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Treatment of Crohn’s disease and ulcerative colitis


Safe, effective treatment options exist for patients with mild-to-moderate Crohn’s disease or ulcerative colitis. However, a significant proportion of patients with moderate-to-severe Crohn’s disease or ulcerative colitis lack effective medical treatment.
In addition, although effective in a significant proportion of patients with Crohn’s disease and ulcerative colitis, immune suppressant and biologic therapy ( or the combination of an immune suppressant and a TNF-alpha inhibitor ) are associated with uncommon, but serious, side effects.

Although patients with mild-to-moderate ulcerative colitis respond well to 5-ASA ( 5-Aminosalicylic acid, also called Mesalamine ), the efficacy of these drugs is limited in patients with severe disease.
5-ASAs have also been used for the treatment of mild-to-moderate Crohn’s disease, although they are less efficacious in this group of patients, particularly in those with small bowel disease.
The remission rate for ulcerative colitis patients treated with 5-ASAs is approximately 50% and, as a result, an escalation in therapy to corticosteroids, immune suppressants or biologic agents is often required.

Corticosteroids are effective for inducing remission, but cannot be used for maintenance due to their significant side-effect profile. Patients that do not respond to 5-ASAs may be maintained on immune suppressants such as 6-Mercaptopurine or Azathioprine ( Imuran ), although these medications are associated with potentially serious side effects including a fourfold increased risk of lymphoma in patients treated with either of these agents.
The clinical utility of these drugs is further limited by their slow onset of action, making them inappropriate for induction therapy.

Other agents that have been used to treat patients with refractory disease include Cyclosporine ( Sandimmune ) and Methotrexate ( MTX ).
Cyclosporine may be used as a short-term induction agent for ulcerative colitis as a bridge to immune suppressant therapy; however, its use is also complicated by its side effect profile. Major adverse events including renal failure, serious infectious complications ( bacterial pneumonia, Pneumocystis jiroveci pneumonia and venous catheter infections ), anaphylaxis and death were reported in 15% of patients included in a retrospective study of 111 IBD patients treated with Cyclosporine. Minor effects, such as paresthesias, hypertension, headache and transient liver function test abnormalities, occurred in 20-50% of patients.
Methotrexate can be used to achieve clinical response in both Crohn’s disease and ulcerative colitis and is often better tolerated than Cyclosporine. A systematic review conducted by the Cochrane Library found data to support the use of intramuscular Methotrexate ( 25 mg/week ) for the induction of remission in patients with Crohn’s disease. In a retrospective study of 131 patients who failed or were intolerant to Azathioprine / 6-Mercaptopurine, Methotrexate has achieved a clinical response rate, defined as steroid withdrawal, normalization of C-reactive protein, or physician’s clinical assessment of improvement, greater than 60% in both Crohn’s disease and ulcerative colitis. In the same study, side effects were observed in 17% of patients and included abnormal liver function tests, dyspnea, nausea and vomiting, and neutropenia. Two multicenter randomized trials are currently underway to determine the efficacy of parenteral Methotrexate in patients with ulcerative colitis.

The development of monoclonal antibodies against TNF-alpha has provided physicians with an additional class of drugs for treating patients with Crohn’s disease or ulcerative colitis. Unfortunately, these agents are expensive, may require administration in a monitored setting, and are associated with a number of potentially serious side effects including serious infection, opportunistic infection, lupus-like reactions, psoriaform eruptions and lymphoma.
Infliximab, the first TNF-alpha inhibitor approved for use in inflammatory bowel disease, is capable of inducing and maintaining remission in both ulcerative colitis and Crohn’s disease. In patients with moderate-to-severe Crohn’s disease who were treated with Infliximab, 81% had a clinical response at week 4 compared with 17% who had been treated with placebo. In a follow-up study, patients with active Crohn’s disease who continued maintenance Infliximab therapy after responding to a single open-label infusion of Infliximab were more likely to maintain clinical remission at week 30 than those receiving placebo ( odds ratio, OR=2.7; 95% CI: 1.6–4.6 ). In moderately-to-severely active ulcerative colitis, Infliximab has induced clinical response in 61–69% of patients at week 8 compared with 37% of those treated with placebo ( p less than 0.001 for both doses tested vs placebo ).
Other TNF-alpha inhibitors include Adalimumab ( Humira ) and Certolizumab pegol ( Cimzia ), both of which are indicated in the USA for the treatment of patients with moderately-to-severely active Crohn’s disease who do not respond to conventional therapy.
Adalimumab is also indicated for the treatment of moderately-to-severely active Crohn’ disease in Europe; however, Certolizumab pegol is not.
TNF-alpha inhibitors work well in a significant proportion of patients; however, the remission rate for induction in patients with Crohn’s disease is less than 35% at week 4 and is less than 50% for maintenance therapy ( assessed at 20-30 weeks ).
ACCENT I followed patients with Crohn’s disease for 54 weeks and demonstrated that Infliximab maintained clinical remission at week 54 in approximately 30-40% of patients who responded to Infliximab induction by week 2 compared with approximately 15% in those who received placebo after induction ( p less than 0.01 for both doses tested vs placebo ).
The Crohn’s trial of the fully Human antibody Adalimumab for Remission Maintenance ( CHARM ) trial has demonstrated clinical remission in approximately 50% of patients with moderate-to-severe Crohn’s disease who were maintained with Adalimumab after receiving induction therapy compared with approximately 35% of those who received placebo after Adalimumab induction ( p less than 0.05 for both weekly and every other week dosing vs placebo ).
Certolizumab pegol was shown to maintain clinical remission at week 26 in 29% of patients with moderate-to-severe Crohn’s disease versus 18% of those treated with placebo after open-label induction therapy and has also been shown to result in improvements in work productivity and health-related quality of life in patients with active Crohn’s disease who lost response to or could not tolerate Infliximab.

Although a variety of medical therapies are available to treat patients with inflammatory bowel disease, limitations to current treatment modalities do exist.
In addition to the safety concerns described above, certain patients, termed primary nonresponders, do not respond to treatment with TNF-alpha inhibitors.
An additional subset of patients, secondary non-responders, lose their ability to respond over time. It is thought that the development of endogenous antibodies to these drugs, accelerated drug clearance, ongoing fibrosis or aberrant immune pathways is responsible for this effect. Other factors complicating treatment with biologic agents include infusion reactions, occurring in 9-17% of patients receiving Infliximab, and injection site reactions, occurring in less than 5% of patients receiving Certolizumab pegol and approximately 10% of those receiving Adalimumab.

Even though a variety of medications exist for treating Crohn’s disease and ulcerative colitis, many patients will still require surgery despite utilization of maximal medical therapy.
Colectomy is thought to be curative in patients with ulcerative colitis; however, when performed in combination with an ileal pouch anal anastomosis, the procedure is not without complications.
Surgery for patients with Crohn’s disease is not curative and these patients often require additional intestinal resections for recurrent disease. Approximately 29% of Crohn’s disease patients in North America undergo surgery within 5 years of diagnosis, although these rates have dropped somewhat in recent years. Approximately 33% of Crohn’s disease patients who undergo one surgery will require at least one additional surgery during their lifetime. ( Xagena )

McLean LP et al, Immunotherapy 2012; 4: 883–898

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