Association of neutrophil-to-lymphocyte ratio with peripheral neuropathy in rheumatoid arthritis

Abstract

Aim: Peripheral neuropathy is a frequent but often under-recognized extra-articular manifestation of rheumatoid arthritis (RA), frequently linked to chronic systemic inflammation. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a simple marker of systemic inflammatory burden. This study aimed to investigate the association between NLR and peripheral neuropathy in RA.

Methods: This cross-sectional study included 230 RA patients. Peripheral neuropathy was identified through clinical evaluation and nerve conduction studies. Demographic and clinical data, serological status, disease activity [28-joint Disease Activity Score (DAS28)], inflammatory markers, and complete blood counts were obtained. NLR was calculated from absolute neutrophil and lymphocyte counts. Multivariable logistic regression was used to identify factors associated with peripheral neuropathy. Discriminatory performance of NLR was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: Peripheral neuropathy was present in 93 of 230 patients (40.4%). Patients with neuropathy exhibited significantly higher NLR compared with those without neuropathy (median 3.8 vs. 2.3; P < 0.001). In multivariable logistic regression adjusting for age, disease duration, disease activity (DAS28), C-reactive protein (CRP), serological status, and glucocorticoid use, elevated NLR remained independently associated with the presence of peripheral neuropathy [adjusted odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.48–2.49; P < 0.001]. Other factors significantly associated with neuropathy included older age, longer disease duration, higher DAS28, and seropositive status. CRP and glucocorticoid use were not significantly associated with neuropathy in the adjusted model. In the overall cohort, the model including NLR demonstrated significantly improved discrimination for peripheral neuropathy compared with the base model without NLR, with the area under the ROC curve (AUC) increasing from 0.75 (95% CI: 0.69–0.81) to 0.83 (95% CI: 0.77–0.89) after including NLR (P < 0.001).

Conclusions: Elevated NLR is independently associated with the presence of peripheral neuropathy in RA after adjustment for major confounders, and it demonstrates incremental discriminatory value for distinguishing neuropathy status in RA.

Keywords

rheumatoid arthritis / peripheral neuropathy / neutrophil-to-lymphocyte ratio / systemic inflammation

References

[1] Agarwal V, Singh R, Wiclaf, Chauhan S, Tahlan A, Ahuja CK, et al. A clinical, electrophysiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008; 27: 841-4.

[2] Bayrak AO, Durmus D, Durmaz Y, Demir I, Canturk F, Onar MK. Electrophysiological assessment of polyneuropathic involvement in rheumatoid arthritis: relationships among demographic, clinical and laboratory findings. Neurol Res. 2010; 32: 711-4.

[3] Bharadwaj A, Haroon N. Interstitial lung disease and neuropathy as predominant extra-articular manifestations in patients with rheumatoid arthritis: a prospective study. Med Sci Monit. 2005; 11: CR498-502.

[4] Biswas M, Chatterjee A, Ghosh SK, Dasgupta S, Ghosh K, Ganguly PK. Prevalence, types, clinical associations, and determinants of peripheral neuropathy in rheumatoid patients. Ann Indian Acad Neurol. 2011; 14: 194-7.

[5] Kaeley N, Ahmad S, Pathania M, Kakkar R. Prevalence and patterns of peripheral neuropathy in patients of rheumatoid arthritis. J Family Med Prim Care. 2019; 8: 22-6.

[6] Ibrahim IK, Medani SH, El-Hameed MMA, Imam MH, Shaaban MMA. Tarsal tunnel syndrome in patients with rheumatoid arthritis, electrophysiological and ultrasound study. Alexandria J Med. 2013; 49: 95-104.

[7] Li Y, Liu J, Hu Y, Cong C, Chen Y, Fang Y. The neutrophil-to-lymphocyte ratio in rheumatoid arthritis: The dual perspectives from literature and clinic. Medicine (Baltimore). 2025; 104: e44554.

[8] O’Neil LJ, Kaplan MJ. Neutrophils in Rheumatoid Arthritis: Breaking Immune Tolerance and Fueling Disease. Trends Mol Med. 2019; 25: 215-27.

[9] Erre GL, Paliogiannis P, Castagna F, Mangoni AA, Carru C, Passiu G, et al. Meta-analysis of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio in rheumatoid arthritis. Eur J Clin Invest. 2019; 49: e13037.

[10] Yang X. The supplementary value of the neutrophil-to-lymphocyte ratio in the diagnosis of rheumatoid arthritis. Medicine (Baltimore). 2025; 104: e43048.

[11] Garg R, Thakre A. Inflammatory footprints: Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as novel biomarkers for diabetic peripheral neuropathy. J Hematol Allied Sci. 2025; 5: 189-96.

[12] Steffen U, Sieghart D, Steiner G. Rheumatoid factor and anti-citrullinated protein IgA antibodies in the diagnosis, prognosis and monitoring of patients with rheumatoid arthritis. J Transl Autoimmun. 2025; 11: 100332.

[13] Rönnelid J, Turesson C, Kastbom A. Autoantibodies in Rheumatoid Arthritis - Laboratory and Clinical Perspectives. Front Immunol. 2021; 12: 685312.

[14] Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010; 62: 2569-81.

[15] Keenan RT, Swearingen CJ, Yazici Y. Erythrocyte sedimentation rate and C-reactive protein levels are poorly correlated with clinical measures of disease activity in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis patients. Clin Exp Rheumatol. 2008; 26: 814-9.

[16] Orr CK, Najm A, Young F, McGarry T, Biniecka M, Fearon U, et al. The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis. Front Med (Lausanne). 2018; 5: 185.

[17] Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007; 21: 907-27.

[18] Conforti A, Di Cola I, Pavlych V, Ruscitti P, Berardicurti O, Ursini F, et al. Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmun Rev. 2021; 20: 102735.

[19] Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD, Tanasescu R. Extra-articular Manifestations in Rheumatoid Arthritis. Maedica (Bucur). 2010; 5: 286-91.

[20] Ateş A, Kinikli G, Turgay M, Akay G, Tokgöz G. Effects of rheumatoid factor isotypes on disease activity and severity in patients with rheumatoid arthritis: a comparative study. Clin Rheumatol. 2007; 26: 538-45.

[21] Wu D, Deng Y, Huang Y, Zhao J, Long W, Peng Y, et al. Refining synovial inflammation assessment: A modified General Synovitis Score for active rheumatoid arthritis. Exp Ther Med. 2025; 29: 58.

[22] Masoumi M, Bozorgi M, Nourmohammadi Z, Mousavi MJ, Shariati A, Karami J. Evaluation of hematological markers as prognostic tools in rheumatoid arthritis. BMC Rheumatol. 2024; 8: 75.

[23] Mercan R, Bitik B, Tufan A, Bozbulut UB, Atas N, Ozturk MA, et al. The Association Between Neutrophil/Lymphocyte Ratio and Disease Activity in Rheumatoid Arthritis and Ankylosing Spondylitis. J Clin Lab Anal. 2016; 30: 597-601.

[24] O’Byrne AM, Bolt JW, van Ansenwoude CMJ, van der Heijde M, Semmelink JF, Jongejan A, et al. Divergent gene signatures and neutrophil enrichment in lymph nodes of inflammatory arthritis patients. Arthritis Res Ther. 2025; 27: 94.

[25] Teng X, Mou DC, Li HF, Jiao L, Wu SS, Pi JK, et al. SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis. Mol Med. 2022; 28: 135.

[26] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008; 133: 775-87.

[27] Valencia X, Lipsky PE. CD4⁺CD25⁺FoxP3⁺ regulatory T cells in autoimmune diseases. Nat Clin Pract Rheumatol. 2007; 3: 619-26.

[28] Sarkar S, Fox DA. Regulatory T cells in rheumatoid arthritis. Curr Rheumatol Rep. 2008; 10: 405-12.

[29] McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity. 2008; 28: 445-53.

[30] Astry B, Venkatesha SH, Moudgil KD. Involvement of the IL-23/IL-17 axis and the Th17/Treg balance in the pathogenesis and control of autoimmune arthritis. Cytokine. 2015; 74: 54-61.