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Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio as predictors of 12-week treatment response and drug persistence of anti-tumor necrosis factor-α agents in patients with rheumatoid arthritis: a retrospective chart review analysis

  • Han-Na Lee
  • Yun-Kyung Kim
  • Geun-Tae Kim
  • Eunyoung Ahn
  • Min Wook So
  • Dong Hyun Sohn
  • Seung-Geun LeeEmail author
Observational Research
  • 43 Downloads

Abstract

Data are scarce regarding the association of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with treatment response and persistence of anti-TNF-α agents in patients with rheumatoid arthritis (RA). Thus, we investigated whether baseline NLR and PLR could predict 12-week treatment response and long-term persistence of anti-TNF-α agents in RA patients. This is a retrospective chart review analysis of 82 women with RA who started anti-TNF-α agents as the first-line biologic therapy and 328 healthy age-matched women. RA patients were divided into high and low baseline NLR or PLR subgroups using the median split. European League against Rheumatism (EULAR) treatment response was evaluated at 12 weeks. RA patients had significantly higher NLR and PLR than controls. High baseline NLR and PLR groups showed higher 12-week EULAR non-response rate than low NLR (30% vs 7.1%, p = 0.01) and PLR groups (27.5% vs 9.5%, p = 0.047), respectively. After adjusting for confounding factors, high baseline NLR (OR 5.57, p = 0.014) and PLR (OR 4.24, p = 0.04) were significantly associated with a higher risk of EULAR non-response at 12 weeks. During the study period, 47 (57.3%) RA patients (lack of efficacy: n = 31; adverse events: n = 16) discontinued anti-TNF-α agents. High baseline NLR was associated with an increased risk of anti-TNF-α agent withdrawal due to lack of efficacy (HR 2.12, p = 0.045). Our data suggest that baseline NLR and PLR are useful markers for predicting the treatment outcome of anti-TNF-α agents in RA patients.

Keywords

Rheumatoid arthritis Tumor necrosis factor-alpha Blood cells Treatment outcome Biomarkers 

Notes

Acknowledgements

We specially thank the late Professor Sung-Il Kim who devoted himself to education, research, and patient care in Division of Rheumatology, Department of Internal Medicine, Pusan National University School of Medicine (1963–2011).

Author contributions

HNL: study design, data collection and analysis and writing manuscript, YKK: data interpretation, GTK: data interpretation and revision of manuscript, MWS: data interpretation and revision of manuscript, EA: data interpretation, DHS: data interpretation and revision of manuscript, SGL: study design, data analysis and interpretation, writing manuscript and coordination of entire study.

Funding

This work was supported by a clinical research Grant from Pusan National University Hospital in 2019.

Compliance with ethical standards

Conflict of interest

The authors have declared no conflicts of interest.

Ethical standards

This study protocol was approved by the by the Research and Ethical Review Board of the Pusan National University Hospital, which waived written informed consent due to retrospective study design (IRB no. 1809-010-071).

Supplementary material

296_2019_4276_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 KB)
296_2019_4276_MOESM2_ESM.docx (14 kb)
Supplementary material 2 (DOCX 13 KB)
296_2019_4276_MOESM3_ESM.tif (1.3 mb)
Supplementary figure 1. Persistence with anti-tumor necrosis factor-alpha agents in patients with rheumatoid arthritis II (TIF 1306 KB)

References

  1. 1.
    Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, Kvien TK, Navarro-Compan MV, Oliver S, Schoels M, Scholte-Voshaar M, Stamm T, Stoffer M, Takeuchi T, Aletaha D, Andreu JL, Aringer M, Bergman M, Betteridge N, Bijlsma H, Burkhardt H, Cardiel M, Combe B, Durez P, Fonseca JE, Gibofsky A, Gomez-Reino JJ, Graninger W, Hannonen P, Haraoui B, Kouloumas M, Landewe R, Martin-Mola E, Nash P, Ostergaard M, Ostor A, Richards P, Sokka-Isler T, Thorne C, Tzioufas AG, van Vollenhoven R, de Wit M, van der Heijde D (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75(1):3–15.  https://doi.org/10.1136/annrheumdis-2015-207524 CrossRefGoogle Scholar
  2. 2.
    Park EY, Lee SG, Park EK, Koo DW, Park JH, Kim GT, Tag HS, Kim HO, Suh YS (2018) Drug survival and the associated predictors in South Korean patients with rheumatoid arthritis receiving tacrolimus. Korean J Intern Med 33(1):193–202.  https://doi.org/10.3904/kjim.2015.385 CrossRefGoogle Scholar
  3. 3.
    Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, Nam J, Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M, Buckley CD, Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-Hustings Y, Emery P, Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE, Hazes JMW, Huizinga T, Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette X, McInnes I, Mysler E, Nash P, Pavelka K, Poor G, Richez C, van Riel P, Rubbert-Roth A, Saag K, da Silva J, Stamm T, Takeuchi T, Westhovens R, de Wit M, van der Heijde D (2017) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 76(6):960–977.  https://doi.org/10.1136/annrheumdis-2016-210715 CrossRefGoogle Scholar
  4. 4.
    Simsek I (2012) Predictors of response to TNF inhibitors in rheumatoid arthritis—do we have new tools for personalized medicine?. Bull NYU Hosp Jt Dis 70 (3):187–190Google Scholar
  5. 5.
    Simsek I (2010) TNF inhibitors—new and old agents for rheumatoid arthritis. Bull NYU Hosp Jt Dis 68(3):204–210Google Scholar
  6. 6.
    Zhang Y, Lu JJ, Du YP, Feng CX, Wang LQ, Chen MB (2018) Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in gastric cancer. Medicine 97(12):e0144.  https://doi.org/10.1097/MD.0000000000010144 CrossRefGoogle Scholar
  7. 7.
    Fang Q, Tong YW, Wang G, Zhang N, Chen WG, Li YF, Shen KW, Wu BW, Chen XS (2018) Neutrophil-to-lymphocyte ratio, obesity, and breast cancer risk in Chinese population. Medicine 97(30):e11692.  https://doi.org/10.1097/MD.0000000000011692 CrossRefGoogle Scholar
  8. 8.
    Arruda-Olson AM, Reeder GS, Bell MR, Weston SA, Roger VL (2009) Neutrophilia predicts death and heart failure after myocardial infarction: a community-based study. Circ Cardiovasc Qual Outcomes 2(6):656–662.  https://doi.org/10.1161/CIRCOUTCOMES.108.831024 CrossRefGoogle Scholar
  9. 9.
    Isaac V, Wu CY, Huang CT, Baune BT, Tseng CL, McLachlan CS (2016) Elevated neutrophil to lymphocyte ratio predicts mortality in medical inpatients with multiple chronic conditions. Medicine 95(23):e3832.  https://doi.org/10.1097/MD.0000000000003832 CrossRefGoogle Scholar
  10. 10.
    Sun Y, Xia L, Wang H, Chen Z, Wu Y, Chen B, Shi H, Feng Y, Yin S (2018) Is nucleate cell count and neutrophil to lymphocyte ratio related to patients with audiographically distinct sudden sensorineural hearing loss? Medicine 97(20):e10586.  https://doi.org/10.1097/MD.0000000000010586 CrossRefGoogle Scholar
  11. 11.
    Zhang L, Wang Y, Han J, Shen H, Zhao M, Cai S (2018) Neutrophil-lymphocyte ratio, gamma-glutamyl transpeptidase, lipase, high-density lipoprotein as a panel of factors to predict acute pancreatitis in pregnancy. Medicine 97(26):e11189.  https://doi.org/10.1097/md.0000000000011189 CrossRefGoogle Scholar
  12. 12.
    Erre GL, Paliogiannis P, Castagna F, Mangoni AA, Carru C, Passiu G, Zinellu A (2018) Meta-analysis of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio in rheumatoid arthritis. Eur J Clin Investig.  https://doi.org/10.1111/eci.13037 Google Scholar
  13. 13.
    Nishida Y, Hosomi S, Yamagami H, Yukawa T, Otani K, Nagami Y, Tanaka F, Taira K, Kamata N, Tanigawa T, Shiba M, Watanabe K, Watanabe T, Tominaga K, Fujiwara Y (2017) Neutrophil-to-lymphocyte ratio for predicting loss of response to infliximab in ulcerative colitis. PloS One 12(1):e0169845.  https://doi.org/10.1371/journal.pone.0169845 CrossRefGoogle Scholar
  14. 14.
    Coskun BN, Oksuz MF, Ermurat S, Tufan AN, Orucoglu N, Dogan A, Dalkilic E, Pehlivan Y (2014) Neutrophil lymphocyte ratio can be a valuable marker in defining disease activity in patients who have started anti-tumor necrosis factor (TNF) drugs for ankylosing spondylitis. Eur J Rheumatol 1(3):101–105.  https://doi.org/10.5152/eurjrheumatol.2014.034 CrossRefGoogle Scholar
  15. 15.
    Jiang Y, Zang M, Li S (2017) Serum PLR and LMR in Behcet’s disease: can they show the disease activity? Medicine 96(21):e6981.  https://doi.org/10.1097/MD.0000000000006981 CrossRefGoogle Scholar
  16. 16.
    Peng YF, Cao L, Zeng YH, Zhang ZX, Chen D, Zhang Q, Zhu YS (2015) Platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in patients with rheumatoid arthritis. Open Med (Wars) 10(1):249–253.  https://doi.org/10.1515/med-2015-0037 Google Scholar
  17. 17.
    Uslu AU, Kucuk A, Sahin A, Ugan Y, Yilmaz R, Gungor T, Bagcaci S, Kucuksen S (2015) Two new inflammatory markers associated with Disease Activity Score-28 in patients with rheumatoid arthritis: neutrophil–lymphocyte ratio and platelet-lymphocyte ratio. Int J Rheum Dis 18(7):731–735.  https://doi.org/10.1111/1756-185X.12582 CrossRefGoogle Scholar
  18. 18.
    Tekeoglu I, Gurol G, Harman H, Karakece E, Ciftci IH (2016) Overlooked hematological markers of disease activity in rheumatoid arthritis. Int J Rheum Dis 19(11):1078–1082.  https://doi.org/10.1111/1756-185X.12805 CrossRefGoogle Scholar
  19. 19.
    Chandrashekara S, Mukhtar Ahmad M, Renuka P, Anupama KR, Renuka K (2017) Characterization of neutrophil-to-lymphocyte ratio as a measure of inflammation in rheumatoid arthritis. Int J Rheum Dis 20(10):1457–1467.  https://doi.org/10.1111/1756-185X.13157 CrossRefGoogle Scholar
  20. 20.
    Chandrashekara S, Rajendran A, Bai Jaganath A, Krishnamurthy R (2015) Neutrophil-lymphocyte ratio, pain perception, and disease activity score may serve as important predictive markers for sustained remission in rheumatoid arthritis. Reumatismo 67(3):109–115.  https://doi.org/10.4081/reumatismo.2015.838 CrossRefGoogle Scholar
  21. 21.
    Maden M, Pamuk GE, Pamuk ON (2017) Development of atherosclerotic cardiovascular mortality in gouty arthritis and rheumatoid arthritis patients: are they associated with mean platelet volume and neutrophil-lymphocyte ratio? A comparative study. Arch Rheumatol 32(1):39–45.  https://doi.org/10.5606/ArchRheumatol.2017.6033 CrossRefGoogle Scholar
  22. 22.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324CrossRefGoogle Scholar
  23. 23.
    Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38(1):44–48CrossRefGoogle Scholar
  24. 24.
    van Riel PL (2014) The development of the disease activity score (DAS) and the disease activity score using 28 joint counts (DAS28). Clin Exp Rheumatol 32(5 Suppl 85):S–S65Google Scholar
  25. 25.
    van Gestel AM, Prevoo ML, van ‘t Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL (1996) Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum 39(1):34–40CrossRefGoogle Scholar
  26. 26.
    Fisher A, Bassett K, Wright JM, Brookhart MA, Freeman H, Dormuth CR (2014) Comparative persistence of the TNF antagonists in rheumatoid arthritis—a population-based cohort study. PloS One 9(8):e105193.  https://doi.org/10.1371/journal.pone.0105193 CrossRefGoogle Scholar
  27. 27.
    Lee WJ, Briars L, Lee TA, Calip GS, Suda KJ, Schumock GT (2016) Use of tumor necrosis factor-alpha inhibitors in children and young adults with juvenile idiopathic arthritis or rheumatoid arthritis. Pharmacotherapy 36(12):1201–1209.  https://doi.org/10.1002/phar.1856 CrossRefGoogle Scholar
  28. 28.
    Sauer BC, Teng CC, Tang D, Leng J, Curtis JR, Mikuls TR, Harrison DJ, Cannon GW (2017) persistence with conventional triple therapy versus a tumor necrosis factor inhibitor and methotrexate in US veterans with rheumatoid arthritis. Arthritis Care Res 69(3):313–322.  https://doi.org/10.1002/acr.22944 CrossRefGoogle Scholar
  29. 29.
    Wilke T, Mueller S, Lee SC, Majer I, Heisen M (2017) Drug survival of second biological DMARD therapy in patients with rheumatoid arthritis: a retrospective non-interventional cohort analysis. BMC Musculoskelet Disord 18(1):332.  https://doi.org/10.1186/s12891-017-1684-0 CrossRefGoogle Scholar
  30. 30.
    Lee MY, Shin JY, Park SY, Kim D, Cha HS, Lee EK (2018) Persistence of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: an analysis of the South Korean National Health Insurance Database. Semin Arthritis Rheum 47(4):485–491.  https://doi.org/10.1016/j.semarthrit.2017.08.007 CrossRefGoogle Scholar
  31. 31.
    Jones G, Hall S, Bird P, Littlejohn G, Tymms K, Youssef P, Chung E, Barrett R, Button P (2018) A retrospective review of the persistence on bDMARDs prescribed for the treatment of rheumatoid arthritis in the Australian population. Int J Rheum Dis 21(8):1581–1590.  https://doi.org/10.1111/1756-185X.13243 CrossRefGoogle Scholar
  32. 32.
    Yang Z, Zhang Z, Lin F, Ren Y, Liu D, Zhong R, Liang Y (2017) Comparisons of neutrophil-, monocyte-, eosinophil-, and basophil- lymphocyte ratios among various systemic autoimmune rheumatic diseases. APMIS Acta Pathologica Microbiologica Et Immunologica Scandinavica 125(10):863–871.  https://doi.org/10.1111/apm.12722 CrossRefGoogle Scholar
  33. 33.
    Hao X, Li D, Wu D, Zhang N (2017) The relationship between hematological indices and autoimmune rheumatic diseases (ARDs), a meta-analysis. Sci Rep 7(1):10833.  https://doi.org/10.1038/s41598-017-11398-4 CrossRefGoogle Scholar
  34. 34.
    Cascao R, Rosario HS, Souto-Carneiro MM, Fonseca JE (2010) Neutrophils in rheumatoid arthritis: more than simple final effectors. Autoimmunity Rev 9(8):531–535.  https://doi.org/10.1016/j.autrev.2009.12.013 CrossRefGoogle Scholar
  35. 35.
    Boilard E, Blanco P, Nigrovic PA (2012) Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol 8(9):534–542.  https://doi.org/10.1038/nrrheum.2012.118 CrossRefGoogle Scholar
  36. 36.
    Gasparyan AY, Stavropoulos-Kalinoglou A, Mikhailidis DP, Douglas KM, Kitas GD (2011) Platelet function in rheumatoid arthritis: arthritic and cardiovascular implications. Rheumatol Int 31(2):153–164.  https://doi.org/10.1007/s00296-010-1446-x CrossRefGoogle Scholar
  37. 37.
    Ghang B, Kwon O, Hong S, Lee CK, Yoo B, Kim YG (2017) Neutrophil-to-lymphocyte ratio is a reliable marker of treatment response in rheumatoid arthritis patients during tocilizumab therapy. Mod Rheumatol 27(3):405–410.  https://doi.org/10.1080/14397595.2016.1214340 CrossRefGoogle Scholar
  38. 38.
    Koiwa M, Goto S, Takahashi K, Kamada T, Takai S, Nakamura H (2016) Neutrophil/lymphocyte ratio in patients with rheumatoid arthritis treated with biological agents. J Nippon Med Sch 83(3):118–124.  https://doi.org/10.1272/jnms.83.118 CrossRefGoogle Scholar
  39. 39.
    Gasparyan AY, Sandoo A, Stavropoulos-Kalinoglou A, Kitas GD (2010) Mean platelet volume in patients with rheumatoid arthritis: the effect of anti-TNF-alpha therapy. Rheumatol Int 30(8):1125–1129.  https://doi.org/10.1007/s00296-009-1345-1 CrossRefGoogle Scholar
  40. 40.
    Du Pan SM, Dehler S, Ciurea A, Ziswiler HR, Gabay C, Finckh A (2009) Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis. Arthritis Rheum 61(5):560–568.  https://doi.org/10.1002/art.24463 CrossRefGoogle Scholar
  41. 41.
    Gomez-Reino JJ, Rodriguez-Lozano C, Campos-Fernandez C, Montoro M, Descalzo MA, Carmona L (2012) Change in the discontinuation pattern of tumour necrosis factor antagonists in rheumatoid arthritis over 10 years: data from the Spanish registry BIOBADASER 2.0. Ann Rheum Dis 71(3):382–385.  https://doi.org/10.1136/annrheumdis-2011-200302 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of Internal MedicinePusan National University School of Medicine, Pusan National University HospitalBusanSouth Korea
  2. 2.Biomedical Research InstitutePusan National University HospitalBusanSouth Korea
  3. 3.Division of Rheumatology, Department of Internal Medicine, KosinUniversity College of MedicineBusanSouth Korea
  4. 4.Division of Rheumatology, Department of Internal MedicinePusan National University Yangsan HospitalYangsanSouth Korea
  5. 5.Department of Microbiology and ImmunologyPusan National University School of MedicineYangsanSouth Korea

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