Low infliximab serum trough levels and anti-infliximab antibodies are prevalent in rheumatoid arthritis patients treated with infliximab in daily clinical practice: results of an observational cohort study

BMC Musculoskeletal Disorders

Alfons A den Broeder¹  Piet LCM van Riel²  Frank HJ van den Hoogen⁴  Gertjan Wolbink³  Bart JF van den Bemt⁴  Aatke van der Maas¹ 

[1] Department of Rheumatology, Sint Maartenskliniek, Hengstdal 3, 6522 JV, Nijmegen, The Netherlands;Department of Rheumatology, Radboud University Nijmegen Medical Center Geert Grooteplein-Zuid 10, Postbus 9101, 6500 HB, Nijmegen, The Netherlands;Department of Rheumatology, Reade, Dr. Jan van Breemenstraat 2, 1056 AB, Amsterdam, The Netherlands;Department of Pharmacy, Sint Maartenskliniek, Hengstdal 3, 6522 JV, Nijmegen, The Netherlands

关键词: Low disease activity;    Anti-infliximab antibodies;    Serum trough levels;    Therapeutic drug monitoring;    Infliximab;    Rheumatoid arthritis;   

Others  :  1145801
DOI  :  10.1186/1471-2474-13-184

 received in 2011-10-21, accepted in 2012-09-19,  发布年份 2012

【 摘 要 】

Background

To get insight in the prevalence of high, or low/no serum infliximab trough levels in patients with low disease activity and if serum trough levels are stable and reliable longitudinally we conducted a prospective cohort study

Methods

In a longitudinal, observational cohort of RA patients treated with infliximab for at least 6 months, treatment interval, DAS28, infliximab trough levels and anti-infliximab antibodies were assessed. Prevalence of low (<1 mg/l) and high (>5 mg/l) infliximab serum trough levels and anti-infliximab antibodies was recorded. Relationship of a change in anti-infliximab antibodies and treatment interval was described. Reliability of consecutive infliximab serum trough levels and anti-infliximab antibodies in patients with stable DAS28 and treatment was analysed with Spearman correlation and kappa-analysis.

Results

147 patients with a mean disease duration of 11 years (sd7) and DAS28 of 3.5 (sd1.3) at baseline were followed during 1.5 years. Inter-individual variability in infliximab levels in patients with low DAS28 was high (median 1.4 mg/L, IQR 3.35), with 31% (95%CI: 20-42%) having low (<1 mg/L) and 14% (95%CI 5–22) high trough levels (>5 mg/L). Interestingly also in RA patients with DAS28 ≤ 3.2, anti-infliximab antibodies were found in one-third of the patients, with half of them having antibodies every visit during a median of more than one year. Agreement for consecutive measurements of serum trough levels and anti-infliximab antibodies was high in stable patients: r = 0.97 (p = 0.00001) and kappa = 1.0 (SE 0.14) Anti-infliximab antibody appearance was influenced by interval increases (relative risk (RR) 5.2, 2.6-10.7), but patients still showed low infliximab levels.

Conclusions

Low (and high) infliximab serum trough levels are prevalent, interestingly also in patients with low disease activity. Consecutive measurements of serum trough levels and anti-infliximab antibodies are reliable in stable patients. These test could be used to lower or stop infliximab in selected patients.

【 授权许可】

   
2012 van der Maas et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, et al.: Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000, 343:1594-1602.
• [2]St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, et al.: Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004, 50:3432-3443.
• [3]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.
• [4]Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, Bendtzen K: Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 2009, 68:1739-1745.
• [5]Takeuchi T, Miyasaka N, Inoue K, Abe T, Koike T: Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod Rheumatol 2009, 19:478-487.
• [6]Wolbink GJ, Voskuyl AE, Lems WF, de GE , 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.
• [7]Wolbink GJ, Vis M, Lems W, Voskuyl AE, de GE , Nurmohamed MT, Stapel S, Tak PP, Aarden L, Dijkmans B: Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 2006, 54:711-715.
• [8]Lie E, van der Heijde D, Uhlig T, Mikkelsen K, Kalstad S, Kaufmann C, Rodevand E, Kvien TK: Treatment strategies in patients with rheumatoid arthritis for whom methotrexate monotherapy has failed: data from the NOR-DMARD register. Ann Rheum Dis 2011, 70(12):2103-2110.
• [9]Kievit W, Adang EM, Fransen J, Kuper HH, van de Laar MA, Jansen TL, De Gendt CM, de Rooij DJ, Brus HL, Van Oijen PC, et al.: The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data. Ann Rheum Dis 2008, 67:1229-1234.
• [10]Tanaka Y, Takeuchi T, Mimori T, Saito K, Nawata M, Kameda H, Nojima T, Miyasaka N, Koike T: Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis 2010, 69:1286-1291.
• [11]den Broeder AA, van der Maas A, van den Bemt BJ: Dose de-escalation strategies and role of therapeutic drug monitoring of biologics in RA. Rheumatology (Oxford) 2010, 49:1801-1803.
• [12]van der Maas A, Kievit W, van den Bemt BJ, van den Hoogen FH, Van Riel PC, den Broeder AA: Down-titration and discontinuation of infliximab in rheumatoid arthritis patients with stable low disease activity and stable treatment: an observational cohort study. 2012. Ann Rheum Dis annrheumdis-2011-200945Published Online First: 13 April 2012
• [13]Pascual-Salcedo D, Plasencia C, Ramiro S, Nuno L, Bonilla G, Nagore D, Del Ruiz AA, Martinez A, Aarden L, Martin-Mola E, et al.: Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology (Oxford) 2011, 50:1445-1452.
• [14]Ducourau E, Mulleman D, Paintaud G, Chu Miow LD, Lauferon F, Ternant D, Watier H, Goupille P: Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. Arthritis Res Ther 2011, 13:R105. BioMed Central Full Text
• [15]Mulleman D, Meric JC, Paintaud G, Ducourau E, Magdelaine-Beuzelin C, Valat JP, Goupille P: Infliximab concentration monitoring improves the control of disease activity in rheumatoid arthritis. Arthritis Res Ther 2009, 11:R178. BioMed Central Full Text
• [16]Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ: Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 2011, 305:1460-1468.
• [17]Bland JM, Altman DG: Measuring agreement in method comparison studies. Stat Methods Med Res 1999, 8:135-160.
• [18]Rau R, Simianer S, van Riel PL, van De Putte LB, Kruger K, Schattenkirchner M, Allaart CF, Breedveld FC, Kempeni J, Beck K, et al.: Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with methotrexate. Scand J Rheumatol 2004, 33:145-153.
• [19]van den Bemt BJ, den Broeder AA, Wolbink GJ, Hekster YA, van Riel PL, Benraad B, van den Hoogen FH: Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusioncycle: an open-label pharmacokinetic cohort study. BMC Musculoskelet Disord 2011, 12:12. BioMed Central Full Text
• [20]Bakker MF, Jacobs JW, Verstappen SM, Bijlsma JW: Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann Rheum Dis 2007, 66(Suppl 3):iii56-iii60.
• [21]Mease PJ: Improving the routine management of rheumatoid arthritis: the value of tight control. J Rheumatol 2010, 37:1570-1578.