Saudi Journal of Gastroenterology
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Year : 2007  |  Volume : 13  |  Issue : 2  |  Page : 98-100
Adalimumab: A new tumor necrosis factor antagonist and the treatment of Crohn's disease


Gastroenterology Section, Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

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   Abstract 

Antibody-neutralization studies have implicated tumor necrosis factor-α (TNF-α) and IL-12 p40 in the pathogenesis of Crohn's disease (CD). Many randomized controlled trials (RCTs) have demonstrated the efficacy of infliximab, a chimeric monoclonal antibody to TNF, in inducing and maintaining disease remission in patients with moderate to severe CD, including those with draining fistulas. However, infliximab is administered intravenously and is associated with immunological reactions and development of antibodies, and hence reduced efficacy. In this article, we describe the efficacy and safety profiles of a newly available recombinant, fully humanized, subcutaneously-administered, anti-TNF-α monoclonal antibody, adalimumab (Humira) in patients with moderate to severe CD. Many recent RCTs have shown that adalimumab is not only similar to infliximab in the mode of action, efficacy, and safety, but it has the advantages of causing less anaphylactic or immunological reactions, being administered by the subcutaneous route, less need for hospitalization, and a half-life of 2 weeks that allows every other week dosage. Adalimumab has also shown some efficacy in infliximab-intolerant or resistant cases. Therefore, it represents a new horizon in the treatment of CD patients, and may reduce the number of patients who require surgical intervention.

Keywords: Anti-TNFα antibody, fistulizing Crohn′s disease, inflammatory bowel disease

How to cite this article:
Helmy A, Al Kahtani K. Adalimumab: A new tumor necrosis factor antagonist and the treatment of Crohn's disease. Saudi J Gastroenterol 2007;13:98-100

How to cite this URL:
Helmy A, Al Kahtani K. Adalimumab: A new tumor necrosis factor antagonist and the treatment of Crohn's disease. Saudi J Gastroenterol [serial online] 2007 [cited 2020 Oct 29];13:98-100. Available from: https://www.saudijgastro.com/text.asp?2007/13/2/98/32187


Both Crohn's disease (CD) and ulcerative colitis patients have activated innate (macrophage, neutrophil) and acquired (T and B cell) immune responses and show loss of tolerance to enteric commensal bacteria. [1],[2] In normal hosts, tolerance is mediated by regulatory T cells, B lymphocytes, natural killer T cells and dendritic cells that secrete TGF-β and IL-10, IFN-α/β and prostaglandin J2. Antibody-neutralization studies have implicated TNF and IL-12 p40 in the pathogenesis of CD while the effectiveness of T-cell-ablative therapies [3] and the immunosuppresants, cyclosporin and tacrolimus [4] have linked T cells to ulcerative colitis.


   Tumor necrosis factor Antagonism in Crohn's disease Top


Many clinical trials have demonstrated the efficacy of infliximab, a chimeric monoclonal antibody directed against TNF, for induction and maintenance therapy of patients with moderate to severe CD including those with draining fistulas. [5],[6],[7],[8] However, intravenous infusions of infliximab, especially when given episodically, may result in the development of antibodies to infliximab, which in turn may lead to allergic infusion reactions, loss of efficacy and delayed hypersensitivity reactions. [9],[10],[11],[12]


   Why a new TNF-α antagonist? Top


Adalimumab (Humira; Abbott Laboratories, Abbott Park, IL) is a new recombinant, fully humanized, subcutaneously administered, IgG1 monoclonal antibody. It binds with high affinity and specificity to human TNF-α, but not lymphotoxin (TNF-β ) and modulates biologic responses induced or regulated by TNF-α. Controlled trials have demonstrated the efficacy of adalimumab in the treatment of patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis as well as in cutaneous psoriasis lesions. [13],[14],[15],[16]


   Evidence of efficacy in Crohn's disease Top


A phase 3, four week, placebo-controlled induction trial (CLASSIC I) was conducted in 299 patients with moderate to severe CD who were naive to TNF-antagonist therapy. This trial demonstrated that a subcutaneous dosing regimen of adalimumab administered as two loading doses of 160 mg in week 0 and 80 mg in week 2, was significantly more effective than placebo in inducing remission (36% vs 12%, P =0.001). [17] Subsequently, CLASSIC II, a small, phase 2, randomized, placebo-controlled, maintenance follow-up trial to CLASSIC I was conducted in 55 patients with moderate to severe CD naive to TNF-antagonist therapy who had experienced remission with adalimumab induction therapy. CLASSIC II demonstrated that subcutaneous doses of 40 mg adalimumab given weekly or every other week were superior to placebo in maintaining remission over a 56 week period. [18]



More recently, the CHARM trial, [19] a large, phase 3, randomized, double-blind, placebo-controlled, 56 week study was published. It was conducted in patients with moderate to severe CD who may or may not have previously received TNF-antagonist therapy. The CHARM trial assessed the benefits of two adalimumab dosing regimens in maintaining clinical remission at 26 and 56 weeks in 854 patients from 92 centres who had a response to two adalimumab injections of 80 mg each (or two 40 mg injections = 80 mg) in week 0 and 40 mg in week 2. Efficacy results from the CHARM trial proved that adalimumab is as effective as the intravenously administered chimeric IgG1 monoclonal antibody, infliximab. Efficacy was assessed in terms of remission, normalization of CRP, CDAI-100 point and 70 point responses, mean changes in IBDQ total scores which reflected significantly lower disease activity and improved quality of life in patients receiving adalimumab versus those receiving placebo. In addition, adalimumab demonstrated statistically significant and clinically meaningful effects on fistula closure, such as has been previously demonstrated for infliximab. Also comparable to previous reports with infliximab, clinical remission with adalimumab was maintained after the discontinuation of corticosteroids. [3] Reported uniquely in CHARM, however, is the ability to sustain corticosteroid-free remission for > 90 days. [19]

Adalimumab has also been evaluated in patients who are intolerant of or who have failed to respond to infliximab in a number of small studies. [20],[21],[22],[23],[24] These studies suggest that these patients may benefit from switching to adalimumab. These results were subsequently confirmed in the CHARM trial although patients naive to TNF antagonists achieved slightly better results than those who had received TNF antagonists in the past. Indeed, the efficacy of adalimumab in patients selected for intolerance and / or loss of efficacy due to infliximab failure has been confirmed in a recently published small, randomised, controlled trial. [25]


   Safety issues of Adalimumab Top


According to the CHARM trial, adverse events occur at similar frequencies in the adalimumab and placebo groups. A smaller percentage of patients in the adalimumab groups discontinued treatment because of adverse events compared to the placebo group (6.9% and 4.7% for 40 mg every other week and 40 mg weekly groups respectively, vs 13.4% in the placebo group). Serious infectious adverse events were infrequent, occurring in 2.7% of patients in each of the adalimumab groups, compared with 3.4% of patients in the placebo group. Overall, the safety profile exhibited by adalimumab in the CHARM trial is consistent with previous experience with adalimumab from more than 150,000 patients for the treatment of CD, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis. [14],[17],[18],[26],[27]

The occurrence of anti-adalimumab antibodies was evaluated among patients with CD in the CLASSIC-II maintenance study. During the 52-week study, two of 54 patients (3.7%); one in the placebo group and one in the adalimumab-every-other-week group in the randomized arm and six of 215 patients (2.8%) in the open-label arm of the study were positive for anti-adalimumab antibodies. [18],(28)


   Conclusion Top


Adalimumab is a new horizon in the treatment of patients with moderate to severe CD, similar to infliximab in the mode of action, efficacy, and safety, but it has the advantages of causing less anaphylactic or immunological reactions. Being administered by the subcutaneous route, there is less need for hospitalization and a half-life of 2 weeks that allows every other week dosage for CD patients receiving adalimumab. While the cost of therapy is relatively higher, this needs to be balanced against the clinical and quality-of-life benefits and the costs of surgery that may be needed in these advanced cases.

 
   References Top

1.Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al . A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor a for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 1997;337:1029-35.  Back to cited text no. 1    
2.Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, et al . Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med 2004;351:2069-79.  Back to cited text no. 2    
3.Sawada K, Kusugami K, Suzuki Y, Bamba T, Munakata A, Hibi T, et al . Leukocytapheresis in ulcerative colitis: Results of a multicenter double-blind prospective case-control study with sham apheresis as placebo treatment. Am J Gastroenterol 2005;100:1362-9.  Back to cited text no. 3    
4.Minami M, Ohta M, Ohkura T, Ando T, Ohmiya N, Niwa Y, et al . Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841-5.  Back to cited text no. 4    
5.Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al . Maintenance infliximab for Crohn's disease: The ACCENT I randomized trial. Lancet 2002;359:1541-9.  Back to cited text no. 5    
6.Present HD, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al . Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999;340:1398-405.  Back to cited text no. 6    
7.Rutgeerts P, D'Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, et al . Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999;117:761-9.   Back to cited text no. 7    
8.Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al . Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004;350:876-85.  Back to cited text no. 8    
9.Baert F, Noman M, Vermeire S, Van Assche G, D'Haens G, Carbonez A, et al . Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003;348:601-8.   Back to cited text no. 9    
10.Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, et al . The incidence and management of infusion reactions to infliximab: A large center experience. Am J Gastroenterol 2003;98:1315-24.  Back to cited text no. 10    
11.Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: A randomized controlled trial. Gastroenterology 2003;124:917-24.  Back to cited text no. 11    
12.Hanauer SB, Wagner CL, Bala M, Mayer L, Travers S, Diamond RH, et al . Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol 2004;2:542-53.   Back to cited text no. 12    
13.Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, et al . Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003;30:2563-71.  Back to cited text no. 13    
14.Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH. eAdalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:3279-89.  Back to cited text no. 14    
15.Haibel H, Rudwaleit M, Brandt HC, Grozdanovic Z, Listing J, Kupper H, et al . Adalimumab reduces spinal symptoms in active ankylosing spondylitis. Arthritis Rheum 2006;54:678-81.   Back to cited text no. 15    
16.Gordon KB, Bonish BK, Patel T, Leonardi CL, Nickoloff BJ. The tumour necrosis factor-alpha inhibitor adalimumab rapidly reverses the decrease in epidermal Langerhans cell density in psoriatic plaques. Br J Dermatol 2005;153:945-53.  Back to cited text no. 16    
17.Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al . Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: The CLASSIC-I trial. Gastroenterology 2006;130:323-33.  Back to cited text no. 17    
18.Sandborn WJ, Hanauer S, Enns R, Lukas M, Wolf D, Isaacs K, et al . Maintenance of remission over 1 year in patients with active Crohn's disease treated with adalimumab: Results of CLASSIC II, a blinded, placebo-controlled study (oral presentation OP-G-353). Gut 2005;54:A81-2.  Back to cited text no. 18    
19.Colombel J, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al . Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: The CHARM trial. Gastroenterology 2007;132:52-65.  Back to cited text no. 19    
20.Barthel HR, Gille T, Halbsguth A, Kramer M. Successful treatment with adalimumab in infliximab-resistant Crohn's disease. J Gastroenterol Hepatol 2005;20:1464-5.  Back to cited text no. 20    
21.Papadakis KA, Shaye OA, Vasiliauskas EA, Ippoliti A, Dubinsky MC, Birt J, et al . Safety and efficacy of adalimumab (D2E7) in Crohn's disease patients with an attenuated response to infliximab. Am J Gastroenterol 2005;100:75-9.  Back to cited text no. 21    
22.Stallmach A, Giese T, Schmidt C, Meuer SC, Zeuzem SS. Severe anaphylactic reaction to infliximab: Successful treatment with adalimumab-report of a case. Eur J Gastroenterol Hepatol 2004;16:627-30.  Back to cited text no. 22    
23.Stallmach A, Giese T, Schmidt C, Meuer SC, Zeuzem SS. Severe anaphylactic reaction to infliximab: Successful treatment with adalimumab - report of a case. Eur J Gastroenterol Hepatol 2004;16:1984-9.  Back to cited text no. 23    
24.Hinojosa J, Gomollo NF, Garcia S, Bastida GJ, Cabriada, Saro CD, et al . Efficacy and safety of short-term adalimumab treatment in patients with active Crohn's disease who lost response or showed intolerance to infliximab: A prospective, open-label, multicentre trial. Aliment Pharmacol Ther 2007;25:409-18.  Back to cited text no. 24    
25.Burmester G, Pangan A, Kent JD, Lovell DJ, Gordon KB, Dijkmans BA, et al . Adalimumab is safe in global clinical trials in multiple indications and reduced mortality in rheumatoid arthritis. Ann Rheum Dis 2006;65: 181-2.  Back to cited text no. 25    
26.Schiff MH, Burmester GR, Kent JM, Pangan AL, Kupper H, Fitzpatrick SB, et al . Safety analysis of adalimumab (HUMIRA) in global clinical trials and US post-marketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:889-94.  Back to cited text no. 26    
27.Sandborn WJ, Hanauer S, Lukas M, Wolf D, Isaacs K, MacIntosh D, et al . Clinical remission and response in patients with Crohn's Disease treated with open label for 1 year with fully human anti-TNF-a monoclonal antibody adalimumab (oral presentation OP-G-78). Gut 2005;54:A18.  Back to cited text no. 27    

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Correspondence Address:
Ahmed Helmy
Gastroenterology Section, Department of Medicine, King Faisal Specialist Hospital and Research Centre (KFSH & RC), MBC: 46, P.O. Box: 3354, Riyadh 11211
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-3767.32187

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