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1 Novel Treatment of Inflammatory Bowel Disease Informed by Science and Patient Choice Unanswered Questions March 11, 2015 Russell D. Cohen, MD, FACG, AGAF Medical marijuana in IBD 1. Unfortunately, with the federal Controlled Substances Act as to Cannabis Sativa, there will be great difficulty in conducting controlled double blind, placebo controlled studies. The efficacy will likely remain anecdota.. 2. I m a Neurologist. My involvement with chronic inflammatory bowel disease patients occurs via their participation in a state-authorized medicinal cannabis program. IBD is one of the very few chronic, severe conditions authorized for this palliative program. MMP is efficacious for palliative, symptomatic therapy in several chronic, neuroinflammatory conditions, including MS, CIDP, and others. The IBD patients report significant palliative effect And the biological umabs you refer to seem to parallel several of the same class agents now available for treating MS, especially the lymphocytic sequestration agents (Dimethyl fumarate, etc.). Reply to both: Controlled clinical trials with cannabis or related substances have not been possible in the past due to federal regulations on the agent. Recent studies presented at medical meetings and published in abstract form have suggested that patients symptoms may improve, but most have failed to date to show objective evidence of disease modification. It is not known what ingredients are necessary, or what mode of delivery, and it very well may vary with individual patients. Storr M, Devlin S, Kaplan GG, Panaccione R, Andrews CN. Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn's disease. Inflammatory bowel diseases Mar;20(3): Naftali T, Bar-Lev Schleider L, Dotan I, et al. Cannabis induces a clinical response in patients with Crohn's disease: a prospective placebocontrolled study. Clin Gastroenterol Hepatol Oct;11(10): e1.

2 Switching medications 1. Young adult male stable on Humira for several years but wants to switch to more convenient medication doesn t like need for refrigeration travels a lot during the summer, doing a semester abroad in the fall would you offer switch and if so, what would you switch to and how? Reply: It is not suggested that you switch patients from one biological drug to the other for convenience. This was the focus of a clinical trial where many patients who were well flared when the switched drugs. Restarting the previously successful drug may not be successful, as the drug free hiatus will make the patient more likely to develop anti-drug antibodies when restarted. Hoentjen F, Haarhuis BJ, Drenth JP, et al. Elective switching from infliximab to adalimumab in stable Crohn's disease. Inflammatory bowel diseases Mar-Apr;19(4): Please note that there was a recent label change for adalimumab that allows it to be kept at room temperature for up to two weeks. Please read the manufacturer s instructions carefully before proceeding. (accessed 4/23/15) y/o with UC, on humira 2 years, lialda, flare, colonoscopy shows pancolitis. Labs just back antibodies and low drug levels after dose. Pt. s son has Crohn s (19 y/o). Good response for a year to remicade, then flare, anaphylactic Rx. Now on humira - almost 4 years -doing well with humira qoweek and delzicol. 53 y/o has not been on any other treatment with the exception of steroids (currently budesonide). Thoughts for next treatment? Reply patients who form neutralizing antibodies (ie. blood tests positive for antibodies, with little or no drug present) to one biological agent often can be switched to a different biological agent with success. However, they are more prone to develop anti-drug antibodies, so combination therapy of the biological agent with a thiopurine (ie. azathioprine, 6- mercaptopurine) or azathioprine is strongly recommended. In some patients, these traditional therapies may be successful alone, when appropriately dosed.

3 Frederiksen MT, Ainsworth MA, Brynskov J, Thomsen OO, Bendtzen K, Steenholdt C. Antibodies against infliximab are associated with de novo development of antibodies to adalimumab and therapeutic failure in infliximabto-adalimumab switchers with IBD. Inflammatory bowel diseases Oct;20(10): van Schaik T, Maljaars JP, Roopram RK, Verwey MH, Ipenburg N, Hardwick JC, et al. Influence of combination therapy with immune modulators on anti-tnf trough levels and antibodies in patients with IBD. Inflammatory bowel diseases Dec;20(12): Currently, the other FDA-approved biological therapies for ulcerative colitis (other than infliximab and adalimumab) are golimumab and vedolizumab. Gut Microbiome 1. What's the entire hullabaloo about 'fecal transplants" restoring the gut micro biome, and consequently reversing IBD conditions? That's not an assertion, just a question. Reply Hot on the tails of surprisingly good success rates of eradicating relapsing Clostridium difficile in medical patients using a fecal transplant, there has been much speculation that it may be also a potential therapy for Crohn s disease and ulcerative colitis. Studies have shown that there are different types of predominant bacterial strains in many patients with Crohn s and ulcerative colitis, and these or similar strains have been linked to colitis (or more severe colitis ) in mouse models of colitis. So far, the data for fecal transplants have been very disappointing for Crohn s disease (and may make some patients worse), and have been mixed for ulcerative colitis (with the most recent studies negative). Please be aware, that unlike treatment for Clostridium difficile, the use of fecal transplants for other diseases requires the health care provider to obtain FDA approval (an IND). It is not known what other negative factors may be transmitted with the donor stool. Colman RJ, Rubin DT. Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis. Journal of Crohn's & colitis Dec 1;8(12): Rossen NG, Fuentes S, van der Spek MJ, Tijssen J, Hartman JH, Duflou A, et al. Findings from a Randomized Controlled Trial of Fecal

4 Transplantation for Patients with Ulcerative Colitis. Gastroenterology Mar 30. Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, Onischi C, et al. Fecal Microbiota Transplantation Induces Remission in Patients with Active Ulcerative Colitis in a Randomized, Controlled Trial. Gastroenterology Apr 6. Treatment Options Top-Down Treatment 1. I worry that if we adopt this top down treatment theory we will run out of options too early REPLY: smart use of our available therapies should allow you to provide your patients with the best chance of corticosteroid-free response or remission, while sparing them the morbidity that accompanies under-treatment of disease or prolonged steroid-exposure. We current have multiple biological agents for IBD, three immunosuppressants, and likely more therapies in the upcoming years. D'Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet Feb 23;371(9613): Adolescents I see a fair number of adolescents with IBD. Does age impact your treatment algorithm? REPLY: None of us on the panel are pediatric gastroenterologists; I would recommend that you address treatment of children with one of the many fine colleagues who provide excellent care. The older adolescents are often seen in adult GI practices; the care paradigms are the same for these older teens. In fact, many studies suggest that the sooner you start effective therapy with immunomodulators and/or biologics, the more likely the patient is to respond to therapy. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-tosevere Crohn's disease in children. Gastroenterology Mar;132(3):863-73

5 Miyoshi J, Hisamatsu T, Matsuoka K, et al. Early intervention with adalimumab may contribute to favorable clinical efficacy in patients with Crohn's disease. Digestion. 2014;90(2): Mild-to-Moderate IBD What about the mild to moderate UC patient, do you start with Mesalamine and still get patients to remission despite that half will go on to have increased disease severity? REPLY: Mesalamine is effective in many patients with mild to moderate ulcerative colitis; if patients go into remission, they are far less likely to relapse if they remain on their mesalamine therapy (ie. indefinitely). Patients who are not well on mesalamine, or who relapse while still on therapy, should be started on additional or alternate therapies. Kane S, Huo D, Aikens J, Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. The American journal of medicine Jan;114(1): o Race Factors What about the role of race in treatment selection? REPLY: To the best of our knowledge, none of the large studies have shown a convincing difference in treatment response or side-effects based on patient race. Be aware that the vast majority of patients in IBD clinical trials are Caucasian; however, studies in countries with a large proportion of non-caucasians have not yet revealed any red-flags. o Elderly Can anti-tnfs be used in elderly (70 y/o) patient with Parkinson s plus and ostomy? REPLY: Studies in patients older than age 60 have shown that the anti-tnf agents are safe and effective. However, be aware that older patients are more prone to infection with corticosteroids and potentially other therapies that affect the immune system. It is important to limit corticosteroid exposure in this population; more frequent safety monitoring may be advisable.

6 Shung DL, Abraham B, Sellin J, Hou JK. Medical and Surgical Complications of Inflammatory Bowel Disease in the Elderly: A Systematic Review. Digestive diseases and sciences Dec 12. Desai A, Zator ZA, de Silva P, Nguyen DD, Korzenik J, Yajnik V, et al. Older age is associated with higher rate of discontinuation of anti-tnf therapy in patients with inflammatory bowel disease. Inflammatory bowel diseases Feb;19(2): o Patients with MS 1. In that regard (the parallelity of use of agents) what is the penetration of use of rituxan and methotrexate in IBD, where those, as well as azathioprine, are used in treating Neuromyelitis Optica and Optic Neuritis, conditions which track and follow MS. 2. I have a female patient with MS and is symptomatic with standard therapy. Where would you go next? REPLY TO BOTH: It is currently advised that patients with multiple sclerosis (MS) not be treated with an anti- TNF agent, due to concerns of possible worsening. Natalizumab is an excellent choice for patients with MS who also have Crohn s disease, as it treats both. Vedolizumab does not have the warnings about MS that the anti-tnfs carry and likely can also be used for Crohn s disease or ulcerative colitis. The immunomodulators most commonly used in IBD patients are azathioprine, 6- mercaptopurine, and methotrexate. Rituximab has not been shown to be effective, to date, in the clinical trials that have been performed in IBD. Leiper K, Martin K, Ellis A, Subramanian S, Watson AJ, Christmas SE, et al. Randomised placebo-controlled trial of rituximab (anti- CD20) in active ulcerative colitis. Gut Nov;60(11): o Pregnancy 1. I have a patient I have treated for years and she is now pregnant. I am treating her with infliximab. Would you change her treatment? REPLY: many experts in IBD preach that the most important part of care of the pregnant patient is to keep their IBD inactive. As a result, in many instances, the IBD medications are not altered in patients who become pregnant. The exceptions are methotrexate and thalidomide, which are both not permitted in pregnancy. Referral for an opinion to an IBD specialist may be

7 desired to get further information regarding medication use during pregnancy, nursing, and preferred mode of delivery. Nielsen OH, Loftus EV, Jr., Jess T. Safety of TNF-alpha inhibitors during IBD pregnancy: a systematic review. BMC medicine. 2013;11:174. Schulze H, Esters P, Dignass A. Review article: the management of Crohn's disease and ulcerative colitis during pregnancy and lactation. Alimentary pharmacology & therapeutics Nov;40(9): o Efficacy of Rectal Foam 1. Are you using rectal foam in moderate patients? Any efficacy? REPLY rectally applied therapies (foams, enemas, suppositories) are often very helpful as a sole therapy in some patients with disease limited to the rectum, or as combination therapy in patients with more extensive or resistant disease. Some patients on biologics may still find a benefit with rectally applied therapies. Often these might be needed nightly at first, but then may be given twice a week to help maintain the response. Sandborn WJ, Bosworth B, Zakko S, et al. Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis. Gastroenterology Apr;148(4): Regueiro M, Loftus EV, Jr., Steinhart AH, Cohen RD. Clinical Guidelines for the Medical Management of Left-Sided Ulcerative Colitis and Ulcerative Proctitis: Summary Statement. Inflammatory bowel diseases Oct;12(10): o Risk of Cancer 1. Can you give me the data on risk of lymphoma in patients with our medicines thiopurines/biologics/azothioprine etc.? REPLY there are multiple studies accessing risk of lymphoma with our current therapies; it is a rare adverse event, and must be taken in perspective with the need to treat patients with effective therapies. There is some data that thiopurines may decrease colorectal cancer risk in IBD colitis; this is by far a more common cancer faced by IBD patients than lymphoma. Exposure to radiation is

8 also linked to lymphoma risk; switching from ionizing radiation to low or no radiation-based imaging (ie. MRI, ultrasound) should also be considered when assessing the lymphoma risk in your patients. Jess T, Lopez A, Andersson M, Beaugerie L, et al. Thiopurines and risk of colorectal neoplasia in patients with inflammatory bowel disease: a meta-analysis. Clin Gastroenterol Hepatol Nov;12(11): Lim YJ. Does radiation exposure from abdominal computed tomography increase cancer risk in patients with inflammatory bowel disease and Behcet disease? Gut and liver Jul;8(4): Can you comment on the role of healing mucosa and cancer risk? I have patients ask about this all time. What is the evidence? REPLY: There is a growing body of evidence that healing the mucosa leads to better outcomes in patients with IBD; some recent research suggests that this may extend to lower rates of colorectal cancer, although definitive studies have not been completed to date. Rubin DT, Huo D, Kinnucan JA, et al. Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: a case-control study. Clin Gastroenterol Hepatol 2013;11: Discontinuation of Therapy 1. Do you generally stop immunomodulators or biologics in patients when their achieve remission? How do you define remission? REPLY: The clinical trials of available agents have suggested that patients who achieve remission and are then placed on placebo relapse at a much higher rate than those who stay on effective therapy. As a general rule, we continue effective (nonsteroid) therapies in patients with IBD. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):

9 Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut Sep;56(9): Therapeutic Drug Monitoring 1. Therapeutic drug monitoring just makes treatment more costly. Comment? REPLY: There are published studies suggesting the opposite; ie. therapeutic monitoring has been shown to be cost-effective in this setting. Remember that in the case of biologics, due to the high drug cost of each dose, simply avoiding one unnecessary dose or dose escalation by analyzing the trough drug level (and antibodies) easily sets off the cost of the testing. Dubinsky MC, Reyes E, Ofman J, et al. A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. The American journal of gastroenterology Oct;100(10): Velayos FS, Kahn JG, Sandborn WJ, Feagan BG. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn's disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol Jun;11(6): Steenholdt C, Brynskov J, Thomsen OO, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-tnf treatment: a randomised, controlled trial. Gut Jun;63(6):