Review article: medical treatment of moderate to severe Crohn s disease

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1 Aliment Pharmacol Ther 2003; 17 (Suppl. 2): Review article: medical treatment of moderate to severe Crohn s disease M. SCRIBANO & C. PRANTERA Division of Gastroenterology, Azienda Ospedaliera S.Camillo-Forlanini, Rome, Italy SUMMARY The treatment for patients with Crohn s disease of moderate to severe activity includes traditional drugs, such as corticosteroids, the primary therapy for these forms of disease, able to induce the remission of symptoms in a high percentage of patients. Because of the side-effects produced by systemic steroids, a new glucocorticoid derivative, budesonide, which acts locally in the mucosa, has recently been introduced with positive results. On the assumption that intestinal bacteria play a role in the causing Crohn s disease symptoms, antibiotics are often used in the treatment of active phases, as an alternative to or in association with steroids. The most widely employed antibiotics are metronidazole and ciprofloxacin. Immunosuppressors, such as azathioprine and 6-mercaptopurine, are useful for the treatment of chronic active disease and for maintaining remission, but they have only a marginal role in the therapy of an acute flare-up of Crohn s disease. Methotrexate acts more rapidly and its use in patients with active disease resistant to standard therapy is of interest. The discovery of biological agents represents a new era in the management of patients. To date, infliximab is the more extensively studied biological therapy in the treatment of Crohn s disease and clinical studies have demonstrated its efficacy in inducing remission of refractory disease. INTRODUCTION Despite advances in our knowledge of Crohn s disease, the aetiology of this chronic intestinal inflammatory disease, which is characterized by phases of relapse and intervals of remission, is still unknown. Therefore, a specific causal treatment of the disease is not currently available. The management of moderate and severe forms of Crohn s disease includes traditional medical therapies, more recent therapies, such as the new generation of corticosteroids, the antibiotics, the immunosuppressive drugs, and treatments which are even more recent, infliximab and the other biological agents. CORTICOSTEROIDS Corticosteroids are the primary treatment for patients with Crohn s disease of moderate to severe activity, and Correspondence to: Dr C. Prantera, Divisione di Gastroenterologia, Azienda Ospedaliera S.Camillo- Forlanini, Via Portuense 292, Roma, Italy. prantera@tin.it are an effective therapy in inducing remission of symptoms. Two landmark studies have reported the high efficacy of these drugs in the active phases. 1, 2 On the other hand, the same drugs have no role in the maintenance of remission in patients with Crohn s disease because of their poor efficacy at lower doses and the high rate of side-effects produced by their long-term therapy. For these reasons, new glucocorticoid derivatives, such as budesonide, which act locally in the mucosa with little systemic activity and consequently reduced or absent side-effects, have recently been introduced. Budesonide The advantage of budesonide is its controlled ileal release (CIR) formulation, which allows delivery of the drug directly in the ileum and proximal colon. Several randomized controlled trials have reported the efficacy of budesonide in the treatment of active Crohn s disease involving the distal ileum and or right colon. 3 7 In the first, large study, budesonide at a dosage of Ó 2003 Copyright Blackwell Publishing Ltd 23

2 24 M. SCRIBANO & C. PRANTERA 9mg day was shown to induce remission at a significantly higher rate than placebo. 3 In the other studies, budesonide was compared with conventional corticosteroids and was found to be similarly effective with fewer steroid-related side-effects. 4 7 Uncontrolled trials have yielded similar results, and data from dose-finding studies suggest that the optimal dosage for treating active disease is 9 mg of budesonide 3, 6, 8 given once daily. Another promising steroid with a low bioavailability is beclomethasone dipropionate. ANTIBIOTICS On the assumption that enteral flora play a role in the causes of Crohn s disease symptoms, antibiotics are often employed in the treatment of active phases as an alternative to, or in combination with steroids, in spite of 9, 10 few studies supporting their efficacy in this disease. Metronidazole Metronidazole, which is active against anaerobic bacteria and some parasites, is the most widely employed antibiotic. This imidazole compound was first reported to be effective in Crohn s disease in an open study in It is widely used in treating perianal Crohn s disease, and open studies have shown its efficacy in closing fistula and healing perianal abscesses, even if these lesions often reappear when the therapy is discontinued. 12, 13 Randomized controlled trials of metronidazole therapy in active Crohn s disease have demonstrated that this antibiotic is efficacious in Crohn s colitis or ileocolitis, but probably not in small bowel location The positive results obtained with metronidazole when only the colon is involved might be due to the higher concentration of anaerobic bacteria in colitis, and the efficacy of this antibiotic seems to be correlated with luminal Bacteroides concentration. Metronidazole is well tolerated and its side-effects vary between 10% and 20%, according to dosage and length of treatment. The most frequent of these are gastrointestinal intolerance, neurotoxicity and metallic taste. Peripheral neuropathy occurs in 50 85% of cases of long-term metronidazole use. 17 Ciprofloxacin Ciprofloxacin is a quinolone derivative with a selective suppressive effect on the intestinal microflora. Escherichia coli and Enterobacteriacae are sensitive to this antibiotic, which, in contrast, does not particularly affect Bacteroides and Clostridium spp. Ciprofloxacin has been anecdotally reported to be effective in the long term treatment of 10 patients with active perianal Crohn s disease, 18 in 4 cases of Crohn s ileitis 19 and, associated with metronidazole, in an uncontrolled series of 31 patients with active Crohn s disease. 20 Five randomized controlled trials have employed ciprofloxacin in the treatment of acute phases of Crohn s disease, generally reporting positive results The efficacy of a therapy with ciprofloxacin, alone or associated with metronidazole, in active Crohn s disease has been confirmed in a retrospective analysis of 233 patients. 26 The results showed that the antibiotic combination was more effective than one antibiotic alone and that all the diseased locations responded to antibiotic treatment, except for the reduced efficacy of ciprofloxacin in colitis. The poor efficacy of this antibiotic against anaerobic bacteria could be the cause. Again, antibiotics, alone or in combination, were more efficacious in recurrent than in primary ileitis. When the ileocecal valve is resected, the concentration of anaerobes in the ileum is similar to the concentration in the colon, and the small bowel overgrowth can become more relevant in causing symptoms such as abdominal pain and diarrhoea. As expected, a higher percentage of side-effects responsible for the interruption of therapy was reported with the antibiotic association (21.8%). The most common side-effects were epigastric pain, nausea and vomiting. The percentage of side-effects reported in the studies on ciprofloxacin depended on the dosage and the length of treatment. The most frequent are of gastrointestinal origin, but skin reactions and an increase in transaminase levels have also been described. In conclusion, metronidazole and ciprofloxacin have shown themselves to be an effective alternative to steroids in the treatment of acute flares of Crohn s disease, particularly in patients with abscesses, fever, pus in the stools and toxic signs, all of which suggest a bacterial participation in the inflammatory process. IMMUNOSUPPRESSIVE THERAPY Numerous controlled and uncontrolled studies using immunomodulatory therapy in Crohn s disease have been published, with variable and sometimes conflicting

3 REVIEW: MEDICAL TREATMENT OF CROHN S DISEASE 25 results. The immunosuppressive agents used in patients with steroid-dependent or refractory disease are azathioprine (AZA), 6-mercaptopurine (6-MP) and more recently, cyclosporin and methotrexate. The first two drugs act slowly and the mean time to response reported in patients with Crohn s disease is about 3 months. Therefore, azathioprine and 6-mercaptopurine have only a marginal role in the therapy of an acute attack of Crohn s disease, but they are useful for the treatment of chronic active disease and for the maintenance of remission. Cyclosporin Cyclosporin, which is widely used in organ transplation, is a potent immunosuppressive agent that was first used in a patient with Crohn s disease in Some anecdotal reports and open studies have suggested that cyclosporin may be of benefit for patients with active disease refractory to conventional agents. The major advantage of this drug is its prompt onset of action, and benefit is usually observed within the first 2 3 weeks of treatment. The first controlled trial, performed by Brynskov et al., in which cyclosporin was used at a median dosage of 7.6 mg kg per day by mouth, demonstrated positive results in the treatment of acute steroid-resistant disease. 28 However, three other subsequent randomized controlled studies, each using oral cyclosporin doses of 5 mg kg day or less in active disease, reported no benefit It is probable that cyclosporin, if employed as continuous intravenous treatment, as it is in ulcerative colitis, could also be effective in Crohn s disease acute flares. The risk of nephrotoxicity is dose dependent, increasing with a dosage of 5 mg kg daily. However, this sideeffect was not confirmed in a study that reported the follow-up of 1663 patients that had been treated with cyclosporin at doses of between 3 and 6 mg kg per day. 32 A small number of severe opportunistic infections have been reported in patients with inflammatory bowel disease treated with high dose of cyclosporin and steroids, suggesting that this combination increases the risk for infectious complications. Methotrexate Methotrexate is a folic acid antagonist which has antimetabolic and anti-inflammatory properties. Its efficacy in the treatment of rheumatoid arthritis and psoriasis is well known. Since its effects in refractory Crohn s disease were first reported in an open study 12 years ago, several uncontrolled and a small number of controlled trials using methotrexate to treat Crohn s disease have been published The largest study compared parenteral methotrexate at a dose of 25 mg week with placebo in 141 patients with chronic active disease. 34 Thirty-nine per cent of patients taking methotrexate were able to discontinue steroids and entered remission, compared with 19% on placebo. The efficacy of methotrexate when given by mouth has been less conclusive. In fact, in a more recent double-blind controlled trial, methotrexate at a weekly oral dose of 12.5 mg was no more effective than placebo in inducing or maintaining remission. 35 The most frequent side-effects reported with the relatively low doses of methotrexate used in Crohn s disease are nausea, vomiting, stomatitis and leukopenia. Serious complications of therapy are hepatic fibrosis and hypersensitivity pneumonitis. BIOLOGICAL THERAPIES Infliximab Tumor necrosis factor-a (TNF-a), a pro-inflammatory cytokine involved in immune regulation, is markedly elevated in the intestinal mucosa of patients with Crohn s disease, and it plays a pivotal role in the inflammatory cascade in this disease. 36 Based on animal models and clinical studies in patients with rheumatoid arthritis, infliximab, an anti-tnf-a chimeric monoclonal antibody, was administered as a single intravenous infusion at a dose of 10 mg kg in active Crohn s disease patients refractory to steroids. 37 The results of this uncontrolled study showed a dramatic clinical improvement in 8 of 10 patients within 2 weeks. Endoscopic findings were even more impressive, with complete healing of deep ulcerations at 4 weeks. This first observation was subsequently confirmed by double-blind placebo-controlled trials. In 1997, 108 patients with active Crohn s disease, who had not responded to steroid, 6-MP or AZA therapies, were randomized to receive placebo or a single infusion of infliximab at a dosage of 5, 10 or 20 mg kg. 38 At 4 weeks, 64% of the patients receiving infliximab showed a clinical response vs. 17% in the placebo group. Interestingly, it was the lowest dose, 5mg kg, that yielded the highest benefit. All patients

4 26 M. SCRIBANO & C. PRANTERA with a clinical response after 8 weeks of treatment were randomized to infliximab 10 mg kg or placebo at weeks 12, 20, 28 and 36 and were then observed until week The results showed that retreatment with infliximab every 8 weeks is effective in maintaining disease remission, as 65% of the patients were able to maintain their clinical response through to week 44, whereas the initial beneficial effects declined over time in the placebo group. Another placebo-controlled study, performed in 94 patients with draining enterocutaneous fistulae, including perianal fistulae, showed successful healing in 62% of the infliximab group compared with 26% of the patients taking placebo, with all fistulae closed for at least 1 month in 46% (placebo 13%). 40 Mean duration of closure was not just 1 month, but 12 weeks. Again, the 5 mg kg dose appeared to work best. More recently, a large randomized placebo-controlled trial known as ACCENT I was performed to evaluate the efficacy and safety of infliximab in 573 patients with moderate to severe Crohn s disease. 41 All patients received an initial infusion of 5 mg kg infliximab. At week 2, responder patients were randomized to three treatment groups: placebo at weeks 2, 6 and then every 8 weeks (group I); infliximab 5 mg kg at the same timepoints (group II); infliximab 5 mg kg at weeks 2, 6 and then 10 mg kg every 8 weeks (group III). The results showed that 335 patients (58%) responded to a single infusion of infliximab at week 2. At week 30, clinical remission was observed in 21% of group I patients, compared with 39% of group II and 45% of group III. Median time to loss of response through week 54 was 38 weeks and more than 54 weeks for groups II and III, respectively, compared with 19 weeks for group I. Reported experience with patients treated with infliximab for Crohn s disease, rheumatoid arthritis and other conditions has demonstrated that the drug is generally well tolerated. The most common relatively mild adverse events are headache (22%), nausea (17%), upper respiratory tract infection (23%), abdominal pain (11%), skin rash (10%) or diarrhoea (10%). Serious adverse events include infections such as pneumonia, sepsis, and several cases of tuberculosis. Among the patients treated with infliximab for Crohn s disease and rheumatoid arthritis, tuberculosis was diagnosed in 70 patients. 42 Thus, before receiving the drug, patients should be screened for latent tuberculosis infection or disease. Other serious adverse events observed are fever, cardiac failure, bone fracture, severe abdominal pain and severe diarrhoea. Twenty-six per cent of all patients treated in the ACCENT I study suffered serious adverse events, and the most frequent were in the gastrointestinal system. 41 Serious infections occurred in 22 (4%) of 573 patients, without difference between treatment groups. Five per cent of infliximab infusions resulted in acute infusion reactions (vs. 2.7% of placebo infusions) and 1.0% of patients had serious infusions reactions. These were more common in those patients who received more than one infusion and in those who developed antibodies to infliximab, observed in 14% of patients. In the ACCENT I study six patients (1%) had a malignancy during the study period and three patients died: two of sepsis and one of myocardial infarction. CDP571 CDP571 is a genetically engineered human antibody to TNF-a. This humanized monoclonal antibody (95% human) is potentially less immunogenic than chimeric antibodies. A placebo-controlled study of a single infusion of CDP571 at a dose of 5 mg kg was conducted in 30 patients with mild to moderately active Crohn s disease refractory to medical therapy. 43 Results showed that 6 of 20 patients receiving CDP571 (30%) and none of the placebo group (0%) were in remission at week 2. In patients treated with the active drug the median CDAI (Crohn s Disease Activity Index) 44 score decreased significantly from 263 points at baseline to 167 points at week 2, whereas the placebo-treated group showed no significant change. Very recently, 169 patients with moderate to severe Crohn s disease received CDP571 in a 24-week placebocontrolled trial. 45 Patients were initially randomized to a single dose of 10 mg kg or 20 mg kg CDP571 or placebo to assess dose-response and then retreated with 10 mg kg CDP571 or placebo every 8 or 12 weeks. At week 2 the rate of clinical response was significantly higher in patients receiving CDP571 compared with placebo (45% vs. 27%). Clinical remission rates after 24 weeks were 11% in patients treated with the active drug and 4% in the placebo group, for the 8 weekly dosing patients, and 11% and 3%, respectively, for the 12 weekly dosing patients. CDP571 therapy was quite well tolerated. The frequency of headache (18%) and infusion reactions (12%) was higher in patients receiving CDP571 than in the

5 REVIEW: MEDICAL TREATMENT OF CROHN S DISEASE 27 placebo group. Seven per cent of patients treated with the active drug developed anti-cdp571 antibodies. 45 infliximab infusion. Adverse events were the same as those of the other trials. Etanercept Etanercept is a TNF-a binding protein which is generated by fusing the p75 TNF receptor to an immunoglobulin G1 tail (100% human). Based on the positive results reported by a small uncontrolled pilot study, 46 Sandborn et al. have recently conducted a placebocontrolled trial to evaluate the efficacy and safety of this drug in 43 patients with moderate to severe Crohn s disease. 47 Etanercept at a dose of 25 mg subcutaneously twice weekly, for 8 weeks, showed no efficacy in the treatment of these patients. Thalidomide The use of thalidomide was discontinued in the 1960s because of teratogenic effects. Recently, this drug has been shown to exert a selective suppressive activity on TNF-a production. Two open-label trials of thalidomide 48, 49 for Crohn s disease have been published in In the first, 22 patients with refractory Crohn s disease, also including patients with active perianal fistulae, received thalidomide mg day per os for 12 weeks. 48 Vasiliauskas et al. treated 12 male patients with moderate to severe steroid-dependent Crohn s disease with a lower dose of thalidomide, mg daily for a 12-week period. 49 In both studies, the response was fairly rapid, and the results were quite similar, with 55% responding by week 4 with high-dose therapy and 58% with low-dose therapy. At week 12, clinical response was achieved in 64% of the high-dose group and 70% of the lowdose patients. Taken together, these two small, open trials suggest that thalidomide is effective in rapidly inducing clinical response in refractory Crohn s disease. Overall, thalidomide was quite well tolerated, with drowsiness being the most common adverse event, followed by peripheral neuropathy and skin rash. Low doses appear to be as effective and better tolerated than higher doses. Very recently, a small open study evaluated the efficacy of 100 mg daily thalidomide, for maintenance treatment in 15 patients with chronically active and fistulizing refractory Crohn s disease who had responded to infliximab. 50 Remission rates were 92%, 83% and 83% at 3, 6 and 12 months, respectively, after the last Anti-a4 integrin antibody (natalizumab) a4 integrins are important mediators of leukocyte migration across vascular endothelial cells in the gut. Studies on patients with inflammatory bowel disease suggest that a4 integrin expression is up-regulated on lymphocytes present in inflamed areas of intestinal mucosa. Natalizumab is a recombinant humanized monoclonal antibody to a4 integrin (95% human, 5% murine). In a recent placebo controlled trial of 30 patients with mild to moderately active Crohn s disease, a single infusion of 3 mg kg natalizumab showed no significant efficacy compared with placebo. 51 However, remission at week 2 occurred in a larger rate of the natalizumab patients than in the placebo group (39% vs. 8%, respectively). Interleukin-10 Interleukin-10 (IL-10) is a cytokine with potent antiinflammatory activity. Because of its capacity to down-regulate important activities of T helper 1 (Th1) cells and macrophages, IL-10 has been identified as a potential therapy for inflammatory diseases involving Th1-type responses, such as Crohn s disease. In a randomized, controlled trial, treatment with a daily bolus infusion of recombinant human IL-10 (rhuil-10) for 7 consecutive days in patients with steroid refractory Crohn s disease resulted in an increased clinical remission rate over placebo (50% vs. 23%, respectively). 52 More recently, 329 refractory Crohn s disease patients were treated with different doses of rhuil-10 subcutaneously over 28 days in a multicentre, placebo-controlled study. 53 A tendency toward clinical improvement but not remission was reported in the group of patients receiving a dose of 8 lg kg. In another multicentre trial, also published in 2000, 95 patients with mild to moderate disease received subcutaneous rhuil-10 at different dosages or placebo once daily for 28 days. 54 The results showed that 23.5% of patients treated with 5 lg kg obtained clinical remission and endoscopic improvement, compared with 0% of patients in the placebo group. Higher and lower doses of the drug were less effective.

6 28 M. SCRIBANO & C. PRANTERA The main drug-related adverse event reported in the trials was reversible dose-dependent cytopenia. Interleukin-11 Interleukin-11 (IL-11) is a mesenchymally derived cytokine. Recombinant human IL-11 (rhuil-11) has been shown to have a thrombocytopoietc effect, and anti-inflammatory and mucosal protective activity. A multicentre, double-masked, dose-escalation trial performed in 76 patients with active Crohn s disease to evaluate the safety, tolerability and efficacy of subcutaneous rhuil-11 for 3 weeks, showed that a clinical response was achieved in 42 and 33% of patients receiving 16 lg kg, given five times or twice weekly, respectively, compared with 7% of patients receiving placebo. 55 The treatment was well tolerated: most of the reported adverse events were mild and appeared with similar frequency among rhuil-11 and placebo groups. Very recently, 148 patients with mild to moderate Crohn s disease were randomized to receive subcutaneous rhuil-11 at a dose of 15 lg kg once weekly or 7.5 lg kg twice weekly or placebo, for 6 weeks. 56 The proportion of patients in remission at week 6 was greatest in the 15 lg kg once weekly group (37%), compared to placebo (16%) and to 7.5 lg kg in the twice weekly group (14%). The difference in remission rates between the rha-il11 15 lg kg once weekly group and the placebo group was significant. ICAM-1 antisense oligonucleotide (ISIS 2302) Intercellular adhesion molecule 1 (ICAM-1), a member of the immunoglobulin superfamily, is expressed at low levels on vascular endothelial cells and on leukocytes, and it exerts multiple functions in the propagation of inflammatory processes. ICAM-1 expression is increased in tissues obtained from patients with Crohn s disease and tissue expression correlates with disease activity. ISIS 2302, an ICAM-1 antisense oligonucleotide, is characterized by a highly specific reduction in ICAM-1 mrna and consequently lower ICAM-1 expression. In a pilot study, 20 patients with active, steroid-treated Crohn s disease received 13 intravenous infusions of ISIS 2302 at different doses or placebo over 26 days. 57 At the end of treatment, the results showed a trend towards higher remission rates in the ISIS 2302 group compared to placebo (47% vs. 20%). A subsequent, double-blind, placebocontrolled study that assessed four ISIS 2302 doses administered subcutaneously in 60 patients with steroid refractory Crohn s disease was stopped after interim analysis because of negative results. 58 In another very recent trial, 299 patients with active steroid-dependent Crohn s disease were randomized to receive ISIS 2302 at 2 mg kg intravenously three times a week for 2 or 4 weeks, or placebo. 59 Two treatment courses were administered, in months 1 and 3. Steroid-free remission rates were equivalent in treated patients and in the placebo group. CONCLUSION Besides the standard medical therapy of Crohn s disease, including different classes of drugs that have found a role in the treatment of this complex disease, the discovery of biological agents represents a new era in the management of patients. To date, infliximab is the more extensively studied biological therapy in the treatment of Crohn s disease, and clinical trials have demonstrated its efficacy in inducing and maintaining the remission of refractory disease. A variety of other new biological medications have been tested in a few studies with less impressive results, but more controlled information is necessary to clarify if there is a place for these compounds in the armamentarium of Crohn s disease. REFERENCES 1 Summers RW, Switz DM, Session JT. National Cooperative Crohn s Disease Study (NCCDS): results of drug treatment. Gastroenterology 1979; 77: Malchow H, Ewe K, Brandes JW. European Cooperative Crohn s Disease Study (ECCDS): results of drug treatment. Gastroenterology 1984; 86: Greenberg G, Feagan B, Martin F, et al. Oral budesonide for active Crohn s disease. N Engl J Med 1994; 331: Rutgeers P, Lofberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn s disease. N Engl J Med 1994; 331: Gross V, Andus T, Caesar I. Oral ph-modified release budesonide versus 6-methylprednisolone in active Crohn s disease. Eur J Gastroenterol Hepatol 1996; 8: Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG, and the Global Budesonide Study Group. Oral budesonide is as effective as oral prednisolone in active Crohn s disease. Gut 1997; 41:

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