Medical Advisors - Dr. Michael Krienes

What’ New in IBD?

Inflammatory Bowel Disease (IBD) represents a group of inflammatory disorders, primarily Ulcerative Colitis (UC) and Crohn’s Disease. There is a tremendous amount of ongoing research to determine the cause of, find better therapy for, and to improve the lives of patients and families with IBD. Not intended as a general review, this article will highlight certain aspects of current thinking about IBD.

What’s New in Thinking about What Causes IBD?

There appears not to be one individual cause of IBD, rather it develops as a complex interaction between Genetics, Environment, and Immune regulatory defects.

Genetics Clues: 20% with IBD have a family member who also has IBD. The risk to offspring of a person with IBD is 2-6%. Inheritance may relate to recently discovered IBD genes such as a mutation on the NOD/CARD15 gene on chromosome 16 that is present in 25% with Crohn’s. This and other genes are the subject of current investigations which also correlate individual genes with specific patterns and location of gut inflammation. The potential of gene therapy is speculative and likely not going to be available for many years.

Environmental clues: Smoking has an influence. 75% with Crohn’s smoke (compare with 25-30% of the general adult population). In smokers with Crohn’s, the disease is harder to treat. UC can first develop and can then worsen after smoking cessation. These opposite effects between Crohn’s and UC are intriguing and should not be used to justify smoking in UC but should emphasize encouraging all patients not to smoke. Appendectomy reduces the risk of developing UC. This may imply some currently unknown immune function of the appendix. Bacteria: IBD develops in area of high bacterial concentration in the gut. IBD does not occur in mouse research animals that have no bacteria in their bodies. Remember, we all have a trillion bacteria of many different types in our GI tract. Treatment with antibiotics and probiotics do help some IBD patients presumably by changing the balance of “good vs bad” bacteria and thus their ability to affect the gut immune system. Immune System. Many complicated immune defects have been identified in the IBD gut. One prominent theme is the presence of overly active lymphocytes that do not die off and can overcome normal control mechanisms and continue to inflame the GI tract without regulation.

What’s new in Bowel imaging?

Colonoscopy remains the principle diagnostic tool and allows assessment of disease location and severity, biopsies for dysplasia/cancer and to rule out other diagnoses such as infection and ischemia. Therapeutic balloon dilation of strictures of the colon or of an anastamosis may relieve symptoms but usually needs to be repeated periodically to maintain the lumen diameter.

Other technologies such as Endoscopic Ultrasound and MRI are increasingly being used especially to assess perianal complications. Wireless capsule endoscopy is probably the most accurate way to visualize the small bowel in Crohn’s. The capsule should be used with caution if there is concern for small bowel strictures where it could become lodged.

What’s New in IBD Treatment with 5-ASA (mesalamine)?

This class of drugs includes Sulfasalazine (Azulfadine), Asacol, Colazal, Pentasa, Rowasa enemas, and Canasa suppositories. There are some differences where in the gut these drugs are active, allowing us to select a drug that may tailor therapy to the site of disease. For example, Pentasa is released in both the small bowel and colon and can be used in Crohn’s when it involves these locations. We also have learned that there is a dose-response effect; higher doses yield better response. Pushing to higher doses can be effective and avoid the need for other meds. Combining an oral 5-ASA with a rectally administered preparation adds significant benefit. This class of drugs has an excellent safety and side effect profile and are used for active disease and maintenance of remission. To help make life a little easier (and improve compliance), one can consider the different amounts of 5-ASA per pill in an effort to minimize the number of pills per day. 6 Asacol = 9 Colazal = 5 Pentasa = 12 Azulfadine, by approximate 5-ASA content per pill. A new once-a-day Multimatrix System Mesalamine is also currently being researched.

What’s New in Steroids?

We are now very cognizant of side effects. Virtually 100% of patients experience side effects with prednisone that can include moon face, acne, serum glucose elevation, fluid retention, hypertension, depression, anxiety, osteoporosis, and cataracts. There is no maintenance role of steroids. Side effects should limit use of steroids and direct us to use other therapies. Budesonide (Entocort) is a newer steroid 90% of which is metabolized in the liver after it is absorbed, allowing only about 10% of the drug into the body, significantly limiting side effects. It is useful mainly in ileal Crohn’s disease.

What’s New in Immune-modulators?

6-MP (6- mercaptopurine) and Azathioprine (Imuran, Azasan) are the main immune-modulators used in IBD. They have a long track record of safety and efficacy and are able to achieve therapeutic goals such as reduce/eliminate steroids, control fistula, and maintain remission in 70% of patients. These drugs are not for acute therapy, they take an average of three months to “kick in” and are thus used to control the disease long term. We can now monitor blood levels to “fine tune” therapy and can test for genes that determine a patient’s ability to metabolize the drugs.

What’s New in Remicade?

Remicade, an antibody against Tumor Necrosis Factor (TNF) is the first “biological therapy” available to treat IBD. Biological preparations are blood products, vaccines containing live or killed microorganisms, recombinant peptides/proteins, and cell and gene therapies. Remicade has had a very significant influence on IBD treatment. It can help patients avoid steroids, can reduce or eliminate steroids if already on them, induces remission, maintain remission, and can close fistula. It is used with immune-modulators to reduce side effects. It is an IV infusion that is given as a series of three “induction” infusions then administered q2months as maintenance treatment. We now know that if a patient has been off Remicade therapy for a while, there is a higher risk of reactions if re-administered. The newest aspect of Remicade is its recent FDA approval for use in Ulcerative Colitis. UC patients with moderate or severely active disease who were on or not able to tolerate standard therapies did improve significantly with Remicade.

What’s New in Bacterial/Antibacterial Therapy?

Rifaximin (Xifaxan) is an oral non-absorbed antibiotic with activity against many gut organisms and pathogens. It is useful for traveler’s diarrhea and antibiotic-associated diarrhea. Several small studies show benefit in IBD.

Probiotics are “beneficial” live bacteria that are given to change the balance and type of flora in the gut. Studies in IBD have shown benefit in treating active disease and in maintenance of remission. There have been no significant side effects reported, so far.

What’s New in Investigational Therapies?

Anti-TNF: Remicade, an anti-TNF, has been very effective. It is an antibody composed of human and mouse fragments. Some of the side effects are thought to be due to the body reacting to mouse components. Newer anti-TNF’s are of only human origin. Adalimumab (Humira), given subQ every other week has been studied in Crohn’s Disease. 43% achieve and maintain remission and 69% show significant improvement after one year. If a patient previously experienced no response to Remicade, Adalimumab also did not work. It can be used successfully in patients with a history of reactions to Remicade.

There are many investigational studies in progress at this time. A few of the other Biological Therapies that have published data showing promise include: Certolizumab Pegol (Cimzia) a human Anti-Tumor Necrosis Factor drug. Sargramostim (GM-CSF) Granulocyte-Macrophage Colony Stimulating Factor that stimulates proliferation/activation of immune cells in the intestine.

Other current investigations in IBD

Apheresis. Blood is passed through a filter to remove selected types of lymphocytes that may cause inflammation. In one study, 73% of UC patients achieved remission after 16 days of treatment vs 38% on prednisone.

Stem cell transplant. The profound alteration of beginning a new immune system has lead to dramatic remission in some very ill patients with severe Crohn’s disease.

Worms as treatment for IBD? The “Hygiene Hypothesis” observes that failure of exposure to common infectious agents (parasites, viruses, bacteria) in the industrialized parts of the world alters the immune repertoire established in childhood. IBD is rare in developing countries where it is estimated 1 billion people harbor helminths (worms). Genetically susceptible people not exposed to worms may lack counteractive immune response. Pig whipworm (Trichuris suis) does not cause human illness. IBD patients were given 2,500 worm eggs every 2 weeks for 12 weeks. 56% with UC and 79% with Crohn’s responded to the treatment. It is hypothesized that the worms secrete Immuno-modulatory substances. This therapy may be difficult to ask our patients to swallow…..

Our Current IBD Research (Consultants for Clinical Research 513-872-4549)

Nitazoxanide (Alinia) - an antibiotic active against many gut pathogens
Adacolumn Apheresis System
CCX282-B chemokine antagonist against G-protein
OPC-6535 phosphodiesterase inhibitor
Anti-interleukin-12
Adalimumab (Humira) –anti-TNF
Celltech Anti-TNF-PEG
GM-CSF Sargramostin
Colazal Dose Escalation Study
Mesalamine pellet
DHEA

What’s New in IBD Legislation?

“The Inflammatory Bowel Disease Act”

Proposes to expand research at the National Institute of Diabetes and Digestive and Kidney Diseases with emphasis on genetic research, establish an IBD prevention and epidemiology program, and study insurance coverage. Please do write your Senators and Congressmen to voice your support! Also, keep the CCFA in mind for your patients. Its mission is to fund research, offer support groups, and provide education. We have an excellent local chapter that can be reached at 513-772-3550.

Michael D. Kreines
M.D., FACP, FACG Chief, Section of Gastroenterology The Christ Hospital, Cincinnati, Ohio