Infliximab in ankylosing spondylitis: alone or in combination with methotrexate? A pharmacokinetic comparative study

Denis Mulleman, Francine Lauféron, Daniel Wendling, David Ternant, Emilie Ducourau, Gilles Paintaud, Philippe Goupille, Denis Mulleman, Francine Lauféron, Daniel Wendling, David Ternant, Emilie Ducourau, Gilles Paintaud, Philippe Goupille

Abstract

Introduction: Methotrexate (MTX) has been shown to modify infliximab pharmacokinetics in rheumatoid arthritis. However, its combination with infliximab in the treatment of ankylosing spondylitis (AS) is not recommended. The objective of this study was to examine the influence of MTX on infliximab exposure in patients with AS.

Methods: Patients with AS patients who had predominantly axial symptoms were randomised to receive infliximab alone (infusions of 5 mg/kg at weeks 0, 2, 6, 12 and 18) or infliximab combined with MTX (10 mg/week). Infliximab concentrations were measured before and 2 hours after each infusion and at 1, 3, 4, 5, 8, 10, 14 and 18 weeks. We estimated individual cumulative area under the concentration versus time curves (AUC) for infliximab concentration between baseline and week 18 (AUC(0-18)). Clinical and laboratory evaluations were performed at each visit. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was the primary end point for clinical response.

Results: Twenty-six patients were included (infliximab group: n = 12, infliximab + MTX group: n = 14), and 507 serum samples were available for measurement of infliximab concentration. The two groups did not differ with regard to AUC(0-18) or evolution of BASDAI scores and biomarkers of inflammation.

Conclusions: The combination of MTX and infliximab does not increase the exposure to infliximab over infliximab alone in patients with AS.

Trial registration: ClinicalTrials.gov: NCT00507403.

Figures

Figure 1
Figure 1
Area under the concentration curve versus the time curve for serum infliximab concentration between baseline and week 18 (AUC0-18) for patients with ankylosing spondylitis who had predominantly axial symptoms and were receiving infliximab or infliximab + methotrexate (MTX) treatment. The patient with anti-infliximab antibodies is shown as an open circle.

References

    1. van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, Braun J. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT) Arthritis Rheum. 2005;52:582–591. doi: 10.1002/art.20852.
    1. Haibel H, Brandt HC, Song IH, Brandt A, Listing J, Rudwaleit M, Sieper J. No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial. Ann Rheum Dis. 2007;66:419–421. doi: 10.1136/ard.2006.054098.
    1. Altan L, Bingol U, Karakoc Y, Aydiner S, Yurtkuran M, Yurtkuran M. Clinical investigation of methotrexate in the treatment of ankylosing spondylitis. Scand J Rheumatol. 2001;30:255–259. doi: 10.1080/030097401753180318.
    1. Gonzalez-Lopez L, Garcia-Gonzalez A, Vazquez-Del-Mercado M, Muñoz-Valle JF, Gamez-Nava JI. Efficacy of methotrexate in ankylosing spondylitis: a randomized, double blind, placebo controlled trial. J Rheumatol. 2004;31:1568–1574.
    1. Roychowdhury B, Bintley-Bagot S, Bulgen DY, Thompson RN, Tunn EJ, Moots RJ. Is methotrexate effective in ankylosing spondylitis? Rheumatology (Oxford) 2002;41:1330–1332. doi: 10.1093/rheumatology/41.11.1330.
    1. Chen J, Liu C, Lin J. Methotrexate for ankylosing spondylitis. Cochrane Database Syst Rev. 2006;4:CD004524.
    1. Pérez-Guijo VC, Cravo AR, Castro Mdel C, Font P, Muñoz-Gomariz E, Collantes-Estevez E. Increased efficacy of infliximab associated with methotrexate in ankylosing spondylitis. Joint Bone Spine. 2007;74:254–258. doi: 10.1016/j.jbspin.2006.08.005.
    1. Breban M, Ravaud P, Claudepierre P, Baron G, Henry YD, Hudry C, Euller-Ziegler L, Pham T, Solau-Gervais E, Chary-Valckenaere I, Marcelli C, Perdriger A, Le Loët X, Wendling D, Fautrel B, Fournié B, Combe B, Gaudin P, Jousse S, Mariette X, Baleydier A, Trape G, Dougados M. French Ankylosing Spondylitis Infliximab Network. Maintenance of infliximab treatment in ankylosing spondylitis: results of a one-year randomized controlled trial comparing systematic versus on-demand treatment. Arthritis Rheum. 2008;58:88–97. doi: 10.1002/art.23167.
    1. Pham T, Fautrel B, Dernis E, Goupille P, Guillemin F, Le Loët X, Ravaud P, Claudepierre P, Miceli-Richard C, de Bandt M, Breban M, Maillefert JF, Masson C, Saraux A, Schaeverbeke T, Wendling D, Mariette X, Combe B. Club Rhumatismes et Inflammation (CRI/SFR) Recommendations of the French Society for Rheumatology regarding TNFα antagonist therapy in patients with ankylosing spondylitis or psoriatic arthritis: 2007 update. Joint Bone Spine. 2007;74:638–646. doi: 10.1016/j.jbspin.2007.10.003.
    1. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum. 1984;27:361–368. doi: 10.1002/art.1780270401.
    1. Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados M, van der Heijde D. International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis. 2003;62:817–824. doi: 10.1136/ard.62.9.817.
    1. Ternant D, Mulleman D, Degenne D, Willot S, Guillaumin JM, Watier H, Goupille P, Paintaud G. An enzyme-linked immunosorbent assay for therapeutic drug monitoring of infliximab. Ther Drug Monit. 2006;28:169–174. doi: 10.1097/01.ftd.0000189901.08684.4b.
    1. The R Project for Statistical Computing.
    1. Krzysiek R, Breban M, Ravaud P, Prejean MV, Wijdenes J, Roy C, Henry YD, Barbey C, Trappe G, Dougados M, Emilie D. French Ankylosing Spondylitis Infliximab Network. Circulating concentration of infliximab and response to treatment in ankylosing spondylitis: results from a randomized control study. Arthritis Rheum. 2009;61:569–576. doi: 10.1002/art.24275.
    1. Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J, Bombardier C, Carmona L, van der Heijde D, Bijlsma JW, Boumpas DT, Canhao H, Edwards CJ, Hamuryudan V, Kvien TK, Leeb BF, Martín-Mola EM, Mielants H, Müller-Ladner U, Murphy G, Østergaard M, Pereira IA, Ramos-Remus C, Valentini G, Zochling J, Dougados M. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2009;68:1086–1093. doi: 10.1136/ard.2008.094474.
    1. de Vries MK, Wolbink GJ, Stapel SO, de Vrieze H, van Denderen JC, Dijkmans BA, Aarden LA, van der Horst-Bruinsma IE. Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann Rheum Dis. 2007;66:1252–1254. doi: 10.1136/ard.2007.072397.
    1. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF, Feldmann M. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41:1552–1563. doi: 10.1002/1529-0131(199809)41:9<1552::AID-ART5>;2-W.
    1. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–1549. doi: 10.1016/S0140-6736(02)08512-4.
    1. Baert F, Noman M, Vermeire S, Van Assche G, D' Haens G, Carbonez A, Rutgeerts P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003;348:601–608. doi: 10.1056/NEJMoa020888.
    1. Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum. 2006;54:3782–3789. doi: 10.1002/art.22214.
    1. Wolbink GJ, Voskuyl AE, Lems WF, de Groot E, Nurmohamed MT, Tak PP, Dijkmans BA, Aarden L. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2005;64:704–707. doi: 10.1136/ard.2004.030452.

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