Skip to main content

Advertisement

SpringerLink
Log in

Neutrophil count reduction 1 month after initiating tocilizumab can predict clinical remission within 1 year in rheumatoid arthritis patients

  • Observational Research
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Neutropenia is a common adverse event of tocilizumab (TCZ) in rheumatoid arthritis (RA) patients; however, the association between the decrease in neutrophil counts and the TCZ clinical efficacy remains inconclusive. This study aimed to examine whether TCZ-induced neutrophil decrease at 1 month predicts clinical remission within 1 year. We reviewed medical records of RA patients initiating TCZ between May 2011 and September 2019 in our hospital. The Clinical Disease Activity Index (CDAI) was evaluated at baseline (before initiating TCZ) and 1, 3, 6, and 12 months after administration. Clinical remission was defined when CDAI decreased ≤ 2.8. The ratio of neutrophil counts 1 month after initiating TCZ to those at baseline (neutrophil ratio) was also calculated. Among 255 TCZ-treated patients, 169 with valid CDAI and neutrophil counts were enrolled (with median age of 60 years and 79% females). Rheumatoid factor and anti-cyclic citrullinated peptide antibody were positive in 75% and 83%, respectively, and 56% of the patients had concomitant methotrexate (median dose: 8 mg/week). Multivariate logistic regression analysis suggested baseline CDAI (odds ratio (OR) 0.96, p = 0.045), concomitant PSL (OR 0.42, p = 0.030), and the neutrophil ratio (OR 0.19, p = 0.011) as predictors of CDAI remission. Neutrophil ratio ≤ 0.8 was associated with achieving remission (Fisher's exact test, p = 0.02) with no apparent increase of severe infection. More than 20% reduction of neutrophil count 1 month after initiating TCZ predicts clinical remission within 1 year at an early treatment phase.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Availability of data and materials

The data sets used and analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Aletaha D, Smolen JS (2018) Diagnosis and management of rheumatoid arthritis: a review. JAMA 320(13):1360–1372. https://doi.org/10.1001/jama.2018.13103

    Article  PubMed  Google Scholar 

  2. Dayer JM, Choy E (2010) Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology 49(1):15–24. https://doi.org/10.1093/rheumatology/kep329

    Article  PubMed  CAS  Google Scholar 

  3. Smolen JS, Landewé RBM, Bijlsma JWJ et al (2020) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79(6):685–699. https://doi.org/10.1136/annrheumdis-2019-216655

    Article  PubMed  CAS  Google Scholar 

  4. Smolen JS, Aletaha D, Bijlsma JWJ et al (2010) Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 69(4):631–637. https://doi.org/10.1136/ard.2009.123919

    Article  PubMed  Google Scholar 

  5. Nouri B, Nair N, Barton A (2020) Predicting treatment response to IL6R blockers in rheumatoid arthritis. Rheumatology 59(12):3603–3610. https://doi.org/10.1093/rheumatology/keaa529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Moots RJ, Sebba A, Rigby W et al (2017) Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials. Rheumatology 56(4):541–549. https://doi.org/10.1093/rheumatology/kew370

    Article  PubMed  CAS  Google Scholar 

  7. Arnett FC, Edworthy SM, Bloch DA et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324. https://doi.org/10.1002/art.1780310302

    Article  PubMed  CAS  Google Scholar 

  8. Aletaha D, Neogi T, Silman AJ et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69(9):1580–1588. https://doi.org/10.1136/ard.2010.138461

    Article  PubMed  Google Scholar 

  9. Murata K, Ito H, Hashimoto M et al (2019) Elderly onset of early rheumatoid arthritis is a risk factor for bone erosions, refractory to treatment: KURAMA cohort. Int J Rheum Dis 22(6):1084–1093. https://doi.org/10.1111/1756-185x.13428

    Article  PubMed  CAS  Google Scholar 

  10. Aletaha D, Smolen J (2005) The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 23(5 Suppl 39):S100-108

    PubMed  CAS  Google Scholar 

  11. Smolen JS, Aletaha D (2011) Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: The role of acute-phase reactants. Arthritis Rheum 63(1):43–52. https://doi.org/10.1002/art.27740

    Article  PubMed  CAS  Google Scholar 

  12. Kanda Y (2013) Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48(3):452–458. https://doi.org/10.1038/bmt.2012.244

    Article  PubMed  CAS  Google Scholar 

  13. Pers YM, Fortunet C, Constant E et al (2014) Predictors of response and remission in a large cohort of rheumatoid arthritis patients treated with tocilizumab in clinical practice. Rheumatology 53(1):76–84. https://doi.org/10.1093/rheumatology/ket301

    Article  PubMed  CAS  Google Scholar 

  14. Narváez J, Magallares B, Díaz Torné C et al (2016) Predictive factors for induction of remission in patients with active rheumatoid arthritis treated with tocilizumab in clinical practice. Semin Arthritis Rheum 45(4):386–390. https://doi.org/10.1016/j.semarthrit.2015.07.001

    Article  PubMed  CAS  Google Scholar 

  15. Nakagawa M, Terashima T, D’yachkova Y, Bondy GP, Hogg JC, Van Eeden SF (1998) Glucocorticoid-induced granulocytosis: contribution of marrow release and demargination of intravascular granulocytes. Circulation 98(21):2307–2313. https://doi.org/10.1161/01.cir.98.21.2307

    Article  PubMed  CAS  Google Scholar 

  16. Forsblad-d’Elia H, Bengtsson K, Kristensen LE, Jacobsson LTH (2015) Drug adherence, response and predictors thereof for tocilizumab in patients with rheumatoid arthritis: results from the Swedish biologics register. Rheumatology 54(7):1186–1193. https://doi.org/10.1093/rheumatology/keu455

    Article  PubMed  CAS  Google Scholar 

  17. Kojima T, Yabe Y, Kaneko A et al (2013) Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis. Mod Rheumatol 23(5):977–985. https://doi.org/10.1007/s10165-012-0782-y

    Article  PubMed  CAS  Google Scholar 

  18. Boyapati A, Schwartzman S, Msihid J et al (2020) Association of high serum interleukin-6 levels with severe progression of rheumatoid arthritis and increased treatment response differentiating sarilumab from adalimumab or methotrexate in a post hoc analysis. Arthritis Rheum 72(9):1456–1466. https://doi.org/10.1002/art.41299

    Article  CAS  Google Scholar 

  19. Rubbert-Roth A, Aletaha D, Devenport J et al (2020) Effect of disease duration and other characteristics on efficacy outcomes in clinical trials of tocilizumab for rheumatoid arthritis. Rheumatology 60(2):682–691. https://doi.org/10.1093/rheumatology/keaa259

    Article  PubMed Central  CAS  Google Scholar 

  20. Okano T, Inui K, Tada M et al (2016) Levels of interleukin-1 beta can predict response to tocilizumab therapy in rheumatoid arthritis: the PETITE (predictors of effectiveness of tocilizumab therapy) study. Rheumatol Int 36(3):349–357. https://doi.org/10.1007/s00296-015-3379-x

    Article  PubMed  CAS  Google Scholar 

  21. Hirata S, Marotta A, Gui Y, Hanami K, Tanaka Y (2015) Serum 14–3-3η level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab. Arthritis Res Ther 17(1):280. https://doi.org/10.1186/s13075-015-0799-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Dennis G, Holweg CTJ, Kummerfeld SK et al (2014) Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Arthritis Res Ther 16(2):R90. https://doi.org/10.1186/ar4555

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Nishina N, Kikuchi J, Hashizume M, Yoshimoto K, Kameda H, Takeuchi T (2014) Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab: implications for molecular targeted therapy. Ann Rheum Dis 73(5):945–947. https://doi.org/10.1136/annrheumdis-2013-204137

    Article  PubMed  CAS  Google Scholar 

  24. Daïen CI, Gaihac S, Audo R et al (2015) High levels of natural killer cells are associated with response to tocilizumab in patients with severe rheumatoid arthritis. Rheumatology 54(4):601–608. https://doi.org/10.1093/rheumatology/keu363

    Article  PubMed  CAS  Google Scholar 

  25. Enevold C, Baslund B, Linde L et al (2014) Interleukin-6-receptor polymorphisms rs12083537, rs2228145, and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis. Pharmacogenet Genomics 24(8):401–405. https://doi.org/10.1097/fpc.0000000000000071

    Article  PubMed  CAS  Google Scholar 

  26. Maldonado-Montoro M, Cañadas-Garre M, González-Utrilla A, Plaza-Plaza JC, Calleja-Hernández MŸ (2016) Genetic and clinical biomarkers of tocilizumab response in patients with rheumatoid arthritis. Pharmacol Res 111:264–271. https://doi.org/10.1016/j.phrs.2016.06.016

    Article  PubMed  CAS  Google Scholar 

  27. Sanayama Y, Ikeda K, Saito Y et al (2014) Prediction of therapeutic responses to TOCILIZUMAB in patients with rheumatoid arthritis using biomarkers identified by genome-wide DNA microarray analysis in peripheral blood mononuclear cells. Ann Rheum Dis 73:383. https://doi.org/10.1136/annrheumdis-2014-eular.2293

    Article  Google Scholar 

  28. Crawford J, Dale DC, Lyman GH (2004) Chemotherapy-induced neutropenia: Risks, consequences, and new directions for its management. Cancer 100(2):228–237. https://doi.org/10.1002/cncr.11882

    Article  PubMed  Google Scholar 

  29. Wright HL, Moots RJ, Edwards SW (2014) The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol 10(10):593–601. https://doi.org/10.1038/nrrheum.2014.80

    Article  PubMed  CAS  Google Scholar 

  30. Tanaka D, Kagari T, Doi H, Shimazato T (2006) Essential role of neutrophils in anti-type II collagen antibody and lipopolysaccharide-induced arthritis. Immunology 119(2):195–202. https://doi.org/10.1111/j.1365-2567.2006.02424.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Desgeorges A, Gabay C, Silacci P et al (1997) Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid. J Rheumatol 24(8):1510–1516

    PubMed  CAS  Google Scholar 

  32. Suwa T, Hogg JC, English D, Van Eeden SF (2000) Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow. Am J Physiol Heart Circ Physiol 279(6):H2954–H2960. https://doi.org/10.1152/ajpheart.2000.279.6.H2954

    Article  PubMed  CAS  Google Scholar 

  33. Wright HL, Cross AL, Edwards SW, Moots RJ (2014) Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology 53(7):1321–1331. https://doi.org/10.1093/rheumatology/keu035

    Article  PubMed  CAS  Google Scholar 

  34. Hashizume M, Higuchi Y, Uchiyama Y, Mihara M (2011) IL-6 plays an essential role in neutrophilia under inflammation. Cytokine 54(1):92–99. https://doi.org/10.1016/j.cyto.2011.01.007

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank all patients enrolled in the study, Masanobu Ishio for extracting the cohort data, and Enago (www.enago.jp) for the language review.

Funding

This work was in part supported by JSPS KAKENHI Grant Number 20K17418 to RW.

Author information

Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Tomoya Nakajima, Kosaku Murakami, Koji Kitagori, Shuji Akizuki, Ran Nakashima, Hajime Yoshifuji, Koichiro Ohmura & Akio Morinobu

  2. Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Ryu Watanabe, Motomu Hashimoto, Koichi Murata, Masao Tanaka, Hiromu Ito & Wataru Yamamoto

  3. Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Koichi Murata, Hiromu Ito & Shuichi Matsuda

  4. Department of Health Information Management, Kurashiki Sweet Hospital, Okayama, Japan

    Wataru Yamamoto

Authors
  1. Tomoya Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryu Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Motomu Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koichi Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kosaku Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masao Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiromu Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wataru Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Koji Kitagori
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shuji Akizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ran Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hajime Yoshifuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Koichiro Ohmura
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shuichi Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Akio Morinobu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TN, RW and MH conceived and designed the study. All authors were involved in patient recruitment and data collection. SM and AM supervised the study. TN conducted the statistical analysis and wrote the first draft of the manuscript. RW revised and finalized the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ryu Watanabe.

Ethics declarations

Conflict of interest

The Department of Advanced Medicine for Rheumatic Diseases is supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, UCB Japan Co. Ltd, AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). The KURAMA cohort is also supported by grant from Daiichi Sankyo Co. Ltd. The above-mentioned pharmaceutical companies were not involved in the study design, data collection and analysis, manuscript writing, and manuscript submission. RW received speaker fees from Mitsubishi Tanabe Pharma, Pfizer, Sanofi, AbbVie, Asahi Kasei, Eisai, Eli Lilly, Bristol-Myers Squibb, and Janssen. MH received a research grant and/or speaker fees from Bristol-Myers, Eisai, Ely Lilly, Mitsubishi Tanabe Pharma, Novartis Pharma. KMurat received a speaking fee from Eisai Co., Ltd. and Astellas Pharma Inc. KMurak has received speaking fees from Eisai Co. Ltd, Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, UCB Japan Co. Ltd, Daiichi Sankyo Co. Ltd. and Astellas Pharma Inc.. MT received research grants and/or speaker fees from AbbVie GK, Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Inc., UCB Japan Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Daiichi Sankyo Co. Ltd., Celgene Corp., Takeda Pharmaceutical Company Ltd., and Taisho Pharma Co., Ltd.. HI has received a research grant from Bristol-Myers Squibb, Asahi Kasei Pharma Corporation, Eisai, Mochida and Taisho. KK received research grants from GSK. RN has received research grants from Takeda and Medical & Biological Laboratories Co., Ltd. and speaking fees from Bristol-Myers Squibb, Astellas Pharma, Boehringer Ingelheim, Actelion Pharmaceuticals and Mitsubishi Tanabe Pharma, outside the submitted work. HY received lecture fees from Chugai and has been on the advisory board for a clinical trial conducted by Janssen. KO received research grants and/or speaker fees from AbbVie, Actelion Pharmaceuticals, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, GSK, JB, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Kayaku, Nippon Shinyaku, Mitsubishi Tanabe Pharma, Novartis Pharma, Sanofi, Takeda Pharmaceutical. SM has received a research grant and/or speaker fee from Kyocera Medical Co., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, Eisai Co., Ltd., Pfizer, Eli Lilly, Taisho Pharma Co., Ltd., and Ono Pharmaceutical Co.. AM has received research grants from AbbVie, Asahi Kasei Pharma, Chugai Pharmaceutical, Ono Pharmaceutical and speaking fees from Eli Lilly, AbbVie, Ono Pharmaceutical, Pfizer, Astellas Pharmaceutical, Chugai Pharmaceutical. All other authors have declared no conflicts of interest.

Ethical approval

The study protocol was approved by the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine (No. R0357).

Consent to participate

Written informed consent to participate in the KURAMA cohort was obtained from all patients.

Consent for publication

Written informed consent to publish the study results was obtained from all patients.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakajima, T., Watanabe, R., Hashimoto, M. et al. Neutrophil count reduction 1 month after initiating tocilizumab can predict clinical remission within 1 year in rheumatoid arthritis patients. Rheumatol Int 42, 1983–1991 (2022). https://doi.org/10.1007/s00296-021-04944-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-021-04944-x

Keywords

Search

Navigation