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Inflammatory Bowel Disease: Medical Management

Gregory F. Bonner, M.D.
Department of Gastroenterology
Cleveland Clinic Florida

Objectives:

1) Identify indications for immunosuppressive therapy for Crohn's Disease.
2) Appraise risk and benefits of infliximab therapy.
3) Debate role of prednisone as primary therapy.

Treatment of inflammatory bowel disease is changing with the recent introduction of new biologic therapies and new information on more established therapies. Yet other new therapies are currently under investigation and some of these likely will be available within the next few years.

Mesalamine/5-aminosalicylic Acid

It is now well recognized that oral mesalamine (Asacol,® Pentasa®) is helpful for mild to moderate active ulcerative colitis and for mildly active Crohn's disease.(1) Multiple studies have demonstrated mesalamine enemas to be clearly superior to placebo and equal or superior to steroid enemas in the treatment of active distal ulcerative colitis, though no studies have specifically addressed this therapy for Crohn's colitis. Recent studies have demonstrated that for patients with distal ulcerative colitis, a combined approach with oral and rectal mesalamine offers improved efficacy both for active disease(2) and for maintaining patients with a history of frequent flares.(3)

Balsalazide (Colazal®) is a prodrug with 5-aminosalicylic acid linked to 4-aminobenzoyl-(-alanine, an inert carrier. Like sulphasalazine, colonic bacteria cleave the link releasing 5-ASA in the colon but without the side effects associated with sulphapyradine. The recommended dose of 2.25 g tid delivers the equivalent of 2.34 g of mesalamine to the colon. One controlled trial found balsalazide, 6.75 g/day to be more effective than 2.4 g/day mesalamine for active ulcerative colitis with complete remission in 54% vs 22% of patients respectively (p<0.01).(4) Other studies have found no difference between equivalent doses of balsalazide and sulphasalazine in the treatment of acute ulcerative colitis,(5) or balsalazide vs mesalamine for maintenance of remission in ulcerative colitis.(6)

I find mesalamine to sometimes be useful as a single therapy for mild Crohn's flares or as an adjunct to other therapies for moderate or severe flares. For maintenance of remission, mesalamine is only equivalent to sulphasalazine in ulcerative colitis, though it appears higher doses of mesalamine allowing delivery to the ileum are required for effectiveness at maintaining remission for Crohn's disease.(7) Relatively high doses, approximately 3-4 gm/d, are required for treatment of both active disease and for maintenance therapy for Crohn's disease. Pentasa® delivers throughout the small bowel and colon while Asacol® delivers to the terminal ileum and colon. Sulphasalazine, olsalazine, and balsalazide deliver active drug only to the colon.

Steroids

Glucocorticosteroids remain the most well established therapy for acute flares of inflammatory bowel disease. Studies performed in the 1960's to 1980's have shown that we can expect an approximately 66-75% remission rate for ulcerative colitis(8,9) and an approximately 78-83% remission rate for Crohn's disease.(10,11) Although there is a large body of evidence showing efficacy of steroids for active inflammatory bowel disease, there is no good data demonstrating a role for steroids for maintenance of remission. Once symptoms have been controlled, prednisone should be slowly tapered, usually over a time frame of 6-12 weeks. Still, perhaps as high as 36% of patients who initially respond to steroids will relapse as steroids are tapered.(12) Steroids additionally have numerous side effects including emotional lability, insomnia, hyperglycemia, fluid retention, myopathy, abdominal striae, cataract formation, osteoporosis and osteonecrosis. In light of these limitations there has been increased emphasis in recent years to use immunosuppressive or biologic agents for treatment of IBD.

Budesonide (Entocort-CR®) was recently released by the FDA for treatment of Crohn's disease. It is a rapidly metabolized glucocorticoid with high topical activity but fewer side effects than traditional steroids. The controlled release form delivers the drug to the terminal ileum and right colon. Multiple studies have now shown that budesonide is superior to placebo,(13) and mesalamine(14) and equivalent to prednisolone(15-18) in the treatment of Crohn's disease. Controlled trials have not been performed investigating the role of budesonide in ulcerative colitis. It should be noted that in all the trials were budesonide was compared to prednisolone, the trend was uniformly to a slightly higher efficacy for prednisolone. Budesonide is available in a 3 mg capsule which is roughly equivalent to 15 mg of prednisone.

Budesonide has been studied as a possible agent for maintaining remission in Crohn's disease. To date there have been four controlled trials.(19-22) Though two of these trials imply some efficacy due to a longer mean time to relapse, in all cases the one year relapse rate was nearly identical between budesonide and placebo. Perhaps this finding should not be surprising, as other glucocorticoids have not been proven effective as maintenance therapy. One recent controlled trial specifically addressed the use of budesonide for steroid dependent Crohn's disease.(23) 68% of patients given budesonide 6 mg/d were successfully maintained of prednisolone compared to only 35% in the placebo group (p<0.001).

Immunosuppressant Therapy

6-mercaptopurine/Azathioprine

A substantial minority of patients have inflammatory bowel disease that remains difficult to control even with traditional steroids and mesalamine. Immunosuppressive agents have become accepted therapy for these refractory cases. Though used somewhat less commonly in ulcerative colitis, where surgical therapy is more often pursued for refractory cases, immunosuppressants use for refractory Crohn's disease has become routine.

The longest established immunosuppressants in the treatment of IBD are azathioprine and 6-mercaptopurine (6-MP). Azathioprine is metabolized by the liver to 6-MP. Multiple studies have shown these agents to be efficacious in ulcerative colitis for reducing prednisone dose and maintaining remission, though not specifically for treating acute flares of disease.(24) For Crohn's disease multiple trials have shown efficacy for remission induction and reducing steroid dosage in chronically active disease.(24) A meta-analysis of controlled trials for Crohn's disease demonstrated a 60-70% response rate, 20-25% failure rate and 10% intolerance rate due to side effects.(25) Azathioprine and 6-MP have also been recognized for their ability to maintain remission for both UC and Crohn's disease.(24) A recently presented preliminary report found 6-MP to be superior to placebo and mesalamine in preventing clinical, endoscopic and radiographic post-operative relapse of Crohn's disease.(26) Typical dosages would be 1-1.5 mg/kg for 6-MP and 2-2.5 mg/kg for azathioprine. The effectiveness of azathioprine and 6-MP is limited by their slow onset of action and side-effects. Approximately 10% of patients will not tolerate the medications due to side-effects including nausea, fever, arthralgias, or pancreatitis. There is a delay of onset of action of 1-6 months for both agents. A multicenter study of the use of intravenous azathioprine did not significantly decrease the lag time compared to oral azathioprine, though there was at least the suggestion that more aggressive dosing soon after instituting the drug might give more rapid onset of effect.(27) 6-MP is metabolized by thiopurine methyltransferase (TPMT) to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP). Patients who are genetically deficient of TPMT may suffer excessive leukopenia to even low doses of azathioprine/6-MP. TPMT genotyping is available now but most clinicians simply to start with low doses and increase after checking a CBC at 1 week. For patients experiencing side-effects or with a questionable response, 6-TG and 6-MMP levels can be obtained. A 6-TG level>235 pmol tends to correlate with a therapeutic response, whereas elevated 6-MMP levels tend to indicate a higher incidence of side effects.(28)

More recent reports have focused on 6-thioguanine (6-TG) for patients intolerant of azathioprine or 6-MP. 6-TG is the active metabolite of 6-MP and is commercially available for treatment of acute leukemia. In preliminary reports it was found to be generally well tolerated by patients intolerant of the parent agents.(29)

If a patient has achieved remission and then been maintained in remission for a prolonged period, how long should the medication be continued? Evidence indicates that even after a prolonged remissions, patients who discontinue 6-MP/azathioprine are at increased risk of relapsing compared to those who continue the medication.(30) I now try to convince my patients in prolonged remission to stay on the medication for at least 3-5 years, and even beyond that point I will continue if the patient does not object.

Mycophenolate mofetil

Like azathioprine and 6-MP, mycophenolate mofetil (Cellcept®) is an immunosuppressant inhibiting nucleic acid synthesis. One early uncontrolled trial(31) suggested this agent might be an alternative for patients intolerant of azathioprine and 6-MP. Another controlled but open-label trial of MMF versus azathioprine for up to 6 months of therapy found similar efficacy but fewer side effects associated with MMF.(32) Two more recent uncontrolled trials, however, have had quite pessimistic results with only 4 of 35 patients achieving complete remission with MMF.(33,34) My personal experience has had only 2 of 7 patients responding to MMF, with the other patients being intolerant or not experiencing improvement.

Methotrexate

After uncontrolled trials showed benefit of methotrexate for Crohn's disease patients with steroid-dependent or steroid-resistant Crohn's disease, a single placebo controlled trial has been performed. It investigated efficacy of IM methotrexate (25 mg/wk) for patients with chronically active Crohn's disease.(35) Defining remission as both a CDAI score<150 and complete discontinuation of prednisone, 40% of methotrexate treated patients achieved successful remission compared to 20% of placebo patients. A smaller trial which initiate methotrexate therapy with the oral form (15 mg/wk) showed a less than significant trend for fewer flares with methotrexate therapy.(36) Based on this information, prominent authors now recommend methotrexate be used as the second-line drug to azathioprine/6-MP for chronically active Crohn's disease.(37) A controlled trial comparing methotrexate, 6-MP, or placebo in patients with chronically active Crohn's disease found methotrexate and 6-MP to be similar by most parameters such as such as proportion of patients entering remission, mean Harvey Bradshaw score, or mean monthly steroid dose.(38) However some parameter, such as reduction of steroid dose using patients as their own controls, favored methotrexate. I will typically start methotrexate as 25 mg/wk SQ or IM for the first 8 weeks. If patients respond I will switch them to 15 mg/wk po.

More recently methotrexate has also been shown to have efficacy as a maintenance drug.(39) A 40 week trial of maintenance methotrexate (15 mg/wk IM) found 65% of patients in remission with methotrexate vs. 39% with placebo (p=0.04). Prednisone usage was also significantly less in the methotrexate group.

A single controlled trial of methotrexate for ulcerative colitis failed to show any benefit over placebo for patients with chronically active ulcerative colitis.(40) Notably this trial used both a lower dose of drug and oral administration.

Cyclosporine

Cyclosporine is a potent immunosuppressant used extensively in organ transplant recipients. A single randomized controlled trial has been conducted using intravenous cyclosporine for severe ulcerative colitis refractory to intravenous steroids.(41) 82% of patients responded to cyclosporine compared to 0% of controls. Numerous uncontrolled trials have produced similar results. The success rate declines to 40% on long-term followup.(24) It is now used in specialty centers for severe ulcerative colitis refractory to intravenous steroids. Careful monitoring of renal function, blood pressure, electrolytes, and drug levels is necessary. Seizures may occur if the drug is used in patients with low cholesterol levels. The role of cyclosporin for severe ulcerative colitis must be viewed as being in flux with the emergence of infliximab as a potential therapy. Only uncontrolled trials have been performed and success rates vary from. Simply put, most gastroenterologist fear the potential side effects of cyclosporine but have become comfortable with infliximab.

Out of 4 controlled trials of cyclosporine for Crohn's disease, only the highest dose was significantly better than placebo,(42) and even in that study the beneficial effect was lost after later withdrawing cyclosporine.(43)

Biological Therapy

The newest and most exciting agent for medical management of Crohn's disease is infliximab (Remicade®). Infliximab received FDA approval in November 1998 for treatment of moderate to severe inflammatory Crohn's disease refractory to traditional therapy and for treatment of actively draining external fistulae. It is administered as an intravenous infusion. The original controlled trial showed maximum efficacy at a dose of 5 mg/kg, with a lower response rate at higher doses. Clinical response was demonstrated 4 weeks after infusion in 81% of patients at 5 mg/kg, 50% at 10 mg/kg, and 17% for placebo (p<0.01).(44) This is an impressive response considering many of these patients had disease refractory to other therapies. A clinical response was defined as a 70 point decrease in the CDAI score. The corresponding figures for remission were 48% at 5 mg/kg, 25% at 10 mg/kg, and 4% for placebo (p<0.001). A placebo controlled trial of infliximab for medical management of fistulous Crohn's disease has also been published. For this indication infliximab was given as a series of 3 intravenous infusions at 0, 2, and 6 weeks. Again the 5 mg/kg dose was superior to the 10 mg/kg dose. The primary endpoint of closure of 50% of fistulas occurred in 68% of patients receiving 5 mg/kg, 56% at 10 mg/kg, and 26% of placebo (p=0.002 and p=0.02 respectively).(45) Closure of all fistulas occurred for 55% of patients at 5 mg/kg, 38% at 10 mg/kg, and 13% for placebo (p=0.001 and p=0.04 respectively). The median time response for treating luminal disease was maintained for 241 days.(44) Data are available from the earliest trial of infliximab as maintenance therapy.(46) Patients who had an initial response to infliximab infusion were randomized to maintenance infliximab 10 mg/kg every 8 weeks or placebo infusions. 53% of infliximab treated patients were in remission at completion of the study compared to 20% for placebo (p=0.013).

Preliminary data was presented recently from the large multicenter ACCENT I trial.(47) 573 patients with active Crohn's disease were enrolled with 62% of those patients using steroids at entry. There was no actual placebo control group. All patients received an initial infusion of infliximab at a dose of 5 mg/kd. 59% of patients had a clinical response at week 2. These responders were then randomized to 3 groups. Group 1 received placebo infusions at weeks 2 and 6 and placebo maintenance infusions every 8 weeks. Group 2 received 5mg/kg infusions at weeks 2 and 6 then 5 mg/kg every 8 weeks. Group 3 received 5 mg/kg at weeks 2 and 6 then 10 mg/kg maintenance every 8 weeks. At week 10 there was a 52% clinical response rate among those who received a single induction dose vs 65% for those who received the 3 dose induction regimen (p=0.035). At the 30 week interim analysis the clinical remission rate was 21% in group 1, 39% in group 2 (p=0.003), and 45% in groups 3 (p<0.001 vs group1, p=0.386 vs group 2). Among patients refractory to steroids at entry then followed to week 30 of therapy, 11% were in remission after a single dose of infliximab vs 31% remission in group 2 (p=0.008) and 37% in group 3 (p=0.001).

Safety issues have been raised. Infusion reactions with symptoms of headache, rash, nausea, and/or fever occur in about 20% of patients. Most typically these can be treated by temporarily discontinuing the infusion, treating with acetaminophen and diphenhydramine, and restarting the infusion at a slower rate. Infections, especially respiratory infections, were about twice as common in the infliximab group. The FDA recently released a warning about cases of disseminated tuberculosis following infusions of infliximab and it is now recommended that all patients be screened with a PPD before starting therapy. 2 cases of lymphoma were identified in the early series of Crohn's patients treated with infliximab.(48) However no further reports of lymphoma have emerged after FDA approval and the manufacturer sites data that the incidence of lymphoproliferative disorders or solid tumors is about the expected incidence for the Crohn's disease and rheumatoid arthritis populations on whom it has been tested.

In the 3 years since its release infliximab has become accepted treatment for acute management of refractory disease. Following the release of the ACCENT 1 results, I have taken to using a 3 dose induction regimen for all patients. Infliximab's role as maintenance therapy is still evolving but it is clear that many patients who are sick enough to require initial therapy with infliximab will go on to require maintenance therapy.

Only a few small trials address the efficacy of the use of infliximab for ulcerative colitis and only in the setting of steroid refractory disease. Sands, et al, reported treatment success for 4 of 8 steroid refractory UC patients as opposed to 0 of 3 successes in their placebo group.(49) In an uncontrolled trial, Chey reported clinical remission is 14 of 16 (88%) of steroid refractory UC patients at 4 months and 4 of 16 patients (25%) at 7-10 months.(50)

The humanized antibody to TNF, CDP571, has been investigated and reported in preliminary specifically for steroid dependent Crohn's disease.(51) 71 patients with a CDAI<150 but dependent on 15-40 mg/d of prednisone were randomized to 2 infusions of CDP571 or placebo. Therapy was successful at week 40 in 17 of 39 (43.6%) of patients receiving CDP571 vs 7 of 32 (21.9%) of placebo patients (p=0.049). In a controlled trial of CDP571 for treatment of moderately to severely active Crohn's disease, 45% of CDP571 treated patients achieved a clinical response at 2 weeks compared to 27% for the control group (p=0.023).(52) Etanercept is another tumor necrosis factor antibody which had been anticipated might be helpful for Crohn's disease. However, a recently preliminary report of etanercept for moderate to severe Crohn's disease showed no benefit over placebo during an 8 week course of therapy.(53)

Thalidomide

Thalidomide was originally released as a sedative and antiemetic but withdrawn from the market because of teratogenic effects. Thalidomide has been shown to inhibit tumor necrosis factor (, leading to investigations of its effect in Crohn's disease as well as other inflammatory conditions. Two recent small open-label trials have been performed using thalidomide in Crohn's disease. Both studies enrolled only patients who had been refractory to traditional therapy. Ehrenpreis(54) and Vasiliauskas(55) reported clinical response rates of 100% and 70% respectively but also 36% and 17% patient withdrawal rates. Thalidomide is actually commercially available in the USA, having been approved for the treatment of Hansen's disease but subject to rigorous controls by the FDA. Thalidomide is currently being tested in larger trials and most clinicians will await their results before starting patients on this agent.

Growth Hormone

A single, small randomized controlled trial of growth hormone for moderate to severe Crohn's disease demonstrated a statistically significant decrease in the Crohn's Disease Activity Index in patients treated with growth hormone 5 mg/day SQ for one week then 1.5 mg/day SQ for 4 months.(56) Despite achieving statistical significance by this parameter, the number of patients enrolled was small (37 total). Though growth hormone also is commercially available, like thalidomide larger trials would be needed before routine use of this agent.

Anti-inflammatory Cytokines

Numerous other biologic therapies are in different stages of investigation regarding their effects on the inflammatory cascade in Crohn's disease. Two of these which have had results favorable enough to reach phase III clinical trials are interleukin-10 (IL-10) and interleukin-11 (IL-11).

Interleukin 10, a cytokine with anti-inflammatory and immunoregulatory activities, had been felt in early studies to be a promising new therapy for Crohn's disease. However a recently presented large multicenter trial IL-10 was found to be ineffective for prednisone withdrawal and maintaining remission for steroid dependent Crohn's disease.(57)

IL-11 was found to be effective in reducing inflammation in animal models of colitis. In a placebo controlled trial IL-11 in 148 patients not taking steroids, 15mcg/kg SQ once weekly resulted in a greater percentage of patients achieving remission than placebo (37% vs 16%, p=0.038).(58)

Conclusions

Ongoing research is continuing to provide the clinician with new therapies and new information about old therapies for inflammatory bowel disease. The most notable recent advances have been with immunomodulating agents, particularly infliximab. Budesonide will offer an alternative to traditional prednisone. Clinical trials are ongoing with other promising biologic agents.

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