Research flourished in 2005, bringing with it new and exciting insight to the treatment of inflammatory bowel disease. EndoNurse takes a look at what’s hot, what’s new, and what may lie ahead in 2006.
Inflammatory bowel diseases (IBD) encompass Crohn’s disease (CD) and ulcerative colitis (UC) — maladies characterized by chronic intestinal inflammation.1 It is estimated that some 1.4 million Americans suffer from IBD, with approximately 30,000 new cases diagnosed each year.2
The cause of IBD is unknown, and there is no medical cure for these conditions, which can flare up without warning. Colectomy cures UC, but CD is incurable, with a relapse rate of 75 to 80 percent.2
According to a 1990 study, the medical costs of IBD in the United States totaled $1.4 to $1.8 billion annually.2 Surgery and inpatient care were estimated to account for roughly one-half of this amount. The disability costs of illness (lost labor productivity) were estimated to be $0.4 to $0.8 billion, making the total estimated annual cost of IBD $1.8 billion to $2.6 billion.
According to the Crohn’s and Colitis Foundation of America, CD and UC are unpredictable illnesses. Some patients recover after a single attack or are in remission for years. Others require frequent hospitalizations and surgery, and symptoms often vary in nature, frequency, and intensity. Without proper treatment, symptoms may worsen considerably and complications, such as abscesses, obstruction, malnutrition, and anemia, are frequent.2
Patients with IBD often do not receive optimal medical therapy.3 For example, patients with luminal IBD seeking a second opinion at Brigham and Women’s Hospital between January 2001 and April 2003 were evaluated to determine if the therapy they previously received was beneficial and in accordance with practice guidelines. The study population consisted of 67 patients — 21 with UC, 44 with CD, and two in whom the diagnosis of IBD could not be confirmed. Of the 65 patients with confirmed IBD, 56 patients had symptoms of active disease and nine were asymptomatic. Of the 33 patients treated with aminosalicylates, 64 percent were not receiving maximal doses. Three-quarters of the patients with distal UC were not receiving rectal aminosalicylate therapy. Within six months of their clinic visit, 35 patients had received corticosteroid therapy, and 27 (77 percent) patients had been treated with corticosteroids for greater than three months. In 16 of 27 (59 percent) there was no attempt to start steroid sparing medications such as 6-mercaptopurine (6MP), azathioprine, or infliximab. Of the 11 patients treated with either 6-MP or azathioprine, nine (82 percent) were sub-optimally dosed without an attempt to increase dosage. Of the 27 patients on prolonged corticosteroid therapy, 78 percent received inadequate treatment to prevent metabolic bone disease. Furthermore, 33 percent of patients meeting indications for surveillance colonoscopy for dysplasia had not undergone colonoscopy at the appropriate interval.
“We’re getting a better handle on UC and Crohn’s, because we have found better ways to modulate the immune system,” says Patricia Raymond, MD, FACP, FACG. “Technology has reached a point of having multiple different drugs to treat these conditions, such as Remicade, which was recently approved for UC use, and several more immunomodulators are coming down the track in the near future. So in terms of ‘high technology,’ we’re doing great. We’re also getting better at defining each disorder, and finding the antibodies. The antibodies can tell what types of Crohn’s are going to stricture, which types will ulcerate, which will fistulate, and which will simply demonstrate inflammation.
“People who fistulize don’t seem to stricture; people who just have inflammation don’t seem to have the other problems, so it’s looking more like a ‘family’ of related diseases,” she continues.
In terms of “lower-end” technology, biological pharmacology is emerging as a new wave of possible treatments. Recent releases from the American College of Gastroenterology’s annual conference demonstrated that one probiotic was shown to improve symptoms of UC; others have been shown to prevent pouchitis. One gastroenterologist at the University of Iowa, Joel Weinstock, MD, is using helminthic (worm) therapy to treat Crohn’s disease. Approximately three-quarters of patients in one study utilizing pig whipworms achieved remission.23
Raymond mentions that a physician associated with the University of Virginia is also trying worm therapy for his patients. “They may release a steroid-like substance, and they can also debride the dead tissue,” she explains. “This is a disease of a first-class society — you don’t find it in poor countries. We’re too clean; we’re not eating enough dirt as children anymore,” she quips.
Some diets high in folic acid may help many of the patients with IBD, Raymond adds — their symptoms can be improved with better dietary manipulation. “We’re getting to understand IBD on a microscopic level, with whiz-bang drugs to treat it,” she says.
Nearly all patients would rather try a new therapy than face surgery, according to a survey initiated by the European Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA). In this first-ever pan-European survey of more than 5,000 patients with IBD, it is revealed that more needs to be done to manage these disorders. The survey found that while most patients reported some level of satisfaction with their current treatment (76 percent UC, 76 percent CD), a large number also admitted their symptoms continue to adversely affect their daily lives (leisure activities — 73 percent UC and 78 percent CD; work — 66 percent UC and 72 percent CD). Approximately two-thirds of patients (both CD and UC) rated their quality of life after surgery as greatly improved. However, a large number of patients (43 percent UC and 69 percent CD) still had a recurrence of symptoms with many reporting serious complications after surgery (32 percent UC and 26 percent CD).
According to a study conducted at the University of North Carolina, Chapel Hill, the number of products under study for the treatment of IBD has increased from three products and one target in 1993 to more than 30 products and more than 10 targets in 2005.1
The conventional medical treatment of IBD consists of aminosalicylates, corticosteroids, immunosuppressive drugs (azathioprine, 6-MP, methotrexate, and cyclosporin), biologic therapies, and antibiotics.
IBD is commonly treated with the immunomodulators azathioprine and its metabolite 6-MP.4 The appropriateness of immunosuppressants in the management of IBD was assessed this year using the RAND method.5 The results of this Italian study show that only azathioprine, 6-MP, and methotrexate are appropriate in the treatment of IBD. In addition, cyclosporine A was found to be appropriate only in severe UC after the failure of steroids.
The only drugs able to modify the disease course are azathioprine, 6-MP, and methotrexate.6 However, these drugs have a slow onset of action and are associated with important side effects in some patients, often necessitating the discontinuation of the drug. Moreover, up to 60 percent of patients do not respond to these drugs long-term. Furthermore, serious drug toxicity leads to cessation of therapy in 9 percent to 25 percent of patients, and there is failure to achieve efficacy in approximately 15 percent of cases.7
Data also suggest an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine/ 6-MP.4 The increased risk of lymphoma could be a result of the medications, the severity of the underlying disease, or a combination of the two, the researchers concluded.
Nodular regenerative hyperplasia of the liver (NRH) also can develop in IBD patients treated with azathioprine.8 “Clinicians should be aware of this serious complication which may occur with any of the purine analogues (azathioprine, 6-MP, and 6-thioguanine),” according to the researchers who presented four such cases.
Mesalamine and budesonide are antiinflammatory drugs used to induce and maintain remission of IBD.9 Both drug substances are intended to act locally at the inflamed sites of the gastrointestinal (GI) tract. The problem with this therapeutic objective is that the oral treatment and various dosage forms of mesalamine and budesonide display varying release patterns as the dosage form moves through the GI tract — increasing the need for individually tailored therapy. Balsalazide, which is a mesalamine prodrug, is generally welltolerated, effective, and useful in the treatment of IBD.10
An anti-inflammatory therapy utilizing proteins called type 1 interferon IFN-alpha and IFN-beta (IFN-alpha/beta) has been shown by researchers at the University of California, San Diego (UCSD) School of Medicine and their colleagues in Japan and Israel to offer relief in mouse models of CD and UC.11 The study provides the first description of the molecular mechanism by which IFN-alpha/beta inhibits the severity of colitis and maintains intestinal homeostasis, or the “constant state” of the gut, by suppressing proinflammatory activity by the immune system macrophages.
Bacterial antigens, such as intestinal microflora, are known to play a role in the pathogenesis of human IBD. Tylosin, a macrolide antimicrobial agent, has recently been proven effective in cat and dog chronic colitis, but the reasons underlying this efficacy are still unclear.12
In this study evaluating the effects of tylosin on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rat models, in comparison with the antibacterial drug metronidazole and the corticosteroid budesonide, tylosin and metronidazole significantly lowered macroscopic lesion score, reduced colon weight, the severity of histologic lesions, and myeloperoxidase activity. However, budesonide did not significantly change the parameters of colonic inflammation. These data indicate a protective effect of tylosin against intestinal inflammation, suggesting a major role for bacteria — anaerobes in particular — in the development of TNBS-induced mucosal damage.
Another drug therapy evaluated for both CD and UC is alicaforsen.13 Alicaforsen, a human ICAM [intercellular adhesion molecules]-1 antisense oligonucleotide, alters the local inflammatory reaction in the intestinal wall. In enema form, alicaforsen also shows promising acute and long-term benefits in patients with mild to moderate descending UC.14
It has recently been shown that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than the conventional drugs used for IBD, and they might change the treatment strategy of IBD in the near future.15
Scientists examined the effects of thalidomide treatment in the development of experimental colitis (using DNBS [dinitrobenzene sulfonic acid]-treated mice) and found that when treated with thalidomide at 200 mg/kg orally, the mice subjected to DNBS-induced colitis experienced a significantly lower rate in the extent and severity of the histological signs of colon injury. Thalidomide also caused a substantial reduction of the rise in mucosa, leaving the scientists to conclude that thalidomide treatment reduces the degree of colitis.
Three biologic therapies — Alequel™, adalimumab (Humira®), and infliximab (Remicade®) — are showing promising results that may provide new treatment options.16 The development of new biological therapies began in the 1990s.6 They are effective in decreasing the severity of IBD symptoms and increasing rates of clinical remission and response in IBD patients.16 Infliximab is a genetically engineered monoclonal antibody that targets the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha).17 Infliximab initially was developed to be used in patients with moderate to severe luminal or fistulizing CD who were not responding to standard medical therapy.
Infliximab rapidly induces remission in CD, and when given chronically, it can provide long-term maintenance of remission. In addition, there are some data to support its use as a steroid-sparing agent and treatment for various extra-intestinal manifestations of IBD and, although used predominantly to treat CD, recent data suggest that infliximab also may have a role in the management of UC. Infliximab does, however, require careful patient monitoring to avoid rare but significant toxicities. The infliximab drug Remicade recently has been approved by the FDA for treatment of patients with moderate to severe CD who have not responded to conventional therapy.
Infliximab also has been proven superior to placebo in the treatment of pyoderma gangrenosum (PG), a chronic ulcerating skin condition that often occurs in association with IBD.18 Despite the existence of multiple therapies, the medical treatment of these diseases often prove insufficient and surgery is frequently required.17
During the last two decades, the general availability of high resolution ultrasound has greatly improved the diagnostic potential of ultrasound in the assessment of IBD.19 This technique proves useful as a screening imaging modality in patients with symptoms or clinical signs of IBD as well as for assessing CD lesions.
Although the role of bowel ultrasound in the assessment of disease activity is limited at this time, colour Doppler flow imaging may, perhaps, help to differentiate inflammatory from fibrotic intestinal strictures. New ultrasound technologies — such as those using oral and intravenous contrast agents — may prove to further increase the diagnostic capability of ultrasound.
Magnetic resonance imaging (MRI)-based colonography, mostly used in the past for polyp screening, also may represent a future imaging tool for IBD. One recent study concluded it was only able to sufficiently visualize severe colonic inflammation in patients with CD20. However, another German study concluded it may be considered a promising alternative to endoscopic biopsy in monitoring IBD activity or assessing therapeutic effectiveness.21 In the later study, the diagnostic accuracy of magnetic resonance colonography (MRC) was assessed for its ability to detect and quantify IBD affecting the colon. MRC detected and characterized clinically relevant IBD of the large bowel with sensitivity and specificity values of 87 percent and 100 percent, respectively, for all investigated colonic segments. In addition, all severely inflamed segments were correctly identified as such and there were no false positive findings.
Endoscopy has of course played an integral role in the diagnosis, management, and surveillance of IBD for many years — and will continue to do so.
“Because there is no single pathognomonic test that establishes the diagnosis of IBD, endoscopy is useful in establishing the diagnosis, excluding other etiologies, distinguishing Crohn’s disease from ulcerative colitis, defining the patterns, extent, and activity of mucosal inflammation, and obtaining mucosal tissue for histologic evaluation,” writes David Fefferman, MD, from the Center for Inflammatory Bowel Disease, division of gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School. “In established IBD, endoscopy helps define the extent and severity of involvement, which in turn influences medical and surgical decisions, aids in targeting medical therapies, and allows for the management of IBD-related complications. Furthermore, endoscopy plays a key role in the surveillance of patients with long-standing colitis who are at increased risk for dysplasia and the development of colorectal cancer.”22
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IBD Pharmaceutical News
Mesavance™ Induces Ulcerative Colitis Remission in Phase III Study
HONOLULU — Results of two Phase III clinical studies of an advanced formulation of high-strength mesalamine, SPD476, were presented at the 70th annual American College of Gastroenterology (ACG) meeting in Honolulu, Hawaii. These results demonstrated that SPD476 met its primary endpoint of induction of remission of active, mild-to-moderate ulcerative colitis (UC) and was well tolerated as once-daily and twice-daily dosing.
Although mesalamine is routinely used for the treatment of UC, SPD476 utilizes an advanced proprietary Multi-Matrix System™ (MMX) technology to provide the highest mesalamine dose per tablet (1.2g) and deliver delayed and extended medication consistently through the colon.
Study 302, a double-blind, multi-center Phase III study of efficacy and tolerability, found that remission rates were 41.2 percent, 40.5 percent, 32.6 percent and 22.1 percent for SPD476 4.8g (QD), SPD476 2.4g/day (QD), Asacol and placebo, respectively. Similarly, SPD476 2.4g/day and 4.8g/day (QD) significantly increased clinical remission (complete resolution of symptoms) compared with placebo. Study 301 was a multi-center, prospective, double-blind Phase III study of safety and efficacy of SPD476 once daily or twice daily versus placebo in adults with acute, mild-to-moderate UC. Remission rates were 29.2 percent, 34.1 percent and 12.9 percent for SPD476 4.8g (QD), 2.4g/day (BID) and placebo, respectively.
“Because of the once-daily dosing, SPD476 has the potential to improve patient compliance,” said Study 301 lead investigator Gary Lichtenstein, MD. Previous studies of UC patients have demonstrated that up to 68 percent of patients do not regularly take the medication needed to control their condition, despite orders from their doctors.1
1. Kane, S. Adherence issues in the patient with inflammatory bowel disease. Practical Gastroenterology. September 2004; 28(9):16-22.
Source: Shire Pharmaceuticals Group plc
Sargramostim Therapy Demonstrates Quality-of-Life Improvements for Crohn’s Disease Patients
HONOLULU — Sargramostim therapy was associated with improved and maintained quality-of-life (QOL) in patients with moderately to severely active Crohn’s disease, according to data presented at the same ACG meeting. In the multi-center, randomized, double-blind, placebo-controlled Phase II trial, sargramostim treatment resulted in significant improvements in quality-of-life from baseline to Day 57 versus placebo, as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Short Form 36 (SF-36) health surveys. Improvements in QOL ranging from moderate to large occurred early and were maintained throughout the treatment.
Sargramostim may address a primary defect of Crohn’s disease by helping to improve immune cell function within the intestinal barrier, unlike other therapies that broadly suppress immune response and inflammatory symptoms.
Source: Brian K. Dieckgraefe, MD, PhD, co-investigator and assistant professor of medicine, division of gastroenterology, Washington University School of Medicine, St. Louis.
HUMIRA® Shows Promise in Long-Term Treatment of Crohn’s Disease
ABBOTT PARK, Ill. — Data from an analysis of 55 patients with moderate to severely active Crohn’s disease who achieved clinical remission through treatment with HUMIRA® (adalimumab) show 74 percent of patients maintained clinical remission through continued treatment with HUMIRA every other week (eow) for one year. Eighty-three percent of patients on HUMIRA every week maintained clinical remission for one year, according to results from a Phase III extension study presented at the American College of Gastroenterology annual meeting. Source: Abbott
Current Medication Trends
Medications currently available to those suffering IBD alleviate inflammation and reduce symptoms, but do not provide a cure or prevent long-term complications.
The principal drugs used to treat both Crohn’s disease and ulcerative colitis are 5-ASA preparations, corticosteroids (e.g., prednisone, budesonide), and immunosuppressants. 5-ASA is the active ingredient of sulfasalazine, which was widely prescribed to treat IBD for many years. Today, other 5-ASA preparations, which have fewer side effects than sulfasalazine, are FDA-approved for treatment of ulcerative colitis: Asacol®, Rowasa®, Dipentum®, and Pentasa®. Though they have not been approved for this indication, Asacol and Pentasa are useful in Crohn’s disease because they are delivered to the small intestine.
Immunosuppressive agents, such as azathioprine (Imuran®) and 6-mercaptopurine (6-MP, Purinethol®), are helpful in persons who do not respond to 5-ASA and corticosteroids, or who have recurrent flare-ups of disease when steroids are tapered.
Antibiotics are useful in Crohn’s disease of the colon. Source: Crohn’s and Colitis Foundation of America. “About Crohn’s Disease and Ulcerative Colitis” www.ccfa.org/about/press/ibdfacts (accessed Oct. 26, 2005.)
1. Isaacs KL, et al. "State of the Art: IBD Therapy and Clinical Trials in IBD." Inflamm Bowel Dis. 2005 Nov;11 Suppl 1:S3-S12.
2. Crohn's and Colitis Foundation of America. "About Crohn's Disease and Ulcerative Colitis." www.ccfa.org/about/press/ibdfacts (accessed Oct. 26, 2005.)
3. Reddy SI, et al. "Are patients with inflammatory bowel disease receiving optimal care?" Am J Gastroenterol. 2005 Jun;100(6):1357-61.
4. Kandiel A, et al. "Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine." Gut. 2005 Aug;54(8):1121-5.
5. Caprilli R, et al. "Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement." Dig Liver Dis. 2005 Jun;37(6):407-17.
6. Baert F, et al. "Management of ulcerative colitis and Crohn's disease." Acta Clin Belg. 2004 Sep-Oct;59(5):304-14.
7. Gearry RB, Barclay ML. "Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease." J Gastroenterol Hepatol. 2005 Aug;20(8):1149-57.
8. Daniel F, et al. "Azathioprine induced nodular regenerative hyperplasia in IBD patients." Gastroenterol Clin Biol. 2005 May;29(5):600-3.
9. Klein S, et al. "Site-specific delivery of anti-inflammatory drugs in the gastrointestinal tract: an in-vitro release model." J Pharm Pharmacol. 2005 Jun;57(6):709-19.
10. Baker DE. "Safety of balsalazide therapy in the treatment of inflammatory bowel disease." Rev Gastroenterol Disord. 2005 Summer;5(3):135-41.
11. Katakura K, et al. "Toll-like receptor 9-induced type I IFN protects mice from experimental colitis." J Clin Invest. 2005 Mar;115(3):695-702.
12. Menozzi A, et al. "Effect of the macrolide antibacterial drug, tylosin, on TNBS-induced colitis in the rat." Pharmacology. 2005 Jun;74(3):135-42. Epub 2005 Mar 8.
13. Barish CF. "Alicaforsen therapy in inflammatory bowel disease." Expert Opin Biol Ther. 2005 Oct;5(10):1387-91.
14. van Deventer SJ, "A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis." Gut. 2004 Nov;53(11):1646-51.
15. Mazzon E, et al. "Thalidomide treatment reduces colon injury induced by experimental colitis." Shock. 2005 Jun;23(6):556-64.
16. Digestive Disease Week. "Biologic therapies for bowel disease show promise in clinical trials." Press release. May 16, 2005.
17. Travassos WJ, Cheifetz AS. "Infliximab: Use in Inflammatory Bowel Disease." Curr Treat Options Gastroenterol. 2005 Jun;8(3):187-196.
18. Brooklyn TN, et al. "Infliximab for the treatment of pyoderma gangrenosum: a randomised, double-blind placebo-controlled trial." Gut. 2005 Sep 27; [Epub ahead of print].
19. Parente F, et al. "Imaging inflammatory bowel disease using bowel ultrasound." Eur J Gastroenterol Hepatol. 2005 Mar;17(3):283-91.
20. Schreyer AG, et al. "Comparison of magnetic resonance imaging colonography with conventional colonoscopy for the assessment of intestinal inflammation in patients with inflammatory bowel disease: a feasibility study." Gut. 2005 Feb;54(2):250-6.
21. Ajaj WM, et al. "Magnetic resonance colonography for the detection of inflammatory diseases of the large bowel: quantifying the inflammatory activity." Gut. 2005 Feb;54(2):257-63.
22. Fefferman DS, Farrell RJ. "Endoscopy in inflammatory bowel disease: indications, surveillance, and use in clinical practice." Clin Gastroenterol Hepatol. 2005 Jan;3(1):11-24.