Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis
The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks.
One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels.
Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks.
Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.
KeywordsRheumatoid arthritis Tocilizumab C-reactive protein Interleukin-6
- 2.Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005;52:3381–90.PubMedCrossRefGoogle Scholar
- 3.Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26–37.PubMedCrossRefGoogle Scholar
- 4.Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372:375–82.PubMedCrossRefGoogle Scholar
- 8.St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46:1451–9.PubMedCrossRefGoogle Scholar
- 9.Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68:1739–45.PubMedCrossRefGoogle Scholar
- 10.Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an X-ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66:1162–7.Google Scholar
- 11.Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987–97.PubMedCrossRefGoogle Scholar
- 12.Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58:2968–80.PubMedCrossRefGoogle Scholar
- 13.Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19:12–9.PubMedCrossRefGoogle Scholar
- 16.Yabe Y, Kojima T, Kaneko A, Asai N, Kobayakawa T, Ishiguro N. A review of tocilizumab treatment in 122 rheumatoid arthritis patients included in the Tsurumai Biologics Communication Registry (TBCR) Study. Mod Rheumatol. 2012 [Epub ahead of print].Google Scholar
- 19.Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112:3959–64.PubMedCrossRefGoogle Scholar
- 23.Yamanaka H, Matsuda Y, Tanaka M, Sendo W, Nakajima H, Taniguchi A, et al. Serum matrix metalloproteinase 3 as a predictor of the degree of joint destruction during the six months after measurement, in patients with early rheumatoid arthritis. Arthritis Rheum. 2000;43:852–8.PubMedCrossRefGoogle Scholar
- 25.Kaneko A, Kida D, Saito K, Tsukamoto M, Sato T. Clinical results for tocilizumab over one year in the clinical setting as assessed by CDAI (clinical disease activity index): CRP at week 12 and MMP-3 at week 24 are predictive factors for CDAI. Rheumatol Int. 2011.Google Scholar
- 27.Tanaka Y, Takeuchi T, Inoue E, Saito K, Sekiguchi N, Sato E, et al. Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan: one-year clinical outcomes (RECONFIRM-2). Mod Rheumatol. 2008;18:146–52.PubMedCrossRefGoogle Scholar
- 28.Kaneko A, Hirano Y, Fujibayashi T, Hattori Y, Terabe K, Kojima T, et al. Twenty-four-week clinical results of adalimumab therapy in Japanese patients with rheumatoid arthritis: retrospective analysis for the best use of adalimumab in daily practice. Mod Rheumatol. 2012 [Epub ahead of print].Google Scholar
- 29.Takeuchi T, Tanaka Y, Kaneko Y, Tanaka E, Hirata S, Kurasawa T, et al. Effectiveness and safety of adalimumab in Japanese patients with rheumatoid arthritis: retrospective analyses of data collected during the first year of adalimumab treatment in routine clinical practice (HARMONY study). Mod Rheumatol. 2012;22:327–38.PubMedCrossRefGoogle Scholar
- 30.Takahashi N, Kojima T, Terabe K, Kaneko A, Kida D, Hirano Y, et al. Clinical efficacy of abatacept in Japanese rheumatoid arthritis patients. Mod Rheumatol. 2012 [Epub ahead of print].Google Scholar
- 31.Takeuchi T, Miyasaka N, Tatsuki Y, Yano T, Yoshinari T, Abe T, et al. Inhibition of plasma IL-6 in addition to maintenance of an efficacious trough level of infliximab associated with clinical remission in patients with rheumatoid arthritis: analysis of the RISING Study. Ann Rheum Dis. 2012;71:1583–5.PubMedCrossRefGoogle Scholar