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Published on 21 September 2007

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The latest developments of medication therapy in Crohn’s disease

teaser

Milan Lukáš
MD PhD

Professor

Dana Ďuricová
MD

IBD Clinical and Research Centre
Clinical Centre ISCARE IVF Lighthouse
First Medical Faculty
Charles University
Prague
Czech Republic

E: milan.lukas@email.cz

Crohn’s disease, a type of inflammatory bowel disease (IBD), is a chronic inflammation of the small and/or large bowel with unknown aetiology and partially solved ­pathogenesis. ­Currently, it is believed that the loss of immunological ­tolerance against microbial antigens and dysregulation of immune response in genetically predisposed subjects are involved in the pathogenesis of both ulcerative ­colitis (UC) and Crohn’s disease (CD). CD is ­characterised as segmental and transmural ­inflammation of the gastrointestinal tract, ­leading towards formation of strictures and fistulas. More than 80% of patients with CD are operated on during their lifetime. Current medication therapy, containing amino‑salicylates, corticosteroids, ­immunosuppressants and antibiotics, is still far from optimum due to limited efficacy and relatively serious side-effects. The most potent anti-inflammatory agents – corticosteroids – which were introduced into IBD therapy during the 1950s, are associated with significant side-effects and limited mucosal healing capabilities.(1) Aminosalicylates represent safe drugs, but efficacy is documented only in large bowel disease with mild to moderate inflammatory activity. Immunosuppressants (thiopurins) are associated with potentially serious side-effects (bone-marrow toxicity), a long latent period of 3–6 months and the need for regular laboratory monitoring.(2) Anti‑microbial drugs are effective only in septic ­complications (abscesses and fistulas) but efficacy on the small bowel is not well proven. Intensive basic and clinical research during the last 15 years has allowed us to introduce new therapeutic options into clinical practice.

Anti-TNFα therapy
The most effective drug treatment in CD is ­currently considered to be anti-TNFα therapy. It has been shown that proinflammatory glycoprotein TNFα (Th-1 cytokine) produced by activated immuno‑competent cells (macrophages, T-lymphocytes and monocytes) is a crucial proinflammatory mediator in IBD.(3) The first generation of anti-TNFα therapy is ­represented by the chimaeric IgG1 anti-TNFα antibody (infliximab), which was introduced into clinical ­practice in the USA in 1998 and in Europe one year later. ­Controlled clinical studies suggest that ­infliximab at a dose of 5 mg/kg intravenously is highly ­effective in patients with luminal and fistulising CD. After an ­induction treatment regimen at zero, two and six weeks, maintenance therapy every eighth week is ­recommended. Clinical response is achieved in 70-90% patients and remission in 40–55% of patients. The higher clinical response and remission are observed in children.(4) Primary unresponsiveness is relatively rare, described in 10–15% of patients, and secondary unresponsiveness (loss of clinical effect during ­infliximab repetitive administration after primary positive response) is detected in 20–25% of patients.(5) ­During the last two years, it has been proven that ­infliximab is also a potent drug in patients with ­ulcerative colitis (UC). At the moment, infliximab is used as a rescue therapy in patients with a severe course of UC not responding to standard corticosteroid therapy. Therefore, infliximab has replaced ciclosporin A, used in the indication as ­salvage therapy in UC patients.(6)

Side-effects of infliximab therapy include allergic reactions and activation of intracellular infections. The allergic reactions involve acute infusion ­reactions, ­occurring during infusion or within two hours of ­infusion (2–5%), and delayed infusion reaction (“serum ­sickness disease”), usually observed 3–12 days after the infusion (3–5%). The risk of intracellular infection activation, including mycobacterial infection, requires rigorous screening prior to introduction of anti-TNFα therapy. The question of possible development of lympho‑proliferative disease (including hepatosplenic ­lymphoma) due to long-term immunosuppressive and anti-TNFα therapy, which was reported last year, has not yet been resolved.(7)

New-generation anti-TNFα therapy
A new generation of anti-TNFα therapy is represented by adalimumab and certolizumab. ­Adalimumab, a fully human IgG1 antibody against TNFα, was tested in many controlled clinical trials in patients with ­moderate to severe active CD. It is considered highly effective in patients with luminal or fistulising CD as well as in patients who failed to respond to infliximab. The therapeutic regimen includes ­induction therapy with adalimumab 80 mg or 160 mg at week 0 and 40 mg or 80 mg at week 2, followed by ­maintenance therapy of 40 mg every other week.(8–10) In patients with loss of response, maintenance therapy should be applied every week. Clinical studies ­focusing on efficacy in UC are ongoing. The advantages of ­adalimumab therapy are the lack of allergic ­reactions and s­ubcutaneous drug application by patients. ­Indirect comparison with infliximab suggests the same ­efficacy regarding clinical response and remission rate.

In ­February 2007 in the USA and in June 2007 in the EU, adalimumab was approved for the treatment of moderate to severe CD in clinical practice.

Certolizumab is a pegylated humanised Fab ­fragment of anti-TNFα antibody which was proved effective in moderate to severe Crohn’s disease at a dose of 400 mg subcutaneously. After an ­induction period of three subcutaneous injections every other week, ­maintenance therapy at 400 mg monthly ­follows.(11) Clinical trials are ongoing and the introduction of certolizumab into ­clinical practice is expected next year.

Anti-adhesive molecules
Another potent drug type in treating CD might be agents which block leukocytes trafficking from the blood pool to tissues. The integrins are ­glycoprotein molecules expressed on leukocyte membranes which enable trafficking of activated inflammatory cells to the intestinal mucosa and associated lymphatic ­tissues. Natalizumab, a humanised monoclonal IgG4 antibody against integrin α4β2, has been shown to be a very efficacious drug in patients with severe CD in four controlled clinical trials.(12,13) Unfortunately, a fatal course of multifocal progressive leucoencephalo‑dystrophy in three patients treated with natalizumab caused a temporary withdrawal of the drug from ­clinical trials.(14) However, subsequent investigations in 3,500 cases treated uisng natalizumab yielded normal ­findings. Natalizumab has already been approved for clinical practice in the indication of sclerosis multiplex, and approval for CD might be expected soon.7 New agents against the α4β7 receptor are ­currently being tested, with the first preliminary results expected within a few months.

Worms
Another future possibility might be Trichuris suis ova therapy, based on its unique capacity to decrease hyperreactive immune response to common microbial antigens in the human bowel. A preliminary open-label study with ova therapy has shown very ­promising results in CD and UC. The results of ­controlled ­clinical trials regarding efficacy and safety are expected. ­Manipulation with innate immune response seems to be a very exciting theory regarding how to solve ­problems with chronic courses in IBD.(15,16)

Manipulation with innate immunity
In the past few years, it has been shown that reduced expression of mucosal antimicrobial ­peptides (defensines and cathelicidines) compromises the host’s mucosal defences and predisposes patients to CD of the ileum and colon.(17) The defensins ­substitution in patients with ileal and large bowel involvement seems to be a very attractive therapeutic approach for the future. Sargramostim-leukine GM-CSF is a growth ­factor which acts on various cell lineages, including macrophages, leukocytes and dendritic cells. Two ­controlled clinical trials have proved sargramostim to be effective in the treatment of moderate active CD. However, further clinical trials are needed.(18)

Autologous haematopoietic stem-cell transplantation
Autologous haematopoietic stem-cell transplantation (HCST) is an extension of immune modulation/­suppression by maximising immune suppression to the point of immune ablation. The transplant ­conditioning ablates aberrant disease-causing immune cells, while haematopoietic stem cells regenerate a new and antigen-naive immune system similar to the normal ontogeny of the immune system during fetal development. The dramatic and sustained improvement in health status was described in 12 CD patients refractory to standard therapy who underwent stem-cell transplantation.(19) The efficacy of transplantation in the most severe cases of CD should be confirmed by the ASTIC study, which has already started in the EU.

Conclusions
The main area of progress in medication therapy in Crohn’s disease is represented by biological ­therapy ­including anti-TNFα antibodies (infliximab and ­adalimumab), currently the most potent anti-­inflammatory drugs. At the moment, infliximab and adalimumab belong to the standard therapy of ­moderate to severe luminal or fistulising Crohn’s ­disease.(20) The advantages of this therapy are prompt onset of anti-inflammatory activity and rapid clinical improvement within a few days of one infusion.(21) Some questions remain unsolved:

  • How should patients who will benefit most from therapy, with the highest degree of efficacy and minimal side-effects, be selected?
  • How long should anti-TNFα antibody treatment be administered for, and when should maintenance therapy be discontinued?
  • Are these biological agents disease-modifying drugs that change the course of the disease, including complications, surgery and mortality rate?
  • How can patients be checked and the potential side-effects of long-term therapy monitored?

This year, the European Crohn’s and Colitis ­Organisation has organised meetings focusing on these unresolved questions and a European ­consensus is expected soon.

However, despite the high efficacy of ­biological ­therapy, it should be emphasised that these ­treatments only symptomatic, with no influence on the still unknown aetiology that leads to chronic and ­uncontrolled ­inflammation in the gastro‑intestinal tract.

References
1. Gut 1990;31:325-8.
2. Gastroenterology 2005;128:1812-8.
3. Gastroenterology 2000;119:1148-57.
4. Gastroenterology 2007;132:863-73.
5. Gastroenterology 2004;126:1593-610.
6. N Engl J Med 2005;353:2462-76.
7. Inflamm Bowel Dis 2007;13:769-96.
8. Gastroenterology 2006;130:323-33.
9. Gut 2007;56:1232-9.
10. Gastroenterology 2005;128: Abstract A-112-A.
11. Gastroenterology 2005;129:807-18.
12. Aliment Pharmacol Ther 2003;17:1435-50.
13. N Engl J Med 2005:353:1912-25.
14. N Engl J Med 2005;353:362-8.
15. Am J Gastroenterol 2003;98:2034-41.
16. Gastroenterology 2005;128:828-32.
17. Gut 2007;53:1240-7.
18. Digestion 2003;68;2-3:63-70.
19. Gastroenterology 2005;128:552-63.
20. Gut 2004;53:1366-73.
21. Gut 2005;54:Abstract A17(OP-G-74).



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