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Infliximab (Remicade®) is a chimeric monoclonal antibody against tumour necrosis factor (TNF)-α that has shown efficacy in Crohn’s disease and rheumatoid arthritis with a disease-modifying activity and rapid onset of action. It is administered intravenously, generally in a schedule with initial infusions at 0, 2 and 6 weeks, followed by administration once every 8 weeks.
Infliximab is effective in the treatment of patients with moderately to severely active Crohn’s disease with an inadequate response to other treatment options or those with fistulising disease. In combination with methotrexate, infliximab reduced signs and symptoms and delayed disease progression in patients with active, methotrexate-refractory rheumatoid arthritis and in those with early disease. The drug was generally well tolerated. Recrudescence of tuberculosis infection and worsening of heart failure and demyelinating disease are among some of the concerns with anti-TNFα therapy, requiring cautious use of these agents in high-risk patients.
Current data suggest that infliximab may be cost effective, especially when long-term clinical outcomes and burden of the diseases are taken into account. More robust, prospective pharmacoeconomic studies are required to better ascertain the cost effectiveness of infliximab.
Direct head-to-head comparative trials of infliximab with other biological agents are not yet available and would be helpful in determining with greater certainty the place of infliximab in the management of these diseases. Nonetheless, infliximab, like other biological agents, is a valuable treatment option in patients with moderately to severely active Crohn’s disease (including fistulising disease) or rheumatoid arthritis (including early disease).
Infliximab acts by binding to both the soluble and the transmembrane forms of TNFα and antagonising the proinflammatory actions of TNFα. It also downregulates other proinflammatory cytokines in patients with Crohn’s disease or rheumatoid arthritis. In addition, in in vitro studies, infliximab decreased the migration of inflammatory cells to the site of inflammation by reducing levels of chemokines and endothelial adhesion molecules. Importantly, infliximab does not produce a generalised suppression of cellular immune function.
The pharmacokinetics of infliximab are linear within the therapeutic dosage range. The steady-state volume of distribution, clearance, mean residence time and elimination half-life are all dose independent in patients with rheumatoid arthritis or Crohn’s disease. Infliximab has a long elimination half-life (median 8–12 days) and is still detectable in plasma up to 12 weeks after the last dose. However, repeated treatment does not lead to any clinically relevant systemic accumulation. Concomitant administration of methotrexate in patients with rheumatoid arthritis may sustain serum infliximab concentrations for longer. The pharmacokinetic profile in paediatric patients with Crohn’s disease was similar to that in adult patients.
The usual treatment regimen for infliximab in clinical trials involved intravenous administration as a single infusion, followed by subsequent doses 2 and 6 weeks later and then every 8 weeks (or every 4 weeks in one trial) thereafter. Although a broad range of infliximab doses (1–20 mg/kg) was used in these trials, no dose-response relationship was evident and, generally, no significant added benefit was reported when using doses higher than 5 mg/kg in Crohn’s disease and 3 mg/kg in rheumatoid arthritis patients, which are the currently recommended dosages. However, some patients may benefit from increasing the dose up to 10 mg/kg; increasing the frequency of administration to once every 4 weeks may be useful in some rheumatoid arthritis patients. Infliximab treatment induced a rapid onset of clinical response both in Crohn’s disease (within 2 weeks) and rheumatoid arthritis (48 hours) patients.
In randomised, double-blind trials, single infusions of infliximab (dose range 5–20 mg/kg) were effective in the induction of response in patients with moderately to severely active Crohn’s disease. In addition, repeated treatment with infliximab 5 or 10 mg/kg during longer-term therapy (54 weeks) sustained the clinical remission achieved with single infusions. Clinical response was accompanied by endoscopic evidence of mucosal healing. Infliximab treatment was also associated with significant improvements in the health-related quality of life (HR-QOL) of patients. Similarly, in patients with fistulising disease, repeated treatment (54 weeks) with infliximab 5 mg/kg was effective in maintaining remission in patients who had responded to an initial infusion. Sustained closure and healing of fistulas was seen in these patients.
Limited data available from double-blind and noncomparative trials in paediatric patients with Crohn’s disease with or without fistulas indicate that single infusions of infliximab were effective in reducing disease activity and that repeated treatment may be effective in producing a clinical response or inducing and maintaining remission.
In a randomised, double-blind (54-week, followed by 54-week unblinded extension) trial in patients with active, methotrexate-refractory rheumatoid arthritis, infliximab (3 or 10 mg/kg) plus methotrexate was superior to methotrexate plus placebo in producing clinical response and attenuating radiographic progression of the disease. There was also a significant improvement in functional status and HR-QOL. Infliximab 3 or 6 mg/kg for 54 weeks, in combination with methotrexate, was also significantly more effective than methotrexate plus placebo in 1004 patients with early (≤3 year), methotrexate-naive rheumatoid arthritis with respect to improvements in signs and symptoms, disease progression, physical function and HR-QOL. The results of two smaller, double-blind, placebo-controlled studies using more sensitive imaging techniques (e.g. magnetic resonance imaging) have supported the notion that treatment with infliximab retarded disease progression in patients with early rheumatoid arthritis.
Infliximab was generally well tolerated for up to 102 weeks in clinical trials in patients with Crohn’s disease or rheumatoid arthritis, with the incidence of serious adverse events being generally similar in infliximab and placebo recipients. Infusion-related reactions are the most frequent adverse reactions to infliximab therapy. Although there appears to be no need for regular laboratory monitoring of infliximab therapy, patient monitoring, cautious use and/or discontinuation are recommended for other potentially serious adverse events possibly associated with TNFα antagonists as a class. These include tuberculosis and other serious infections, malignancy (particularly lymphoma), heart failure and CNS demyelination disorders.
Infliximab, like other biological agents, is a costly drug and generally more expensive than other available therapies for Crohn’ s disease. However, preliminary data have shown that it may be cost saving as a single-infusion induction regimen and cost effective as maintenance treatment of moderately to severely active Crohn’s disease. Moreover, pharmacoeconomic analyses have demonstrated that the incremental cost of infliximab maintenance therapy might be substantially offset by a reduction in other costs, such as those related to hospitalisation or surgery. In modelled cost-utility analyses, infliximab plus methotrexate was generally associated with acceptable incremental cost-effectiveness ratios relative to methotrexate monotherapy in patients with refractory rheumatoid arthritis. The cost effectiveness of infliximab in early disease has not been evaluated, but is expected to be improved when reductions with early treatment in the costs associated with the long-term disease outcomes are considered. Nevertheless, more robust pharmacoeconomic studies are needed before any conclusion may be drawn regarding the relative cost effectiveness of infliximab.
- 1.Head K, Jurenka JS. Inflammatory bowel disease. Part II: Crohn’s disease-pathophysiology and conventional and alternative treatment options. Altern Med Rev 2004; 9(4): 360–401Google Scholar
- 9.Centocor Inc. Product information (US): Remicade for IV injection (infliximab 100mg vial) [online]. Available from URL: http://www.remicade.com [Accessed 2005 May 10]Google Scholar
- 16.Ohshima S, Saeki Y, Mima T, et al. Long-term follow-up of the changes in circulating cytokines, soluble cytokine receptors, and white blood cell subset counts in patients with rheumatoid arthritis (RA) after monoclonal anti-TNF alpha antibody therapy. J Clin Immunol 1999 Sep; 19(5): 305–13PubMedCrossRefGoogle Scholar
- 18.Cope AP, Londei M, Chu NR, et al. Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis. J Clin Invest 1994 Aug; 94: 749–60PubMedCrossRefGoogle Scholar
- 20.Centocor B.V. Product information (EU): Remicade 100mg powder for concentrate for solution for infusion (infliximab 100mg vial) [online]. Available from URL: http:// www.emea.eu.int/ [Accessed 2005 May 10]Google Scholar
- 22.Boyle A, Tawadros R, Zhu Y, et al. Comparative pharmacokinetics of single and multiple-dose infliximab in Crohn’s disease patients. Gastroenterology 2002 Apr; 122 Suppl. 1: A614–A 615. Plus poster presented at Digestive Disease Week and the 103rd Annual Meeting of the American Gastroenterological Association; 2002 May 19–23; San Francisco (CA)Google Scholar
- 26.Tanabe Seiyaku Co. Ltd. Product information (Japan): Remicade for IV infusion 100 (infliximab 100mg vial). 2003 JulGoogle Scholar
- 39.Asakura H, Yao T, Matsui T, et al. Efficacy of treatment with chimeric monoclonal antibody (Infliximab) to tumor necrosis factor-alpha for Crohn’s disease in Japan: evaluation by rapid turnover proteins, and radiologie and endoscopie findings. J Gastroenterol Hepatol 2001 Jul; 16(7): 763–9PubMedCrossRefGoogle Scholar
- 43.Quinn MA, Conaghan PG, O’Connor PJ, et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005 Jan; 52(1): 27–35PubMedCrossRefGoogle Scholar
- 44.Taylor PC, Steuer A, Gruber J, et al. Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis. Arthritis Rheum 2004 Apr; 50(4): 1107–16PubMedCrossRefGoogle Scholar
- 45.Yocum D, Rahman M, Han C. Infliximab induces disease remission in patients with rheumatoid arthritis: results from the start clinical trial [abstract no. SAT0043]. Ann Rheum Dis 2005; 64 Suppl. III: 422. Plus poster presented at the European League Against Rheumatism Annual Congress; 2005 Jun 8–11; ViennaGoogle Scholar
- 46.Westhovens R, Rahman MU, Han C. Infliximab treatment results in a rapid improvement in all aspects of quality of life assessed by the sf-36 in patients with rheumatoid arthritis: results from the START trial [abstract no. FRI0450]. Ann Rheum Dis 2005; 64 Suppl. III: 392. Plus poster presented at the European League Against Rheumatism Annual Congress; 2005 Jun 8–11; ViennaGoogle Scholar
- 47.Westhovens R, Wolfe F, Rahman MU. Infliximab dose escalation in patients with rheumatoid arthritis: results from the START trial [abstract no. SAT0045]. Ann Rheum Dis 2005; 64 Suppl. III: 423. Plus poster presented at the European League Against Rheumatism Annual Congress; 2005 Jun 8–11; ViennaGoogle Scholar
- 50.Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999 Dec 4; 354(9194): 1932–9Google Scholar
- 58.Hanauer SB, Rutgeerts PJ, D’Haens G, et al. Delayed hypersensitivity to infliximab (Remicaide®) re-infusion after a 2–4 year interval without treatment [abstract no. G3174]. Gastroenterology 1999 Apr; 116 (4 Pt 2): 731Google Scholar
- 65.Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003; 107(25): 3133–40PubMedCrossRefGoogle Scholar
- 66.Centocor Inc. Important drug warning [Dear Healthcare Professional letter; online]. Available from URL: http:// www.fda.gov/medwatch [Accessed 2005 May 16]Google Scholar
- 71.Wong JB, Loftus Jr EV, Sandborn WJ, et al. Estimating the cost-effectiveness of infliximab for Crohn’s disease [abstract no. G0451]. Gastroenterology 1999 Apr; 116 (4 Pt 2): 104–5Google Scholar
- 72.Wong JB, Loftus EV, Sandborn WJ, et al. A cost-effectiveness analysis of maintenance infliximab for chronic active Crohn’s disease in Canada [abstract no. G398]. Gut 2004; 53 (Suppl. 6): 232Google Scholar
- 73.Colombel JF, Rutgeerts P, Yan S, et al. Infliximab maintenance treatment results in lower hospitalization rate in Crohn’s disease patients [abstract no. W1344]. Gastroenterology 2002 Apr; 122 Suppl. 1: A613Google Scholar
- 74.Wong JB, Ballina J, Fernandez-Sueiro JL, et al. Cost-effectiveness of infliximab for rheumatoid arthritis in Spain [abstract no. SAT0464]. Ann Rheum Dis 2004 Jun 12; 63 Suppl. 1: 520–1Google Scholar
- 76.Wong JB, Breedveld FC, Smolen JS, et al. Estimating the cost-effectiveness of lifelong infliximab for rheumatoid arthritis [abstract no. SAT0300]. The European League Against Rheumatism Annual Congress; 2002 Jun 12–15; StockholmGoogle Scholar
- 77.Wong JB, Branco JC, Cobrado N, et al. Cost-effectiveness of lifelong infliximab for rheumatoid arthritis in Portugal. Ann Rheum Dis 2003 Jul; 62 Suppl. 1: 360Google Scholar
- 78.Singh G, Mithal A, Tandon N. Costs of infliximab therapy for rheumatoid arthritis in a large state Medicaid program [abstract no. 368]. Arthritis Rheum 2004 Sep; 50 (9 Suppl.): 188Google Scholar
- 86.Ollendorf DA, Peterson AN, Doyle J, et al. Impact of leflunomide versus biologic agents on the costs of care for rheumatoid arthritis in a managed care population. Am J Manag Care 2002 May; 8 Suppl.: 203–13Google Scholar
- 90.Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 2005; 52(4): 1227–36PubMedCrossRefGoogle Scholar
- 92.Rutgeerts P, Feagan BG, Olson A, et al. A randomized placebo-controlled trial of infliximab therapy for active ulcerative colitis: ACT I trial [abstract no. 689]. Gastroenterology 2005; 128 (4 Suppl. 2): 35–6Google Scholar
- 93.Sandborn WJ, Rachmilewitz D, Hanauer SB, et al. Infliximab induction and maintenance therapy for ulcerative colitis: the ACT 2 trial [abstract no. 688]. Gastroenterology 2005; 128 (4 Suppl. 2): 36Google Scholar
- 107.Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents, specifically tumour necrosis factor alpha (TNFalpha) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2004. Ann Rheum Dis 2004 Nov; 63 Suppl. 2: ii2–ii12PubMedCrossRefGoogle Scholar
- 108.Ledingham J, Deighton C, on behalf of the British Society for Rheumatology Standards Guidelines and Audit Working Group (SGAWG). Update on the British Society for Rheumatology guidelines for prescribing TNFα blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005 Feb; 44(2): 157–63CrossRefGoogle Scholar
- 109.Hochberg MC, Tracy JK, Flores RH. The comparative efficacy of anakinra, etanercept, infliximab and leflunomide when added to methotrexate in patients with active rheumatoid arthritis [abstract no. FRI0034]. The European League Against Rheumatism Annual Congress; 2002 Jun 12–15; StockholmGoogle Scholar
- 111.Van der Bijl AE, Goekoop-Ruiterman YP, Breedveld FC, et al. Many early rheumatoid arthritis patients with a good clinical response to infliximab can discontinue anti-TNFα therapy without relapse [abstract no. OP0010]. Ann Rheum Dis 2005; 64 Suppl. III: 59Google Scholar
- 114.Amgen and Wyeth Pharmaceuticals. Product information (US): Enbrel (etanercpet) for subcutaneous injection (single-use prefilled syringe [50 mg/mL] or multiple-use vial [25mg]) [online]. Available from URL: http://www.wyeth.com/content/ShowLabeling.asp?id=101 [Accessed 2005 Jun 17]Google Scholar
- 115.Abbott Laboratories. Product information (US): Humira (adalimumab) for subcutaneous injection (single-use prefilled syringe [40 mg/mL]) [online]. Available from URL: http:// www.rxabbott.com/pdf/humira.pdf [Accessed 2005 Jun 17]Google Scholar
- 116.Michaud K, Wolfe F. Reduced mortality among ra patients treated with anti-tnf therapy and methotrexate [abstract no. OP0095]. Ann Rheum Dis 2005; 64 Suppl. III: 87Google Scholar
- 117.Lichtenstein GR, Cohen RD, Feagan BG, et al. Safety of infliximab in Crohn’s disease: data from the 5000-patient TREAT Registry [abstract no. 439]. Gastroenterology 2004 Apr; 126 (4 Suppl. 2): 54Google Scholar