Figure 1. Extracellular molecular targets of TNF antagonists in Crohn’s disease (10).
Infliximab exerts its anti-inflammatory effects by acting on multiple constituents in the cytokine network (Figure 1). It has been reported that infliximab downregulates the production of pro-inflammatory cytokines TNF-α, IL-1β, IL-6 by monocytes and decrease expression of IFN-γ by activated T cells. It has also been shown that infliximab significantly reduces levels of intestinal endothelial expressed CD40 and levels of soluble CD40L resulting in the decreased lymphocyte recruitment. Another therapeutic mechanism of infliximab is its assistance with the repair of epithelial barrier (10).
Infliximab in the treatment of Crohn’s Disease
Infliximab therapy has shown the most promise in CD. Two-thirds of patients with chronic active CD unresponsive to conventional therapy respond to infliximab, as do a similar proportion of patients with fistulas (1). Infliximab has been shown to induce endoscopic and histologic healing in patients with CD (12).
Infliximab, chimeric monoclonal antibody to TNF-α, has been demonstrated to be effective for both induction and maintenance of remission in Crohn's disease at a dosage of 5 mg/kg. This may be increased to 10 mg/kg for patients who lose efficacy with the lower dose due to the formation of antibodies to infliximab (2, 12).
Clinical trials have evaluated the efficacy of infliximab for induction and maintenance therapy of patients with moderate to severe CD. The first multicenter, double-blind, placebo-controlled trial demonstrated that 81% of patients given 5 mg/kg of infliximab had a clinical response at week 4, and 33% of patients treated with infliximab went into remission compared with 4% in the placebo group (12).
In the phase III multicenter clinical trial, ACCENT-I in 573 patients with Crohn’s Disease at week 30, 21% of the patients given placebo were in remission compared with 39% in the 5 mg/kg infliximab only group and 45% in the escalated dose group (10 mg/kg infliximab). Furthermore, patients treated with infliximab had an improved quality of life as measured by the Inflammatory Bowel Disease Questionnaire (12).
There have been two randomised, double blind, placebo-controlled trials demonstrating infliximab efficacy for fistulising Crohn's disease. The first trial examined infliximab induction therapy. In 94 patients with draining abdominal or perianal fistulas given placebo or 5 or 10 mg/kg infliximab IV at weeks 0, 2, and 6, 68% receiving 5 mg/kg achieved at least 50% reduction in the number of draining fistulas and 55% had closure of all of their fistulas. In the second ACCENT-II trial, which evaluated infliximab as maintenance therapy, in 282 patients with fistulising CD, 48% had a complete response to infliximab, defined as the absence of draining fistulas (3, 12).
Infliximab has been used widely in paediatric patients since its initial approval in adults. This TNF-α antagonist has been demonstrated to be effective for both induction and maintenance of remission in children with moderate to severely active inflammatory or fistulising CD (4, 6).
Figure 2. Clinical response and remission rates at week 10 in the REACH and ACCENT I trials (13).
The recent open, multicentric and randomized REACH trial assessed the efficacy of infliximab in 112 paediatric patients suffering from moderate-to-severe CD refractory to conventional therapy. Patients were treated with three induction infusions of infliximab at weeks 0, 2 and 6. At week 10, the clinical response rate was 88.4% and clinical remission was demonstrated in 58.9% of the cases. The proportion of paediatric patients achieving clinical response or remission at week 10 in the REACH trial was higher that those observed in adults in the ACCENT I trial (Figure 2) (13).
Side effects of infliximab are uncommon. Adverse consequences observed in patients treated with infliximab include infusion reactions, activation of latent tuberculosis, delayed hypersensitivity reactions, formation of antibodies to infliximab, formation of anti-double-stranded DNA antibodies and occasional manifestation of lupus-like syndrome (1, 3, 12). The development of antibodies to infliximab appears to be associated with increased risk for infusion reactions and shortened duration of response to the therapy (4, 11).
Adalimumab in the treatment of Crohn’s disease
Adalimumab is a complete human IgG1 anti-TNF-α monoclonal antibody. It is indicated for use in moderate to severe Crohn's disease. Response and remission rates appear similar to those following infliximab. Because adalimumab monoclonal antibody is more fully humanized, allergic reactions may be less common (6, 10).
A 4-week randomised, double blind, placebo-controlled, dose-ranging induction trial (CLASSIC-1: Clinical assessment of Adalimumab Safety and efficacy Studied as Induction therapy in Crohn’s disease) evaluated the efficacy of adalimumab induction therapy in 299 patients with moderate to severe CD naive to anti-TNF therapy. The rates of remission at week 4 in the adalimumab 40mg/20mg, 80mg/40 mg, and 160mg/80mg groups were 18%, 24% and 36 % respectively and 12% in the placebo group (Figure 3). Adalimumab has been demonstrated to be superior to placebo for induction of remission in patients with moderate to severe CD (7).
More recently, CLASSIC II, phase 2, randomised, placebo-controlled, maintenance follow-up trial to CLASSIC I, demonstrated that administration of adalimumab 40 mg every other week or weekly was superior to placebo in maintaining remission (14).
Figure 3. Efficacy of adalimumab as induction therapy in Crohn’s disease in the CLASSIC-I trial (7).
The CHARM (the Crohn’s trial of the fully Human Antibody adalimumab for Remission Maintenance) large, phase 3, randomised, double-blind, placebo-controlled, 56-week trial evaluated the efficacy and safety of adalimumab in the maintenance of response and remission in patients with moderate to severe CD. Patients received induction therapy with adalimumab 80mg (week 0) followed by 40mg (week 2). At week 4, patients were randomised to double-blind treatment with placebo or one of the 2 adalimumab dosing regimens (40 mg every other week or weekly). The percentage of responders in remission was significantly greater in the adalimumab 40-mg every other week and 40-mg weekly groups versus placebo at week 26 (40%, 47%, and 17% respectively) and week 56 (36%, 41%, and 12%, respectively) (Figure 4). The results of this trial showed the efficacy of adalimumab in maintaining clinical remission and response as well as maintaining completely closed fistulas (14).
Figure 4. Clinical remission at weeks 26 and 56 in randomised responder population in the CHARM trial (14).
Conclusion
TNF-α antagonists represent a significant advance in the therapy of Crohn’s disease. The clinical success of TNF-α blocking biologics confirms the importance of TNF-α in driving chronic inflammation and opens a new era in the induction and maintenance of remission in moderate to severe Crohn’s disease. Revolutionising anti-TNF-α treatment has shown remarkable therapeutic benefit especially for those unresponsive to conventional therapeutic modalities. However, TNF-α blockade is a treatment, rather than a cure and further research is needed to get closer to a cure.
Word count: 1472
References:
-
Jewell Derek P. (2007). Crohn's disease. Medicine 35: 283-289.
-
Neuman Manuela G. (2007). Immune dysfunction in inflammatory bowel disease. Translational Research 149: 173-186.
-
Griggs L. and Schwartz D.A.( 2007).Medical options for treating perianal Crohn's disease. Digestive and Liver Disease 39: 979-987.
-
Markowitz J. Current treatment of inflammatory bowel disease in children. (2007). Digestive and Liver Disease 40: 16-21.
-
Williams Richard O., Paleolog Ewa and Feldmann Marc. (2007). Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases. Current Opinion in Pharmacology 7: 412-417.
-
Carvalho Ryan and Hyams Jeffrey S. (2007). Diagnosis and management of inflammatory bowel disease in children. Seminars in Pediatric Surgery 16: 164-171.
-
Hanauer Stephen B., Sandborn William J., Rutgeerts Paul, Fedorak Richard N., Lukas Milan, MacIntosh Donald, Panaccione Remo, Wolf Douglas and Pollack Paul (2006). Human Anti–Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn’s Disease: the CLASSIC-I Trial.
Gastroenterology 130: 323-333.
-
Clark Ian A. (2007). How TNF was recognized as a key mechanism of disease. Cytokine & Growth Factor Reviews 18: 335-343.
-
Tincani A., Andreoli L., Bazzani C., Bosiso D. and Sozzani S. (2007). Inflammatory molecules: A target for treatment of systemic autoimmune diseases. Autoimmunity Reviews 7: 1-7.
-
Wong Maida, Ziring David, Korin Yael, Desai Sheetal, Kim Sungjin, Lin Jan, Gjertson David, Braun Jonathan, Reed Elaine and Singh Ram Raj (2008). TNFα blockade in human diseases: Mechanisms and future directions.
Clinical Immunology 126: 121-136.
-
Valesini G., Iannuccelli C., Marocchi E., Pascoli L., Scalzi V. and Franco M. Di (2007). Biological and clinical effects of anti-TNFα treatment. Autoimmunity Reviews 7: 35-41.
-
Lin Jan, Ziring David, Desai Sheetal, Kim Sungjin, Wong Maida, Korin Yael, Braun Jonathan, Reed Elaine, Gjertson David and Singh Ram Raj (2008). TNFα blockade in human diseases: An overview of efficacy and safety.
Clinical Immunology 126: 13-30.
-
Vilar Pere, Carpi Javier Martín, Acuña Claudia E. and Masiques M Luisa (2007). Infliximab in paediatric inflammatory bowel disease. Journal of Crohn's and Colitis 1: 2-9.
-
Colombel Jean–Frédéric, Sandborn William J., Rutgeerts Paul, Enns Robert, Hanauer Stephen B., Panaccione Remo, Schreiber Stefan, Byczkowski Dan, Li Ju, Kent Jeffrey D. and Pollack Paul F. (2007). Adalimumab for Maintenance of Clinical Response and Remission in Patients with Crohn’s Disease: The CHARM Trial. Gastroenterology 132: 52-65.
