ADVANCES IN IBD
`
`C u r r e n t D e v e l o p m e n t s i n t h e Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e s
`
`Section Editor: Stephen B. Hanauer, MD
`
`Step-Up Versus Top-Down
`Therapy in the Treatment of
`Ulcerative Colitis
`
`William J. Sandborn, MD
`Professor of Medicine
`Mayo Clinic School of Medicine
`IBD Interest Group
`Division of Gastroenterology & Hepatology
`Mayo Clinic, Rochester
`
`G&H Can you describe the typical step-up
`treatment algorithm for ulcerative colitis as it
`differs from Crohn’s disease?
`
`WS The first line of therapy for ulcerative colitis (UC) is
`the safe and effective 5-aminosalicylate (5-ASA) class of
`drugs. These include sulfasalazine, delayed-release mesa-
`lamine (Asacol, Procter & Gamble), controlled-release
`mesalamine (Pentasa, Shire), olsalazine (Dipentum,
`Pfizer) and balsalazide (Colazal, Salix), as well as the
`forthcoming multimatrix formulation. These drugs are
`clearly effective for the induction and maintenance of
`clinical remission in patients with mild-to-moderate UC.
`This is in contrast to Crohn’s disease, where the efficacy of
`mesalamine is not clear. Antibiotic therapies, which are
`used in Crohn’s (although of questionable efficacy) are not
`effective in UC.
`Thus, in patients with UC, there is a clear first-line
`therapy that satisfactorily treats a substantial fraction of
`patients, both inducing and maintaining remission. In
`contrast, in Crohn’s disease, there is no safe and effective
`first line for inducing and maintaining remission. Further,
`it has been documented that over a disease course of 20
`years, 80% of patients with Crohn’s disease will require
`at least 1 surgical resection. In the modern era, in com-
`parable patients with UC, rates of surgery are not more
`than 15–20% and thus the prognosis for avoiding surgical
`resection is very different.
`
`G&H Are there specific subgroups among
`UC patients who may have a different prognosis
`and might benefit from a top-down approach
`to therapy?
`
`WS Among UC patients, approximately 30–40% have
`pancolonic UC or total colonic involvement and a sub-
`stantial proportion (40–50%) of those pancolitis patients
`will require colectomy. Many of these colectomies will
`occur within the first 5 years of disease. Further, among
`UC patients in general, approximately 40–50% will
`require treatment with steroids. Of the patients who
`require steroid treatment, within the first year, one third
`of them will require colectomy.
`Patients with pancolitis, those who require cortico-
`steroids and those who are hospitalized for UC, all have
`prognostic indicators for a more severe and refractory
`course of disease. Hypothetically, these are the patients
`who may benefit from top-down therapy, but no studies
`have yet evaluated such a treatment strategy.
`
`G&H Could you describe the studies that have
`led to the recent approval of biologic therapy for
`induction and maintenance of UC remission?
`
`WS The studies that led to the approval of infliximab
`(Remicade, Centocor) in UC are very robust. One could
`argue that they are even more robust than the trials that
`led to the initial approval of infliximab in Crohn’s dis-
`ease. In the UC trials, the investigators selected patients
`with moderate-to-severe disease. In the ACT I study, the
`patients were required to be failing steroids and/or immu-
`nosuppressives. In the ACT II trial, patients had to be
`failing steroids, immunosuppressives, or 5-ASA therapy
`for inclusion. However, most of the patients in ACT II
`were failing steroids or immunosuppressives. At enroll-
`ment, patients received induction treatment with 3 doses
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`of infliximab or placebo over 6 weeks and then continued
`with every-8-week maintenance therapy.
`In the original Crohn’s disease trials, induction and
`maintenance were separated. Patients were treated in
`short-term induction trials first. Later trials employed
`open-label induction, followed by long-term mainte-
`nance only in patients who showed an initial response. In
`contrast, in the UC trials, patients were treated continu-
`ously for 6–12 months with no selection for responders in
`the maintenance phase. Despite this incrementally much
`tougher trial design, the overall efficacy results were simi-
`lar in the UC trials and the Crohn’s disease trials.
`
`G&H Given the demonstrated efficacy of
`infliximab therapy in UC, can any of the
`chemopreventive properties recently ascribed
`to 5-ASA drugs be extended to biologics?
`
`WS We know that there are some remote structural sim-
`ilarities between 5-ASA and aspirin, which may denote
`a directly chemopreventive chemical attribute inherent
`to 5-ASA compounds. There is also the possibility that
`5-ASA therapy simply leads to better disease control and
`resultant reduced inflammation, which is chemopreven-
`tive in and of itself.
`With regard to the immunomodulators azathioprine
`and 6-mercaptopurine (6-MP), Dr. Thomas Ullman from
`the Mt. Sinai School of Medicine recently published data
`suggesting that those drugs are not chemopreventive
`against colorectal cancer in patients with ulcerative coli-
`tis. Conversely, those agents have actually been associated
`with an elevated risk of lymphoma in this patient popula-
`tion. However, they are effective for inducing remission
`and treating inflammation. Whether the potential che-
`mopreventive effect of reduced inflammation is cancelled
`out by a slightly raised risk of cancer, or the lack of an
`inherent chemical chemopreventive effect is responsible
`for Dr. Ullman’s data, we cannot yet be sure.
`Regardless, there is a discordance between 5-ASAs
`and the immunomodulators azathioprine and 6-MP in
`terms of the ability to induce chemoprevention of colorec-
`tal cancer. I think this tells us that each agent will need to
`be examined individually and that applies to infliximab
`as well. Theoretically, it is possible that treatment of the
`disease and inhibition of tumor necrosis factor (TNF) will
`be chemopreventive, but study is required to show that.
`
`G&H Is there any currently ongoing research
`regarding the top-down use of biologic therapies
`for UC?
`
`WS Currently, infliximab is approved for induction and
`maintenance of UC remission. There are several other
`biologic agents directed against TNF and α4 integrin that
`will soon be available for Crohn’s disease, including adali-
`mumab (Humira, Abbott), certolizumab pegol (Cimzia,
`UCB), and, potentially, natalizumab (Tysabri, Elan). At
`least two, and perhaps all three of these agents, will ulti-
`mately go into clinical trials for UC. As more agents come
`into play and top-down trials are staged on a larger scale
`with biologic agents in Crohn’s disease, there will be an
`attempt to do the same kind of research in UC. If I had
`to guess, I would think that those studies would appear
`within the next 3–5 years.
`
`G&H Is there any current research of
`chemoprevention with biologic therapies?
`
`WS Our current understanding of the chemopreventive
`properties of 5-ASAs are based on observational study
`instead of randomized trials. It is almost impossible to
`conduct a chemoprevention trial with an agent that also
`serves as a primary therapy. These drugs need to be intro-
`duced into practice, and in diseases such as UC, where
`associated cancer and dysplasia occur more slowly, the
`drugs need to be used in clinical practice for 5–10 years,
`so that a retrospective analysis of dysplasia rates can be
`performed. Because infliximab was formally adopted for
`UC only 18 months ago, we are most likely at least 5 years
`out from making those sorts of assessments with biologic
`therapy.
`
`Suggested Reading
`
`Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and mainte-
`nance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462-2476.
`Matula S, Croog V, Itzkowitz S, et al. Chemoprevention of colorectal neoplasia
`in ulcerative colitis: the effect of 6-mercaptopurine. Clin Gastroenterol Hepatol.
`2005;3:1015-1021.
`Sandborn WJ. What's new: innovative concepts in inflammatory bowel disease.
`Colorectal Dis. 2006;8:3-9.
`Sandborn WJ. Treatment of ulcerative colitis with oral mesalamine: advances in
`drug formulation, efficacy expectations and dose response, compliance, and che-
`moprevention. Rev Gastroenterol Disord. 2006;6:97-105.
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`Gastroenterology & Hepatology Volume 3, Issue 1 January 2007
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