Evidence & Experience: The Art of Managing Inflammatory Bowel Disease

At an industry-sponsored symposium held in conjunction with the American College of Gastroenterology’s 2002 Annual Scientific Meeting, leaders in the field of gastroenterology and
the treatment of inflammatory bowel disease (IBD) discussed the treatment guidelines for Crohn’s disease (CD), strategies used for the induction and maintenance of remission, and the pharmacoeconomic impact of CD. Topics included the current and future goals of CD therapies and the quality-of-life and pharmacoeconomic considerations associated with the various treatment options.

This program was sponsored by the University of Chicago Pritzker School of Medicine.
This program was supported by an unrestricted educational grant from Centocor, Inc.

This material represents a compilation from a series of industry-sponsored educational symposia presented October 18–23, 2002 in conjunction with the Annual Meeting of the American College of Gastroenterology. This compilation is provided for information and critical scrutiny by physician readers, and is not intended to replace clinical judgment by the physician as to a specific patient.

The proceedings arise from industry-sponsored sessions, not from the official ACG program, and this synopsis/compilation of these sessions does not represent the official viewpoint of the American College of Gastroenterology.

Crohn’s Disease Treatment Guidelines: Customizing Patient Care

Current treatment strategies for Crohn’s disease (CD) use a “step-up” approach, observed William J. Sandborn, MD, Professor of Medicine at the Mayo Medical School, and Head of the Inflammatory Bowel Disease Interest Group at the Mayo Clinic in Rochester, Minnesota. Oral 5-aminosalicylate (5-ASA) agents, sulfasalazine, antibiotics, or budesonide are used as first-line therapies for mild-to-moderate disease. Moderate-to-severe disease is treated with systemic steroids, azathioprine, 6-mercaptopurine (6-MP), methotrexate, or infliximab. Severe, fulminant CD requires infliximab, conventional immunosuppressant drugs (eg, cyclo-sporine), or surgery.

Importantly, asymptomatic patients who still require steroids for maintenance areactually steroid dependent and are not in true remission. Unlike corticosteroids, azathioprine, 6-MP, and methotrexate are useful for long-term maintenance therapy, including in the postoperative setting. Moreover, these drugs are steroid sparing.

The Natural History of CD as Demonstrated in Population-based Studies
A Danish study indicated that 78% of patients experienced a relapse over a 3-year period after diagnosis (Munkholm P, et al. Scand J Gastroenterology. 1995;30:699). Similarly, a US study found that the proportion of patients requiring surgery increased over time, with a steady decline in the probability of their remaining in postsurgical remission (Figure 1) (Silverstein MD, et al. Gastroenterology. 1999;117:49). With current treatment strategies, Dr. Sandborn observed, patients with mild-to-moderate disease often progress to surgery, after which they eventually experience complications and relapses, requiring further surgery.

Are Step-Up Treatment Strategies Effective?
One 1997 meta-analysis of postoperative maintenance and remission trials involving almost 2,000 patients concluded that mesalamine was not effective in maintaining medically induced or postsurgical remission (Camma C, et al. Gastroenterology. 1997;113:1465). Corticosteroids are initially effective, but only 32% of patients show prolonged response rates after 1 year, and 28% become steroid dependent (Faubion WA Jr, et al. Gastroenterology. 2001;121:255).

Although 40%-56% of patients ever receive steroids (Munkholm P, et al. Scand J Gastroenterology. 1995;30:699; Silverstein MD, et al. Gastroenterology. 1999;117:49), almost 70% eventually require surgery (Munkholm P, et al. Gastroenterology. 1993;105:1716). These findings, Dr. Sandborn believes, may indicate that using initial therapies (ie, a step-up approach) that are ineffective or are effective for induction but not for maintenance (eg, sulfasalazine, corticosteroids) could increase the likelihood of subsequent complications and the need for surgery.

Surgery and Postoperative Use of Mesalamine Do Not Change the Natural History of CD
According to Munkholm et al, 40% of patients require surgery within 2 years of diagnosis (Munkholm P, et al. Gastroenterology. 1993;105:1716). Rutgeerts and colleagues (Rutgeerts P, et al. Gastroenterology. 1990;99:956) showed that after surgery, 40% of patients had laboratory indices consistent with recurrent inflammation, 50% of patients had recurrent clinical symptoms, and almost 90% of patients had recurrent CD as diagnosed by endoscopic lesions. Many patients with advanced endoscopic lesions required repeated operations within 1 to 5 years. Cumulative relapse rates with mesalamine and placebo 18 months after surgery were 25% and 31%, respectively (Lochs H, et al. Gastroenterology. 2000;118:264).

Thus, concluded Dr. Sandborn, “current treatment paradigms don’t modify the natural course of CD, which is progression to surgery.” He believes that new treatment approaches are needed that will alter the natural history of CD and prevent the need for surgery.

Strategies for maintaining remission in Crohn’s disease (CD) depend on the induction approach and may differ for medically versus surgically induced remission, reported Stephen B. Hanauer, MD, Professor of Medicine and Clinical Pharmacology, Director of the Section of Gastroenterology and Nutrition, and Co-director of the Inflammatory Bowel Disease Research Center of the University of Chicago Pritzker School of Medicine in Chicago, Illinois. Dr. Hanauer reviewed various drugs used for inducing and maintaining remission in CD.

Drugs Used for Induction of Remission
Mesalamine has achieved response rates of 45%-50% in mild-to-moderate CD (Singleton JW, et al. Gastroenterology. 1993;104:1293; Tremaine WJ, et al. J Clin Gastroenterol. 1994;19:278; Prantera C, et al. Gastroenterology.

1999;116:521), but because of variable placebo rates, some trials have found no statistically significant difference between placebo and mesalamine (Hanauer SB, et al. Gastroenterology. 2001;120: A453).

Data from placebo-controlled studies are lacking, but comparison trials of antibiotics in patients with mild-to-moderate disease show 40%-50% response rates (Hanauer SB, et al. Gastroenterology. 2001;120:A453; Prantera CF, et al. Am J Gastroenterol. 1996;91;328; Ursing B, et al. Gastroenterology. 1982;83:550).

Response rates of 60%-80% have been reported in the first 30 days of corticosteroid therapy in moderate-to-severe CD (Faubion WA Jr, et al. Gastroenterology. 2001;121:255). However, only 23%-33% of patients remained well after 1 year, and nearly 40% subsequently required surgery. Budesonide is not as effective as systemic steroids, but has greater short-term efficacy than mesalamine or placebo (Rutgeerts P, et al. N Engl J Med. 1994; 331:842; Thomsen OO, et al. N Engl J Med. 1998;339:370).

A single infusion of infliximab
5 mg/kg induced a clinical response in 80% of patients, with 50% achieving clinical remission even if they had not previously responded to other therapies (Targan SR, et al. N Engl J Med. 1997; 337:1029). In fistulizing CD, infliximab infusions at 0, 2, and 6 weeks led to healing of enterocutaneous or perianal fistulas in 55% of patients, with cessation of fistula drainage for at least 1 month.

Use of Infliximab in Maintenance of Remission
Among 573 patients receiving a single infusion of infliximab 5 mg/kg, 58% exhibited clinical improvement at 2 weeks (Data on file, Centocor, Inc). At 8 weeks, approximately 50% of infliximab-treated patients were in clinical remission for all endpoints. Patients randomized to infliximab maintenance therapy had an approximately 70% likelihood of sustaining a clinical response throughout the trial.

Infliximab also is steroid sparing: in placebo-controlled experiments, infliximab sustained the clinical response while steroid doses were tapered over 22 weeks.

Infliximab and Mucosal Healing
Endoscopic healing at 10 weeks was achieved in 31% of patients maintained on combined doses of infliximab 5 mg/kg and 10 mg/kg, and approximately 50% had continued mucosal healing at week 54 with 5 mg/kg or 10 mg/kg maintenance doses (Figure 1) (Rutgeerts P, et al. Gastroenterology. 2002. 122(suppl):A-618 W1367).

Mucosal healing reduced the risk of hospitalization and surgery during the 1-year trial. Thus, mucosal healing may alter the natural course of the disease, hypothesized Dr. Hanauer, raising the possibility that earlier intervention with such biologic agents may be beneficial.

Quality-of-Life and Pharmacoeconomic Considerations in Crohn’s Disease

Patient quality of life (QOL) is very important in Crohn’s disease (CD), noted Russell D. Cohen, MD, Co-director of the Clinical Inflammatory Disease Research Center and Assistant Professor of Clinical Medicine at the University of Chicago Pritzker School of Medicine in Chicago, Illinois. The unpredictable nature of CD and its many distressing physical symptoms profoundly affect the psychological and social functioning of patients. Indeed, patients with moderate to severe CD rate their QOL to be only slightly higher than that of people suffering severe pain (Gregor JC, et al. Inflamm Bowel Dis. 1997;3:265).

Effect of Therapies on Improvement of Quality of Life
According to various QOL scales, mesalamine 4 g (Singleton JW, et al. Dig Dis Sci. 1995;40:931), budesonide 9 mg and 15 mg (Irvine EJ, et al. Inflamm Bowel Dis. 2000;6:181), and methotrexate 25 mg/week (Feagan BG, et al. N Engl J Med. 1995;332:292) significantly (P<0.05) improve the QOL of CD patients. Infliximab also substantially increases QOL scores in patients with active CD. Further, doses of 5 mg/kg q 8 wk and 10 mg/kg q 8wk are significantly (P<0.05) more effective than single, episodic doses in maintaining remission up to 54 weeks (Hanauer S, et al. Lancet. 2002;359:1541).

Costs Associated With Crohn’s Disease in the United States
In 1990, the indirect cost of CD was $1.8-2.6 billion, with 5%-10% of CD patients experiencing work disability (Hay JW, et al. J Clin Gastroenterol. 1992;14:309). In a CD trial that evaluated the use of infliximab in a new long-term treatment regimen, only 48% of CD patients were employed full time, and 40% were unemployed (Feagan BG, et al. Gastroenterology. 2002;122: W1292). Interestingly, attaining remission correlated with gaining employment.

With its chronic relapsing nature, young patient age at onset, and the near-normal life expectancy of patients, “CD is associated with a lifetime of costs,” noted Dr. Cohen. Importantly, 80% of these costs are related to hospitalizations and surgery. Further, nearly 40% of accrued costs are attributed to just 10% of patients (Hay JW, et al. J Clin Gastroenterol. 1992;14:309). “Targeting effective therapies at this 10%-20% of patients can have a huge impact on overall treatment costs,” observed Dr. Cohen.

Impact of Infliximab on Hospitalization and Surgery Costs
Inflixmab significantly reduced the number of hospitalized days (P = 0.05), GI surgeries (P<0.05), and all surgeries (P<0.01), and decreased the number of hospitalizations by 11% (P = 0.14) (Rubenstein JH, et al. J Clin Gastroenterol. 2002;35:151). Utilization of emergency department services, endoscopy, and radiology also were significantly (P<0.01) lowered (Rubenstein JH, et al. J Clin Gastroenterol. 2002;35: 151). Repeated maintenance infusions of infliximab 5 mg/kg or 10 mg/kg reduced hospitalizations and surgeries through 54 weeks (Figure 1) (Colombel JF, et al. Gastroenterology. 2002;122 (suppl);A-613 W1344).

The patients’ QOL and indirect costs are essential in determining true cost-effectiveness of care, concluded
Dr. Cohen.

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