Aktuelle Rheumatologie
DOI: 10.1055/a-2243-3308
Original Article

Neutrophil-lymphocyte ratio: an independent predictor of the herpes zoster risk in rheumatoid arthritis patients treated with tofacitinib

Neutrophil-Lymphozyten-Verhältnis: Ein unabhängiger Prädiktor für das Risiko von Herpes Zoster bei rheumatoider Arthritis unter Behandlung mit Tofacitinib
Pengcheng Liu
1   Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
,
Min Zhang
1   Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
,
Yueqin Zhang
1   Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
,
Shujiao Yu
1   Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
,
Rui Wu
1   Department of Rheumatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
› Author Affiliations
Funding Information The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a grant from the National Natural Science Foundation of China (NO.82260898) and the Natural Science Foundation of Jiangxi Province (NO.20192BAB205122).

Abstract

To investigate the role of the neutrophil-lymphocyte ratio (NLR) in the risk of developing herpes zoster (HZ) in patients with rheumatoid arthritis (RA) receiving tofacitinib. This was a prospective observational study recruiting patients who were diagnosed with RA and treated with tofacitinib. Patients with previous herpes zoster infections were excluded from this study. All patients were assessed for HZ every 1–3 months and were followed up for 12 months. Univariate and multivariate logistic regression analyses were used to assess the relationship between NLR and HZ. A cutoff value of NLR was determined based on an ROC curve. A total of 277 patients were included in this study, 19 of whom developed herpes zoster. Univariate and multivariate logistic regression analyses showed that NLR (OR=19.813, p<0.05), neutrophils (OR=15.521, p<0.05) and lymphocytes (OR=0.001, p<0.05) were independent influencing factors of HZ. Through the analysis of the ROC curve, it was found that neutrophils, lymphocytes and NLR had a high predictive value for HZ (AUC=0.75; AUC=0.76; AUC=0.94). The cutoff values were 4.46*10^9/L, 1.70*10^9/L and 3.24, respectively. Given that the NLR is easy to test, NLR was also expected to be a very promising quantitative biomarker for predicting the risk of developing herpes zoster in patients with RA receiving tofacitinib.



Publication History

Received: 08 June 2023

Accepted: 09 January 2024

Article published online:
19 February 2024

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  • References

  • 1 Finckh A, Gilbert B, Hodkinson B. et al. Global epidemiology of rheumatoid arthritis. Nature reviews Rheumatology 2022; 18: 591-602 DOI: 10.1038/s41584-022-00827-y.
  • 2 Fraenkel L, Bathon JM, England BR. et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, NJ) 2021; 73: 1108-1123 DOI: 10.1002/art.41752.
  • 3 Smolen JS, Landewé RBM, Bijlsma JWJ. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Annals of the rheumatic diseases 2020; 79: 685-699 DOI: 10.1136/annrheumdis-2019-216655.
  • 4 Solomon DH, Glynn RJ, Karlson EW. et al. Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. Annals of internal medicine 2020; 172: 369-380 DOI: 10.7326/m19-3369.
  • 5 Xie W, Yang X, Huang H. et al. Risk of malignancy with non-TNFi biologic or tofacitinib therapy in rheumatoid arthritis: A meta-analysis of observational studies. Seminars in arthritis and rheumatism 2020; 50: 930-937 DOI: 10.1016/j.semarthrit.2020.08.007.
  • 6 Singh S, Fumery M, Singh AG. et al. Comparative Risk of Cardiovascular Events With Biologic and Synthetic Disease-Modifying Antirheumatic Drugs in Patients With Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. Arthritis care & research 2020; 72: 561-576 DOI: 10.1002/acr.23875.
  • 7 Guillo L, Rabaud C, Choy EH. et al. Herpes Zoster and Vaccination Strategies in Inflammatory Bowel Diseases: A Practical Guide. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2022; 20: 481-490 DOI: 10.1016/j.cgh.2020.10.027.
  • 8 Yun H, Yang S, Chen L. et al. Risk of Herpes Zoster in Autoimmune and Inflammatory Diseases: Implications for Vaccination. Arthritis & rheumatology (Hoboken, NJ) 2016; 68: 2328-2337 DOI: 10.1002/art.39670.
  • 9 Balanescu AR, Citera G, Pascual-Ramos V. et al. Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial. Annals of the rheumatic diseases 2022; 81: 1491-1503 DOI: 10.1136/ard-2022-222405.
  • 10 Barbulescu A, Askling J, Chatzidionysiou K. et al. Effectiveness of baricitinib and tofacitinib compared with bDMARDs in RA: results from a cohort study using nationwide Swedish register data. Rheumatology (Oxford, England) 2022; 61: 3952-3962 DOI: 10.1093/rheumatology/keac068.
  • 11 Fleischmann R, Kremer J, Tanaka Y. et al. Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies. Int J Rheum Dis 2016; 19: 1216-1225 DOI: 10.1111/1756-185x.12901.
  • 12 Shi Y, Xie Y, Zhang G. et al. Tofacitinib for the treatment of rheumatoid arthritis: a real-world study in China. Internal and emergency medicine 2022; 17: 703-714 DOI: 10.1007/s11739-021-02852-3.
  • 13 Dikranian AH, Gonzalez-Gay MA, Wellborne F. et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: an analysis of pooled data from phase 3 studies. RMD open 2022; 8 DOI: 10.1136/rmdopen-2021-002103.
  • 14 Curtis JR, Xie F, Yun H. et al. Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Annals of the rheumatic diseases 2016; 75: 1843-1847 DOI: 10.1136/annrheumdis-2016-209131.
  • 15 Winthrop KL, Vermeire S, Long MD. et al. Long-term Risk of Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib. Inflammatory bowel diseases 2023; 29: 85-96 DOI: 10.1093/ibd/izac063.
  • 16 Nikiphorou E, de Lusignan S, Mallen C. et al. Haematological abnormalities in new-onset rheumatoid arthritis and risk of common infections: a population-based study. Rheumatology (Oxford, England) 2020; 59: 997-1005 DOI: 10.1093/rheumatology/kez344.
  • 17 Subesinghe S, Kleymann A, Rutherford AI. et al. The association between lymphopenia and serious infection risk in rheumatoid arthritis. Rheumatology (Oxford, England) 2020; 59: 762-766 DOI: 10.1093/rheumatology/kez349.
  • 18 Yamaoka K. Benefit and Risk of Tofacitinib in the Treatment of Rheumatoid Arthritis: A Focus on Herpes Zoster. Drug safety 2016; 39: 823-840 DOI: 10.1007/s40264-016-0430-0.
  • 19 Song M, Graubard BI, Rabkin CS. et al. Neutrophil-to-lymphocyte ratio and mortality in the United States general population. Scientific reports 2021; 11: 464 DOI: 10.1038/s41598-020-79431-7.
  • 20 Herzberg H, Lifshitz K, Golan S. et al. Association between early change in neutrophil-to-lymphocyte ratio after radical cystectomy and treatment outcomes. BJU international 2022; 130: 470-477 DOI: 10.1111/bju.15757.
  • 21 Zattarin E, Manglaviti S, Apollonio G. et al. Prognostic role of neutrophil-to-lymphocyte ratio and EPSILoN score in advanced non-small-cell lung cancer patients treated with first-line chemo-immunotherapy. Future oncology (London, England) 2022; 18: 2593-2604 DOI: 10.2217/fon-2021-1454.
  • 22 Liu M, Feng Y, Zhang Y. et al. Evaluation of Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio on Predicting Responsiveness to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients. BioMed research international 2022; 2022: 3839670 DOI: 10.1155/2022/3839670.
  • 23 Aletaha D, Neogi T, Silman AJ. et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Annals of the rheumatic diseases 2010; 69: 1580-1588 DOI: 10.1136/ard.2010.138461.
  • 24 van Wijck AJM, Aerssens YR. Pain, Itch, Quality of Life, and Costs after Herpes Zoster. Pain practice : the official journal of World Institute of Pain 2017; 17: 738-746 DOI: 10.1111/papr.12518.
  • 25 Asada H. Recent topics in the management of herpes zoster. The Journal of dermatology 2023; 50: 305-310 DOI: 10.1111/1346-8138.16666.
  • 26 Ikeda D, Imano H, Mori Y. et al. Longitudinal changes in cell-mediated immunity after varicella-zoster virus skin test in the general population; Shozu Herpes Zoster Study: SHEZ study. Journal of medical virology 2023; 95: e28336 DOI: 10.1002/jmv.28336.
  • 27 Asada H. VZV-specific cell-mediated immunity, but not humoral immunity, correlates inversely with the incidence of herpes zoster and the severity of skin symptoms and zoster-associated pain: The SHEZ study. Vaccine 2019; 37: 6776-6781 DOI: 10.1016/j.vaccine.2019.09.031.
  • 28 Gialloreti LE, Merito M, Pezzotti P. et al. Epidemiology and economic burden of herpes zoster and post-herpetic neuralgia in Italy: a retrospective, population-based study. BMC infectious diseases 2010; 10: 230 DOI: 10.1186/1471-2334-10-230.
  • 29 Krasselt M, Baerwald C, Liebert UG. et al. Humoral Immunity to Varicella Zoster Virus in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis Compared to Healthy Controls. Vaccines 2021; 9 DOI: 10.3390/vaccines9040325.
  • 30 Krasselt M, Baerwald C, Liebert UG. et al. Humoral immunity to varicella zoster virus is altered in patients with rheumatoid arthritis. Clinical rheumatology 2019; 38: 2493-2500 DOI: 10.1007/s10067-019-04563-9.
  • 31 Meyer DM, Jesson MI, Li X. et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. Journal of inflammation (London, England) 2010; 7: 41 DOI: 10.1186/1476-9255-7-41.
  • 32 Traves PG, Murray B, Campigotto F. et al. JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib. Annals of the rheumatic diseases 2021; 80: 865-875 DOI: 10.1136/annrheumdis-2020-219012.
  • 33 Blagih J, Coulombe F, Vincent EE. et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 2015; 42: 41-54 DOI: 10.1016/j.immuni.2014.12.030.
  • 34 Weyand CM, Goronzy JJ. Immunometabolism in early and late stages of rheumatoid arthritis. Nature reviews Rheumatology 2017; 13: 291-301 DOI: 10.1038/nrrheum.2017.49.
  • 35 McInnes IB, Kato K, Magrey M. et al. Efficacy and Safety of Upadacitinib in Patients with Psoriatic Arthritis: 2-Year Results from the Phase 3 SELECT-PsA 1 Study. Rheumatology and therapy 2023; 10: 275-292 DOI: 10.1007/s40744-022-00499-w.
  • 36 Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140: 883-899 DOI: 10.1016/j.cell.2010.01.025.
  • 37 Bowers NL, Helton ES, Huijbregts RP. et al. Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. PLoS pathogens 2014; 10: e1003993 DOI: 10.1371/journal.ppat.1003993.
  • 38 Ohki S, Shibata M, Gonda K. et al. Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression, inflammation and hypoproteinemia in patients with cancer. Oncology reports 2012; 28: 453-458 DOI: 10.3892/or.2012.1812.
  • 39 Garcia JS, Nowosh V, López RVM. et al. Association of Systemic Inflammatory and Immune Indices With Survival in Canine Patients With Oral Melanoma, Treated With Experimental Immunotherapy Alone or Experimental Immunotherapy Plus Metronomic Chemotherapy. Frontiers in veterinary science 2022; 9: 888411 DOI: 10.3389/fvets.2022.888411.