BEYOND MOLECULAR BIOLOGY: IMPROVING QUALITY OF LIFE IN PATIENTS WITH CROHN S DISEASE. Stephen B. Hanauer, MD*

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1 BEYOND MOLECULAR BIOLOGY: IMPROVING QUALITY OF LIFE IN PATIENTS WITH CROHN S DISEASE Stephen B. Hanauer, MD* ABSTRACT *Professor of Medicine and Clinical Pharmacology; Chief, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago, Chicago, Illinois. Address correspondence to: Stephen B. Hanauer, MD, University of Chicago, 5841 S Maryland Ave, MC 4076, Chicago, Il shanauer@uchicago.edu. Crohn s disease (CD) is a lifelong, incurable illness that typically requires decades of medical care. Patients with CD experience high rates of surgery, significantly impaired quality of life, depression, and economic hardship. Immunosuppressive and immunomodulatory agents have long been used for the treatment of CD, but are often of limited efficacy in patients with moderate-to-severe disease, or are associated with significant safety and tolerability problems. Surgery and nutrition therapy are also important components of the management of patients with CD. Inhibition of the inflammatory cytokine tumor necrosis factor (TNF)-α has recently emerged as an important therapeutic option for patients with CD, as demonstrated by the clinically significant improvement in symptoms with the anti-tnf therapy infliximab. A number of newer anti-tnf therapies have been evaluated in recent clinical trials. Some of these agents, including adalimumab and certolizumab pegol, have been shown to improve the symptoms of CD in initial clinical studies and are currently being evaluated in large randomized trials. Although these therapies are expected to be more expensive than conventional therapies for initial treatment, it is possible that newer treatments may reduce overall long-term treatment costs by reducing the need for hospitalization and surgical expenses, which account for more than 80% of CD-related healthcare costs. Economic analyses of clinical trial data for newer CD therapies have demonstrated reduced medical resource use, including the need for hospitalization and surgery, among patients who received anti-tnf therapies. Patient education and effective patient-physician communication are essential to maintain patient adherence to treatment and to identify and manage psychological consequences of CD and CD therapy. (Adv Stud Med. 2005;5(9C):S860-S867) THE SOCIAL, PSYCHOLOGICAL AND ECONOMIC IMPLICATIONS OF CROHN S DISEASE Crohn s disease (CD) is a lifelong, incurable illness that is associated with considerable pain, embarrassment, and psychological distress. Although it affects individuals of all ages, CD typically first appears during the second or third decade of life, and therefore usually requires many years of medical care. CD affects an estimated to persons in North America, 1 and epidemiologic studies conducted over the last several decades have suggested that the prevalence of CD is increasing. 1 Although it is typically characterized by alternating periods of remission and exacerbation, approximately 13% of patients have an unremitting course. 2 Nearly 60% of patients will require surgery at some point, 2 which can cause permanent disfigurement. As with other chronic, severe illnesses, patients with CD are at increased risk of depression, anxiety, and other psychiatric conditions, 3,4 which may contribute to poor treatment outcomes. 5-7 Health-related quality of life is significantly impaired among patients with active CD, and is improved by effective treatment. 8 CD is also associated with considerable economic burden, primarily as a result of hospitalization and surgery. 9,10 In addition to direct medical costs, CD is also associated with indirect economic consequences such as high rates of unemployment and S860 Vol. 5 (9C) October 2005

2 disability compensation. 11 Anti-inflammatory and immunomodulatory therapies have long been used to treat CD. While 5-aminosalicylates may be beneficial for mild CD, corticosteroids employed to treat moderate-to-severe disease often improve CD symptoms but are associated with significant safety and tolerability problems. During the last decade, a number of new approaches to the treatment of CD have been developed that specifically target the inflammatory cytokine tumor necrosis factor (TNF)-α. The biologic basis of anti TNF-α therapy has been described in an accompanying article by Dr William J. Sandborn. This article reviews the incorporation of anti TNF-α strategies into clinical practice for the treatment of CD. MEDICATION SELECTION: MINIMIZING SIDE EFFECTS, COST, AND ADMINISTRATION TIME The goals of therapy for patients with CD are to induce remission, maintain long-term remission, improve quality of life, and minimize the complications of CD and its treatment. Pharmacoeconomic considerations are also becoming increasingly important with the introduction of new and more costly CD therapies. An important potential goal for future therapies is to modify the course of the disease and prevent tissue damage in the same manner that disease-modifying treatments prevent joint destruction in patients with rheumatoid arthritis. At present, however, there are no generally accepted methods to demonstrate disease modification in patients with CD. Potential endpoints for future studies might include mucosal healing or reduced need for surgery or hospitalization. Identification of therapies that both heal inflammation and prevent fibrotic (stricturing) and transmural (fistulizing) complications of CD is a goal for pharmaceutical development. The selection of a pharmacotherapy treatment strategy is based on the patient s disease severity and the sites of active disease. Thus, assessing disease activity is a critical first step in developing a treatment plan. Although there is no single definitive CD assessment method, the use of a disease rating scale such as the Crohn s Disease Activity Index (CDAI) is common in CD clinical trials The CDAI is a subjective index that primarily reflects CD symptoms such as the frequency of very soft or liquid stools, abdominal pain, anal fissures and fistulae, and abdominal masses. 15 Scores on the CDAI range from 0 to approximately 600, with a higher score indicating more severe CD. 16 The addition of a biologic index such as the acutephase reactant C-reactive protein (CRP) may provide confirmation that the symptoms are the result of an underlying inflammatory process, rather than from another cause (eg, scarring or adhesions from previous surgical resections). 17,18 Unfortunately, the CDAI is not closely linked with the pathophysiology of CD or the endoscopic appearance of mucosal lesions, and is not specific for CD. Due to the nonspecificity of symptoms and the subjectivity of components of the CDAI (eg, general well-being) many patients will have elevated CDAI scores without demonstrable inflammatory disease but may have concomitant irritable bowel syndrome. Accordingly, treatment guidelines developed by the American College of Gastroenterology define severity using more pragmatic descriptions of mild, moderate, or severe disease. The principal pharmacologic treatment recommended for the initial therapy of mild to moderate active ileal, ileocolonic, or colonic disease is an oral aminosalicylate (mesalamine 3.2 to 4 g or sulfasalazine 3 to 6 g/day). Ciprofloxacin 1 g/day is also recommended as an alternative to oral aminosalicylate therapy. 12 Subsequent revisions of the guidelines will likely take into consideration recent evidence-based additions of budesonide for ileal and/or right colonic disease. 19 Guidelines developed by the British Society of Gastroenterology recommend high-dose mesalamine or corticosteroids as initial treatment, with sulfasalazine, metronidazole, azathioprine, or mercaptopurine as second-line treatments. 20 Approximately 40% to 50% of patients attain a clinical response or remission with these agents (approximately 65% with budesonide). However, the true benefit of these medications has recently been questioned by some clinicians because the rate of treatment response among placebo-treated patients has approached this degree of improvement in some double-blind trials. 19 In addition, all of these agents are limited in usefulness by numerous side effects (Table 1) or, with azathioprine/mercaptopurine, a relatively slow onset of effect. 20 For moderate to severe disease, oral corticosteroids (eg, prednisolone mg/day, budesonide 9 mg/day) are the principal treatments. 12,20 Corticosteroids are generally effective and relatively inexpensive but are also associated with significant side effects. Corticosteroids are less effective for long-term therapy, as at least 50% of patients Advanced Studies in Medicine S861

3 Table 1. Common Side Effects with Conventional Therapies for Crohn s Disease Aminosalicylates Headache Nausea Epigastric pain Diarrhea Acute intolerance resembling colitis Thiopurines Flu-like symptoms Methotrexate Gastrointestinal (nausea, vomiting, diarrhea, stomatitis) Hepatotoxicity Cyclosporine Tremor Paresthesia Malaise Headache Abnormal liver function Gingival hyperplasia Hirsutism Renal impairment Infections Neurotoxicity Steroids Cosmetic (acne, edema) Sleep and mood disturbance Dyspepsia Glucose intolerance Cataracts Osteoporosis, osteonecrosis Myopathy Infection Data from Carter et al. 20 become either steroid dependent or refractory to steroid therapy after 1 year. 12 Azathioprine or mercaptopurine should be maintained while steroid use is tapered and discontinued. For severe CD, the principal pharmacotherapy option has been intravenous (IV) steroids (eg, hydrocortisone 400 mg/day or methylprednisolone 60 mg/day). 20 For patients with fistulizing and perianal disease, the initial goal of therapy is treat both the active CD and sepsis. First-line agents include metronidazole 400 mg and/or ciprofloxacin 500 mg twice daily. Azathioprine or mercaptopurine is recommended for the long-term treatment of simple perianal or enterocutaneous fistulae without distal abscess or obstruction. 20 Successful induction of remission is followed by long-term maintenance therapy. Mesalamine is effective maintenance therapy for some patients, but is of limited effectiveness at low doses (<2 g/day) or for patients who required steroids to induce remission. Azathioprine and mercaptopurine are recommended for patients with steroid-induced remission of CD. 12 Corticosteroids (including controlled-release budesonide) are not recommended for maintenance therapy. SURGERY AND NUTRITION THERAPY Surgery is also an important option to ameliorate complications such as strictures or fistulae. For patients with active ileal, ileocolonic, or colonic disease, surgery may be considered either for patients who have not responded adequately to medical management, or as primary therapy for patients with limited ileal or ileocolonic disease. 12,20 Surgery is also appropriate for patients with fistulizing disease, in combination with medical treatment. In a large, prospective, population-based study of patients with CD, surgical treatment was associated with a mean per-patient lifetime treatment cost of $17 526, compared with lifetime costs of $ for aminosalicylate therapy and $5147 for corticosteroids and immunosuppressants. Surgical treatment also produced the longest average duration of remission. 21 Nutrition is an important aspect of the treatment of CD, but it has not been extensively used as primary therapy in the United States and Europe. Many patients with CD have nutritional deficiencies or other nutrition-related complications as a consequence of the gastrointestinal lesions of CD and because of the frequent requirement for intestinal surgery. In principle, it is possible to treat CD by limiting food intake and instituting IV feeding. This approach is rarely used in clinical practice because it is expensive, poorly tolerated, and generally does not modify the long-term course of the disease. 12 Another form of nutritional therapy is the use of elemental diets, although these are very poorly tolerated and are only effective while patients remain on the diet. Many patients also require oral or parental nutritional support to address the complications of CD. For example, oral or IV iron supplementation is often required to correct iron deficiency, and supplemental protein is required for many patients who are undernourished. S862 Vol. 5 (9C) October 2005

4 ANTI TNF-α THERAPY IN CD Infliximab, a chimeric (mouse/human) monoclonal antibody, is the only specific anti TNF-α therapy currently approved for the treatment of CD. Several randomized, double-blind clinical trials have demonstrated the effectiveness of infliximab for induction and maintenance therapy of patients with CD. The first randomized, double-blind clinical trial to examine the efficacy of infliximab for induction therapy of CD was conducted in 108 patients with moderate-tosevere, treatment-resistant CD. 16 Four weeks after a single IV infusion of placebo or 1 of 3 infliximab doses (5, 10, or 20 mg/kg), response to treatment (defined as an improvement of at least 70 points on the CDAI with no change in medications) was noted for 81% of the patients who received infliximab 5 mg/kg, 50% with 10 mg/kg, 64% with 20 mg/kg, and 17% of those who received placebo (P <.001 for the comparison of placebo versus the 3 infliximab groups combined). The differences in response and remission rates between the placebo group and the 3 infliximab groups combined are shown in Figure The efficacy of infliximab for maintenance therapy was examined in A Crohn s Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen (ACCENT-1), in which 335 patients who responded to a single infliximab infusion were randomized to maintenance therapy with infliximab or placebo for up to 46 weeks. 23 At a follow-up evaluation 30 weeks after randomization, remission was attained by 21% of patients who received placebo, 39% with infliximab 5 mg/kg (P =.003), and 45% with infliximab 10 mg/kg (P =.0002). Both infliximab doses were also associated with higher rates of remission through 54 weeks of treatment. ACCENT-2 examined the efficacy of infliximab as maintenance therapy for patients with fistulizing CD. 24 Patients with abdominal or perianal fistulae of at least 3 months duration and who responded to initial therapy with infliximab were randomized to maintenance therapy with infliximab 5 mg/kg or placebo every 8 weeks. At the end of 1 year of follow-up, a response to treatment (defined as the complete absence of draining fistulae) were noted for 36% of patients with infliximab and 19% with placebo (P <.001). Infliximab is approved for induction and maintenance of patients with CD who have had an inadequate response to conventional therapy, and for the treatment of fistulizing CD. 25 A comprehensive guide to the use of infliximab for the treatment of CD has been published, which reviews the goals of CD therapy, infliximab dosing algorithms for specific patient subpopulations, combining infliximab with other therapies, and the prevention and management of adverse events. 26 Recent CD management guidelines developed by the British Society of Gastroenterology recommend the use of infliximab for patients with moderate-to-severe CD who do not respond to other pharmacologic treatments and for whom surgery is considered inappropriate. 20 As noted previously, many patients with CD respond to infliximab even if they did not improve with other treatments. 16 However, once patients have received infliximab, this is often the only agent that will continue to maintain the patients in remission, and it has been difficult to bridge patients back to conventional treatments. 27 In addition, when treatment with infliximab should be initiated is an important unresolved issue. Although approved for use in moderate-to-severe CD for patients who have not responded to other therapy, there is accumulating evidence that patients with mild-to-moderate disease, who have not previously failed to respond to conventional treatment, may benefit from earlier introduction of anti TNF-α therapy. Hommes and colleagues, at the Digestive Disease Week 2005 Annual Meeting, 28 compared a strategy of Figure 1. Infliximab in Active Crohn s Disease Response (%) % P < % 4 Weeks Clinical Response Placebo (n = 25) 4% P = Weeks Clinical Remission All infliximab (n = 83) 33% Copyright MedReviews, LLC. Reprinted with permission of MedReviews, LLC. Hanauer SB. Rev Gastroenterol Disord. 2004;4(suppl 3):S18-S Reviews in Gastroenterological Disorders is a copyrighted publication of MedReviews, LLC. All rights reserved. Advanced Studies in Medicine S863

5 infliximab and azathioprine ( top-down treatment) with prednisone ( bottom-up treatment) for the initial therapy of patients with CD. A total of 129 patients with CD diagnosed within the preceding 4 years, who had never received steroid therapy, were enrolled in this multicenter, open-label trial. Patients who did not respond to their initial therapy or had a disease flare were either retreated with the same therapy or were crossed over to the other treatment strategy. After 6 months, remission rates were similar for the 2 treatment strategies (75% and 73% with top-down and bottom-up treatment, respectively). Remission rates were also similar after 1 year (77% and 76%). However, the need for maintenance steroid treatment was lower among patients who were assigned to the top-down strategy. At 6 months, 75% of patients in the top-down group were in remission and free of steroids, compared with 48% of patients in the bottom-up treatment group. At 12 months, steroid-free remission was attained by 77% and 66% of patients with top-down and bottom-up treatment, respectively. In addition, additional infliximab therapy was required for 25% of patients with the top-down strategy during the first 6 months, whereas additional steroid treatment or a crossover to infliximab was required for 52% of patients with the bottom-up strategy. This study suggests that an initial treatment strategy of infliximab and azathioprine for treatment-naive patients reduced the need for steroid administration during the course of long-term therapy, and that most patients who began treatment with steroids eventually needed additional treatment with steroids or infliximab. As reviewed in an accompanying article by Dr Sandborn, several other agents that block the effects of TNF-α have also been evaluated in clinical trials. Some of these treatments but not all have been shown to improve the symptoms of CD. Adalimumab and certolizumab pegol (CDP-870 conjugated with polyethylene glycol) are currently in phase 3 clinical trials for the treatment of CD. 29 Adalimumab, which is currently approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, has been evaluated for the treatment of CD in preliminary clinical trials. In a recent study of 13 patients with inadequate response to infliximab, 6 months of treatment with adalimumab (initial dose of 80 mg subcutaneously [SC], followed by 40 mg SC every other week) resulted in complete clinical response for 7 patients, and a partial response for 4 patients. 30 Another study found that adalimumab was safe and well tolerated in 7 patients with a history of allergic reactions to infliximab. 31 Initial results from a randomized, placebo-controlled clinical trial of adalimumab, which were presented at the Digestive Disease Week 2005 Annual Meeting, also suggest that this agent is effective for the induction of remission of patients with CD. In the Clinical Assessment of Adalimumab Safety and Efficacy Studied as an Induction Therapy in Crohn s (CLASSIC) trial, 299 patients with moderate-to-severe active CD were randomized to placebo or to 1 of 3 adalimumab treatment strategies: a loading dose of 40 mg with an additional 20 mg at 2 weeks; a loading dose of 80 mg with an additional 40 mg at 2 weeks; and a loading dose of 160 mg with an additional 80 mg dose at 2 weeks. 32 After 4 weeks, the incidence of CD remission was 12% for the placebo group, 18% with low-dose adalimumab (P =.36), 24% with the intermediate dose (P =.06), and 36% with the highest dose (P =.001). An ongoing maintenance study is cited in Dr Sandborn s article. Certolizumab pegol was evaluated in a doubleblind clinical trial in which patients were randomized to SC placebo or 1 of 3 certolizumab doses (100, 200, or 400 mg) at weeks 0, 4, and 8. The number of patients who responded to treatment (defined as improvement in CDAI score of 100 points) was greatest with the 400-mg certolizumab dose, with the largest difference between certolizumab and placebo groups occurring at week 10. By the end of the 12- week study, the difference between certolizumab and Table 2. Clinical Response (% of Patients) Certolizumab Pegol (mg) Placebo Week (n = 73) (n = 74) (n = 72) (n = 72) * * * * *P <.005; P <.01. Data from Schreiber et al. 33 S864 Vol. 5 (9C) October 2005

6 placebo groups was no longer statistically significant (Table 2). 33 Subgroup analyses indicated that the proportion of patients who responded to treatment was greater with certolizumab than with placebo among patients with elevated CRP concentrations at baseline. In the subset of patients without elevated CRP at baseline, no difference was observed in the treatment response between placebo and certolizumab groups. 33 Although certolizumab is being developed as an SC treatment for CD, another recent study evaluated the efficacy and safety of IV certolizumab treatment as a way to administer the agent in higher doses. 34 Patients were randomized to receive single IV injections of placebo or certolizumab at doses of 1.25, 5, 10, or 20 mg/kg (only 2 patients were enrolled at the lowest certolizumab dose; the other groups each contained 17 to 25 patients). CDAI ratings for all treatment groups, including placebo, decreased by more than 50% within 2 weeks of the onset of treatment. Clinical response at week 4 (the primary study endpoint) was noted for 60%, 59%, and 48% for the certolizumab 5-, 10-, and 20-mg/kg dose groups, respectively, and for 56% of patients in the placebo group. Certolizumab has also recently been studied in 2 doubleblind, randomized, placebo-controlled trials of patients with CD (PRECISE-1 and PRECISE-2), the results of which have not yet been disclosed. MINIMIZING THE ECONOMIC IMPACT OF TREATMENT More than 80% of healthcare costs associated with CD treatment are attributable to hospitalization and surgical expenses. 35 Therefore, it is anticipated that therapies that are directed at reducing hospitalizations or minimizing the need for surgery may produce a net economic benefit, even if the treatments are more costly than conventional medications. Some studies have suggested that patients with CD who are treated with infliximab have lower rates of hospitalization and less need for surgery than patients who receive placebo. An economic analysis of data from the ACCENT-1 clinical trial by Lichtenstein and colleagues found that patients with CD who attained CDAI remission with infliximab treatment (a decrease in CDAI score to <150) were less likely to require hospitalization and surgery than patients who did not achieve remission (Figure 2). 36 Remission was also associated with other beneficial outcomes including improved health-related quality of life and an increase in the number of patients who were employed 1 year after beginning treatment. In a second study, these investigators performed an analysis of hospitalization and surgical care using data from the ACCENT-2 clinical trial. 37 The number of hospitalizations and surgeries was lower for patients who were randomized to maintenance infliximab, for both the patient population as a whole and for the subset of patients who responded to induction ther- Figure 2. Average Number of Hospitalizations and Surgeries by Percentage of Time in CDAI Remission Average Number of Events per 100 Patients Figure 3. Infliximab Maintenance Treatment of Crohn s Disease Cumulative Number of Surgeries/Procedures % to 25% (n = 272) Randomization Placebo maintenance 6 > 25% to 50% (n = 88) Weeks Hospitalizations (p < 0.01) Surgeries (p < 0.05) > 50% to 75% (n = 96) % Time in Remission > 75% to 100% (n = 117) CDAI = Crohn s Disease Activity Index. Reprinted with permission from Lichtenstein et al. Am J Gastroenterol. 2004;99: mg/kg infliximab maintenance Reprinted with permission from Lichtenstein et al. Gastroenterology. 2005;128: Advanced Studies in Medicine S865

7 apy (defined as at least a 50% reduction from baseline in the number of draining fistulae for consistency at least 50% at weeks 10 and 14). As shown in Figure 3, the cumulative number of surgeries and procedures over time was lower for patients who were treated with infliximab. Treatment cost may also be influenced by the way that medications are administered. For example, infliximab must be administered by IV infusion, whereas adalimumab and certolizumab pegol are being developed for SC administration in CD. Although it possible that SC formulations may reduce healthcare resources required to administer treatment, the impact on CD treatment costs of this approach has not been rigorously evaluated. PATIENT EDUCATION, COPING STRATEGIES, AND TREATMENT ADHERENCE Adherence to the treatment regimen is an important predictor of treatment outcomes for patients with CD. 38 Patient education is an important part of maintaining treatment adherence and improving overall quality of life. Even a relatively brief discussion of patient concerns can increase treatment adherence and reduce the risk of disease recurrence. 38 CD is a heterogeneous disease with considerable variation in clinical course from patient to patient. Therefore, education must be individualized based on the patient s specific characteristics. Patients should understand the chronic, recurrent nature of CD, the rationale for selecting a particular therapeutic approach, and the expected treatment outcome. CD also typically requires considerable support from the patient s family members or other caregivers. Patients often receive care from a large group of healthcare professionals, including primary care physicians, gastroenterologists or other specialists, nurses or physician assistants, social workers, and dietitians. Patients should be informed of the availability of support groups such as the Crohn s and Colitis Foundation of America (accessible via the Internet at which provides education and support via their Web site and local chapters. Patients with CD have a high incidence of psychological distress and psychiatric disorders as a result of both the disease characteristics, depression associated with pharmacologic treatment (eg, with steroids), and from the psychological consequences of surgical complications (eg, permanent disfigurement, incontinence). Psychological support is required for many patients, and the identification and treatment of depression is an important part of improving quality of life for patients with CD. Patient self-management programs, including the use of guidebooks or selfwritten management plans, have been shown to significantly reduce the number of hospital visits and to improve patient satisfaction with care. 39 SUMMARY CD typically requires decades of intensive medical treatment, which often includes surgery and hospitalization. A number of immunosuppressive agents have long been available for the treatment of CD. Although these agents have been shown to improve symptoms of CD, the interpretation of clinical trials with some agents is complicated by a relatively high placebo response rate. Anti TNF-α therapy with infliximab has been shown to significantly improve the symptoms of CD and to reduce the need for hospitalization and surgery, although it is often difficult to return patients to conventional treatments after they have received infliximab. Other anti TNF-α therapies are being evaluated in large, prospective clinical trials. Initial results from these studies suggest that adalimumab and certolizumab pegol also significantly improve CD symptoms. CD is often associated with considerable psychological distress, and depression is common. Identifying and treating depression can significantly improve the quality of life of patients with CD. REFERENCES 1. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn s disease in Olmsted County, Minnesota, : Incidence, prevalence, and survival. Gastroenterology. 1998;114: Loftus EV Jr, Schoenfeld P, Sandborn WJ. The epidemiology and natural history of Crohn s disease in population-based patient cohorts from North America: A systematic review. Aliment Pharmacol Ther. 2002;16: Helzer JE, Chammas S, Norland CC, Stillings WA, Alpers DH. A study of the association between Crohn s disease and psychiatric illness. Gastroenterology. 1984;86: Elsehety A, Bertorini T. Neurologic and neuropsychiatric complications of Crohn s disease. South Med J. 1997;90: Persoons P, Vermeire S, Demyttenaere K, et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn s disease treatment with infliximab. Aliment Pharmacol Ther. 2005;22: S866 Vol. 5 (9C) October 2005

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