Apr 29;389[10080]:1710-8 ) – to define some of the risk factors that predict more aggressive disease. By using biopsy tissue from the time of diagnosis, investigators could predict who would develop stricturing disease versus penetrating disease. Patients who would develop penetrating disease had up-regulation of inflammatory pathways and responded to anti–tumor necrosis factor therapy, while those who developed a stricturing phenotype had increased expression of extracellular matrix pathways and were significantly less likely to respond to anti-TNF therapy ( Lancet. 2017 Apr 29;389[10080]:1710-8 ). These studies provide a proof of concept that we might someday be able to use for personalized approaches to treating IBD.
 

 

Using new drugs, targeting new pathways

The recently published CALM study tested the hypothesis that treating to a target of no biochemical inflammation (elevated C reactive protein or fecal calprotectin) would be better than symptom-driven treatment alone. Treatment escalation for active disease included adalimumab every other week, then weekly adalimumab, and finally the addition of azathioprine. At the end of the study, patients whose medical therapy was based on both symptoms and biochemical inflammation had a higher degree of mucosal healing than did patients in the clinical management group (Lancet. 2018 Dec 23;390[10114]:2779-89).

Ustekinumab is a monoclonal antibody that targets the p40 subunit of interleukin-12 and interleukin-23 and is approved for Crohn’s disease. Various pharmaceutical companies are now developing anti-p19 antibodies, which block IL-23 only; at DDW 2018, the anti–IL-23 mirikizumab was shown to be effective in UC. We are also seeing the availability of oral medications for IBD. Just prior to DDW, tofacitinib ( N Engl J Med. 2017 May 4;376:1723-36 ), a Janus kinase (JAK) 1/3 inhibitor, which has an effect on multiple different cytokine pathways, received approval for UC. Other JAK inhibitors with different specificities are being tested in trials of UC and Crohn’s disease.
 

Dr. Abreu is a professor of medicine, a professor of microbiology and immunology, and the director of the Crohn’s & Colitis Center at the University of Miami Miller School of Medicine. She has no conflicts of interest. Dr. Abreu made her comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.

 

Here is an update on the rapidly moving field of inflammatory bowel disease (IBD), from the power of the microbiome to the prediction of IBD and new ways to use established drugs.

We have had a high incidence and prevalence of IBD in the Western world, but since the 1990s, that rate has stabilized. Asian and Latin American countries, in the meantime, have witnessed a rapid rise in IBD. This observation offers opportunities to understand what changes in our environment or food supply may be contributing to this rise. It also has important economic implications since Asia, especially China, is highly populous; even small increases in the rates of affected patients represent huge increases in disease burden.

Regarding the microbiome, we now understand that, while the healthy microbiome is diverse and able to produce short-chain fatty acids, such as butyrate, the dysbiotic IBD microbiome is less diverse and characterized by expansion of proinflammatory pathobionts (such as Fusobacterium), the proliferation of sulfate-reducing bacteria, and a decrease in anti-inflammatory butyrate production.

There have now been several promising trials of fecal microbial transplant (FMT) for the treatment of ulcerative colitis (UC). The most effective strategies have involved colonic delivery of FMT, pooled donors, and repeated stool enemas to solidify the response. Following FMT, patients’ microbial diversity increases. The hope is that we can use diet as a complement to maintain the diversity and generation of beneficial metabolites, as well as deliver the therapy orally.
 

Predicting IBD

Although we have made advances in therapy, we continue to miss opportunities to prevent long-term complications. At Digestive Disease Week,^® Jean-Frederic Colombel, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, presented data on the PREDICTS study (Aliment Pharacol Ther. 2016 Jun;43[12]:1300-10), in which serum samples collected from military recruits prior to development of IBD was used to identify serologic markers that could predict those who ultimately developed Crohn’s disease but not UC.

The pediatric medical community, meanwhile, has studied an inception cohort of newly diagnosed, untreated children – the RISK cohort ( Lancet. 2017 Apr 29;389[10080]:1710-8 ) – to define some of the risk factors that predict more aggressive disease. By using biopsy tissue from the time of diagnosis, investigators could predict who would develop stricturing disease versus penetrating disease. Patients who would develop penetrating disease had up-regulation of inflammatory pathways and responded to anti–tumor necrosis factor therapy, while those who developed a stricturing phenotype had increased expression of extracellular matrix pathways and were significantly less likely to respond to anti-TNF therapy ( Lancet. 2017 Apr 29;389[10080]:1710-8 ). These studies provide a proof of concept that we might someday be able to use for personalized approaches to treating IBD.
 

 

Using new drugs, targeting new pathways

The recently published CALM study tested the hypothesis that treating to a target of no biochemical inflammation (elevated C reactive protein or fecal calprotectin) would be better than symptom-driven treatment alone. Treatment escalation for active disease included adalimumab every other week, then weekly adalimumab, and finally the addition of azathioprine. At the end of the study, patients whose medical therapy was based on both symptoms and biochemical inflammation had a higher degree of mucosal healing than did patients in the clinical management group (Lancet. 2018 Dec 23;390[10114]:2779-89).

Ustekinumab is a monoclonal antibody that targets the p40 subunit of interleukin-12 and interleukin-23 and is approved for Crohn’s disease. Various pharmaceutical companies are now developing anti-p19 antibodies, which block IL-23 only; at DDW 2018, the anti–IL-23 mirikizumab was shown to be effective in UC. We are also seeing the availability of oral medications for IBD. Just prior to DDW, tofacitinib ( N Engl J Med. 2017 May 4;376:1723-36 ), a Janus kinase (JAK) 1/3 inhibitor, which has an effect on multiple different cytokine pathways, received approval for UC. Other JAK inhibitors with different specificities are being tested in trials of UC and Crohn’s disease.
 

Dr. Abreu is a professor of medicine, a professor of microbiology and immunology, and the director of the Crohn’s & Colitis Center at the University of Miami Miller School of Medicine. She has no conflicts of interest. Dr. Abreu made her comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.