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SAGES CLINICAL GUIDELINES Anti Tumour Necrosis Factor Antibodies (Anti-TNF) in Inflammatory Bowel Disease

Crohn’s Disease

The FDA approved Infliximab, the first anti-TNF, for the treatment of Crohn’s disease in October 1998. Initial studies showed an 81% response rate 4 weeks after an infusion of Infliximab 5 mg/kg body weight compared to a 17% response rate to placebo (p<0.001). furthermore, 33% of the treatment group went into remission as compared to 4% of the placebo group (p <0.005). ¹

In the ACCENT 1 Study, 58% of 573 patients had a clinical response after 2 weeks.² After 54 weeks, the clinical response was maintained in only 17% of those who received a single infusion as opposed to 43% of those who were maintained on 8 weekly infusions. It thus appears that, although some patients will achieve a remission after a single infusion, many will require maintenance therapy.

In patients with fistulizing Crohn's disease, Infliximab 5 mg/kg body weight at weeks 0, 2 and 6 resulted in closure of the fistulae in 55% as compared to only 13% in the placebo group.³ As with luminal disease, efficacy is however relatively short lived and regular maintenance therapy is recommended. The ACCENT 2 study of 282 patients with Crohn’s fistulae showed that, after 54 weeks, 39 % of those receiving Infliximab every 8 weeks had a complete absence of draining fistulae as opposed to only 19% in the placebo arm.⁴

The response rate to Infliximab appears to be better in children than in adults. In a study similar to the ACCENT 1 Study, 88% of children receiving Infliximab achieved a remission at 10 weeks as opposed to 59% of those who received placebo. At 54 weeks, 60% of children who received 8 weekly infusions were in remission as apposed to about 30% of those on 12 weekly infusions.⁵

Since these initial studies, other anti-TNF agents have been marketed. Adalimumab has recently been shown to yield results similar to Infliximab.^6,7,8

Recent studies have also shown that the traditional approach of treating attacks of Crohn’s disease with Prednisone, followed by immunomodulators and finally with anti-TNF may not be optimal. Early studies suggest that initial treatment with immunosuppressive agents and anti-TNF may produce 1 year clinical and pathological response rates that are better than those achieved with the more traditional approach.^9,10,11

Anti-TNF agents should be used for at least a year in patients who respond. A short course without maintenance treatment is likely to induce resistance to the agent and is not recommended.

Ulcerative Colitis

Making a distinction between ulcerative colitis and Crohn’s disease is important for the following reasons

1. Total colectomy and the creation of an ileal pouch and anal anastomosis (IPAA) will, in theory, cure ulcerative colitis.
   
   
2. Immunomodulators are generally more effective in patients with Crohn’s disease than in those with ulcerative colitis and selecting the optimal form of therapy remains problematic.
   
   

In the first randomized, double-blind, placebo-controlled trial, 364 patients with moderate-to-severe active ulcerative colitis despite conventional treatment (oral corticosteroids ± azathioprine or 6- mercaptopurine) were randomized to receive either Infliximab or placebo at weeks 0, 2, and 6 and every 8 weeks thereafter. After 8 weeks 69% of patients receiving Infliximab had responded compared to 37% of those receiving placebo (p<0.001). after 54 weeks 45% of patients receiving infliximab had responded compared to 20% of those receiving placebo. ¹²

General recommendations for the use of Anti-TNF

In patients with resistant acute disease, anti-TNFs are preferable to repeated courses of corticosteroids.

Corticosteroids significantly increase the risk of serious infection and the concomitant use of a corticosteroid and anti- TNF should, where possible, be avoided.

Treatment with an immunomodulator such as Azathioprine,

6-mercaptopurine or Methotrexate prior to the introduction of an anti-TNF may improve the efficacy of the anti-TNF and prevent the development of antibodies to the anti-TNF. Lower inflammatory markers in patients receiving both an immunomodulator and an anti-TNF may indicate better disease control. Preventing the development of antibodies to the anti-TNF may reduce the likelihood of resistance to the anti-TNF. It may be possible to treat some patients with anti-TNF alone but, in general, dual therapy is recommended.

Anti-TNFs are generally remarkably free of side effects but, when they do occur, they can be severe or even fatal. The risk of promoting tuberculosis and other serious infections as well as malignancy is ever present and these patients need to be monitored carefully. The prognosis of individuals who develop a serious infection or malignancy is poor and this is especially so in those who also have HIV/AIDS. A risk-benefit analysis should always be done before starting treatment with an anti-TNF and it is particularly important in those in whom maintenance therapy is being considered.

Anti-TNF in Crohn’s Disease

Anti-TNFs are the drugs of choice in patients with fistulizing Crohn’s disease and should always be considered prior to any surgical intervention. A real danger however is the flaring of a current or latent associated abscess. Imaging may be needed to exclude an infective collection and prophylactic antibiotics or a draining seton may be appropriate.

In patients with ileal disease and an inflammatory mass, anti- TNFs may result in flaring of an infective process. Anti-TNFs may therefore be relatively contraindicated in this setting.

Anti-TNF in Ulcerative Colitis

At present, anti-TNFs should be viewed as second line therapy in ulcerative colitis.

Patients with moderate to severe disease who do not respond adequately to conventional therapy may benefit from anti-TNF therapy.

Urgent salvage therapy with an anti-TNF is an alternative to Cyclosporine in patients with severe ulcerative colitis in whom surgery is being considered.

Patients with Crohn’s disease generally do better with anti- TNF therapy than with resection + IPAA and it is therefore important to exclude “occult” Crohn’s disease. A careful examination of the small bowel should always precede surgery and, in this setting, capsule endoscopy is the most accurate imaging modality.

Guidelines for the use of anti-TNFs

1. The patient should be managed by a registered gastroenterologist.
   
   
2. The diagnosis of inflammatory bowel disease must be confirmed with raised acute phase reactants, appropriate imaging studies and histology. The exact combination depends on the disease type and location.
   
   
3. Most patients should receive an immunomodulator (Azathioprine, 6-mercaptopurine or Methotrexate) and this should be continued during treatment with anti-TNFs.
   
   
4. Patients with luminal Crohn’s disease should have a CDAI score of >240 and patients with ulcerative colitis a Mayo Score of > 6.
   
   
5. Patients who respond to an initial induction phase should continue to receive the anti-TNF according to a scheduled maintenance regimen.
   
   
6. The duration of maintenance therapy has not yet been established but it is suggested that patients who go into remission continue to receive therapy until the pathologic process has resolved. This usually takes 6 to 12 months and is indicated by normal acute phase reactants and a normal- appearing mucosa. Once this has been achieved, continuation of therapy should be reviewed annually.
   
   
7. Contraindications to the use of anti-TNFs are to be found in the package inserts. Special consideration needs to be given to:
   
   
   1. Patients with active sepsis, congestive cardiac failure and a history of malignancy.
      
      
   2. Tuberculosis has a high mortality in patients receiving anti-TNFs and all individuals in whom such treatment is being considered should have a chest X-ray and a Mantoux test.
      
      
   3. Hepatitis B virus infection may flare up in patients receiving an anti-TNF.
      
      
8. Pregnancy. Both Infliximab and Adalimumab are FDA Category B drugs (Animal studies show no risk or adverse foetal effects but controlled human 1st trimester studies not available/do not confirm; no evidence of 2nd or 3rd trimester risk; foetal harm possible but unlikely).
   
   

REFERENCES

1. A short term study of chimeric monoclonal antibody cA2 to tumour necrosis factor alpha for Crohn’s disease. Targan SR, Hanauer SB; van Deventer SJ et al New Eng J Med 1997;337:1029
2. Maintenance Infliximab for Crohn’s Disease; The ACCENT ! randomized trial. Hanauer S, Feagan BG; Lichtenstein GR al. Lancet 2002; 359:15t41
3. Infliximab for the treatment of fistulas in patients with Crohn’s disease. Present D, Rutgeerts P; Targan S et al. New Eng J Med 1999;340:1398.
4. Infliximab maintenance therapy for fistulizing Crohn's disease. Sands BE; Anderson FH; Bernstein CN et al N Engl J Med 2004:350;876.
5. Induction and Maintenance Infliximab Therapy for the Treatment of Moderate-to-Severe Crohn's Disease in Children. Hyams J; Crandall W; Kugathasan S et al. Gastroenterology. 2007;132:863.
6. Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn's Disease: the CLASSIC-I Trial. Hanauer SB; Sandborn WJ; Rutgeerts P et al Gastroenterology. 2006;130:323.
7. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. AU - Colombel JF; Sandborn WJ; Rutgeerts P et al Gastroenterology. 2007;132:52.
8. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Sandborn WJ; Hanauer SB; Rutgeerts P; Gut. 2007;56:1232.
9. Combination Therapy With Infliximab and Immunomodulators: Is the Glass Half Empty? Amar R. Deshpande, Maria T. Abreu Gastroenterology June 2008;134:2161
10. Management of recent onset Crohn’s Disease: A controlled Randomised trial comparing step up and top down therapy. D Hommes, F Baert, G van Assche, Gastroenterology 2005; 129:371
11. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomized trial. D’Haens G, Beart F, van Assche G Lancet 2008:371:660
12. Infliximab for induction and maintenance therapy for ulcerative colitis. Rutgeerts P; Sandborn WJ; Feagan BG et al N Engl J Med. 2005;353:2462.

The South African Gastroenterology Review • November 2007

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