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Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab: implications for molecular targeted therapy
  1. Naoshi Nishina1,
  2. Jun Kikuchi1,
  3. Misato Hashizume2,
  4. Keiko Yoshimoto1,
  5. Hideto Kameda1,3,
  6. Tsutomu Takeuchi1
  1. 1 Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  2. 2 Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Japan
  3. 3 Division of Rheumatology, Department of Internal Medicine, School of Medicine, Toho University, Tokyo, Japan
  1. Correspondence to Dr Naoshi Nishina, Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; nnishina{at}a7.keio.jp

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Interleukin-6 (IL-6) is a monomeric protein that binds to either soluble or membrane-bound IL-6 receptors (IL-6R)1 ,2 Tocilizumab, a humanised anti-IL-6R monoclonal antibody, binds to soluble IL-6R (sIL-6R) and membrane-bound IL-6R, blocking signal transduction pathways through competitive inhibition of IL-6 binding.3 We have previously demonstrated that baseline plasma tumour necrosis factor (TNF) levels are associated with the clinical response to infliximab, anti-TNF monoclonal antibody binding to soluble and membrane-bound TNF.4 Therefore, it is tempting to speculate that baseline serum levels of sIL-6R, rather than those of IL-6, are associated with clinical response to tocilizumab in patients with rheumatoid arthritis (RA). To test this hypothesis, we analysed serum levels of IL-6 and sIL-6R before tocilizumab treatment in our institution and evaluated their association with clinical remission.

Consecutive patients with RA in our institution who commenced 8 mg/kg tocilizumab treatment every 4 weeks as the first biologic agent between March 2010 and April 2012 were included. At baseline, serum levels of IL-6 and sIL-6R were measured by electrochemiluminescence assay with the Ultra-Sensitive Kit (Meso Scale Discovery, Maryland, USA). In this assay, immunoglobulin inhibiting reagent (Bioreclamation, New York, USA) was used to block heterophilic antibody interference.5

The baseline clinical characteristics of the 43 enrolled patients are shown in table 1. Median Simplified Disease Activity Index (SDAI) decreased from 19.78 at baseline to 4.71 at week 24, resulting in SDAI remission in 18 (42%) patients. Median (IQR) IL-6 and sIL-6R at baseline were 4.70 (1.51–8.54) pg/mL and 84.2 (62.2–98.0) ng/mL, respectively. Baseline levels of sIL-6R were not associated with other parameters (data not shown). Univariate logistic regression analysis revealed that the baseline sIL-6R level was an only significant predictor of SDAI remission at week 24 (p=0.045; figure 1A). Multivariate analysis confirmed us that sIL-6R was solely a significant predictor (data not shown). A cut-off sIL-6R level of 72.6 ng/mL discriminated between SDAI remission and non-remission with a sensitivity of 67% and a specificity of 72% (figure 1B), Clinical Disease Activity Index (CDAI) remission with 65% and 69%, and disease activity score with 28 joint counts, erythrocyte sedimentation rate (DAS28-ESR) remission with 59% and 81%, respectively. The numbers of patients with baseline sIL-6R values of ≤72.6 ng/mL (sIL-6R-low) and >72.6 ng/mL (sIL-6R-high) were 19 and 24, respectively. We could not find significant differences in baseline characteristics between the two groups (table 1).

Table 1

Differences in baseline characteristics between sIL-6R-low and sIL-6-high patients

Figure 1

(A) Logistic regression analysis showing the predicted probability of achieving Simplified Disease Activity Index (SDAI) remission at week 24 as a function of sIL-6R at week 0. (B) ROC curve showing a cut-off sIL-6R level of 72.6 ng/mL discriminated between remission and non-remission at week 24, with a sensitivity of 67% and a specificity of 72%. Percentage of patients categorised by SDAI (C), Clinical Disease Activity Index (CDAI) (D), and DAS28-ESR (E) in sIL-6R-low and sIL-6R-high groups at weeks 0, 4, 8, and 24. AUC, area under the curve; CDAI, Clinical Disease Activity Index; DAS28, disease activity score with 28 joint counts; ESR, erythrocyte sedimentation rate; HDA, high disease activity; LDA, low disease activity; MDA, moderate disease activity; REM, remission; ROC, receiver operating characteristic; SDAI, Simplified Disease Activity Index; sIL-6R, soluble interleukin-6 receptor.

SDAI category changes in sIL-6R-low and sIL-6R-high patients are shown in figure 1C. A significantly higher proportion of patients in sIL-6R-low group achieved SDAI remission compared with those in sIL-6R-high (63% and 25%, respectively; p=0.02 by Fisher's exact test). CDAI and DAS28-ESR category changes are also shown (figure 1D,E). Although the difference in the remission rate of CDAI was marginal between groups (58% in the sIL-6R-low group and 25% in the sIL-6R-high group, respectively; p=0.06), that of DAS28-ESR at week 24 was again significant (84% vs 46%, respectively; p=0.01). Response rate, as assessed by American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria, was numerically better in sIL-6R-low group, although not statistically significant (data not shown).

Baseline levels of sIL-6R predicted clinical remission in RA patients treated with tocilizumab without showing associations with disease activity as shown in previous reports.6 ,7 Our results suggest that the amount of target molecule could be considered as one of the predictors when using molecular targeted therapy. This finding could be of help for establishing treatment strategies with tocilizumab, achieving higher remission rate as early as possible along with the treat-to-target recommendation.

References

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Footnotes

  • Contributors All the authors evaluated the study results, interpreted the data and suggested additional analyses. All authors contributed to the development and critical review of manuscript and approved the final version.

  • Funding This study was supported by Chugai Pharmaceutical Co, Ltd.

  • Competing interests MH is an employee of Chugai Pharmaceutical Co, Ltd. TT has received consulting fees, speaking fees, honoraria and/or research grant support from Abbott Japan Co; Abbvie GK; Asahi Kasei Pharma Corp; Astellas Pharma Inc; Astra-Zeneca KK; Bristol-Myers KK; Chugai Pharmaceutical Co, Ltd; Daiichi-Sankyo Co; Eisai Co; Eli-Lilly Japan KK; Janssen Pharmaceutical KK; Mitsubishi Tanabe Pharma Co; Novartis Pharma KK; Pfizer Japan Inc; Sanofi-aventis KK; Santen Pharmaceutical Co, Ltd; Taisho Toyama Pharmaceutical Co, Ltd; Takeda Pharmaceutical Co, Ltd; and Teijin Pharma Ltd.

  • Patient consent Obtained.

  • Ethics approval The ethics committee at Keio University School of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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