## 4 Discussion  
Our study is the first to analyze the association of NLR to clinical symptoms in mild and severe knee OA, as determined by PROs. The main finding of our study is that NLR was not associated with disease severity as determined by commonly used PROs. In the subgroup multivariate analysis, for patients with mild degenerative modifications, EQ5D VAS, IKDC and KOOSJR were independent predictors of NLR. In addition, age was significantly associated with NLR values for both symptomatic patients as well as healthy controls. Previous research divided patients based on Kellgren-Lawrence radiographic classification into 2 groups: Grades 1 to 3 (mild to moderate) group and grade 4 another group. Age and NLR\(>\)2.1 were independent predictors of advanced OA. By comparison, our patients had higher average NLR values: 1.99/2.82 versus 1.79/2.18 and 1.91/2.16 respectively [10; 11]. Although not great, these differences appear prominent in the severe OA cases. The difference may be explained by the fact that our advanced OA cases were analyzed just before total knee replacement surgery and therefore, possibly, in a more symptomatic time point. Knee degeneration has a broad spectrum, from early modifications to advanced disease. Due to our low number of patients (66) we could not compute the association of NLR to cartilage degeneration, meniscus tears and synovitis. We did not include radiographic Kellgren-Lawrence grading in the numerical analysis because, in our opinion, it would not have been relevant for the early stages. It has been shown that patients with early forms of knee OA have significant overlap of symptom severity with cases in end-stage radiographic aspect [19; 20]. We felt that using common, validated PROs may provide a wider view of symptom severity [14; 17; 21]. Although not perfect, a combination of standardized general and disease specific scores, as well as patient completed and clinician evaluation is more appropriate in defining knee OA burden [2; 3; 15; 17]. [PERSON] et al., determined that normal NLR value in healthy adults should be considered 1.65 but within a broader interval 0.78-3.53 [22]. However, the average value for NLR has also been reported to be higher (2.15) and it is race dependent [23]. In our study, the control group had an average NLR of 1.98 with a higher proportion of females. There is a plethora of inflammation biomarkers studied in knee OA, mainly produced by synovoices and chondrocytes and released into the synovial fluid [6]. The most important are pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, IL-8 and tumor necrosis factor-\(\alpha\) (TNF-\(\alpha\)), as well as fibroblast growth factor 2 (FGF2), transforming growth factor \(\beta\) (TGF-\(\beta\)) and matrix metalloproteinases [4; 5; 10; 11]. In our study, we only analyzed NLR because it is readily available, the rest of osteoarthritis markers being of little routine, clinical value and expensive. NLR as well as platelet to lymphocyte ratio and mean platelet volume are linked to inflammatory arthritis activity such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, or lupus [12]. Rheumatoid arthritis is the prototype inflammatory autoimmune diseases with joint destruction. Figure 2: (**a**) Advanced OA subgroup analysis linear regression Age versus NLR preop; (**b**) Advanced OA subgroup analysis linear regression Age versus NLR postop. The dynamic evolution of synovial inflammation and excessive CD4+ T-cell mediated immune response can be followed up using NLR. It has comparable efficacy to CRP (C reactive protein) and ESR (erythrocyte sedimentation rate) but is less influenced by cytokines [5; 24]. Patients with fractures and trauma have higher NLR compared to controls. However, neither age, gender nor admission NLR or CRP are useful in predicting short term postoperative mortality in elderly patients with hip fracture [25]. A significant limitation is our low number of subjects and somewhat bimodal distribution of disease severity (early and advanced).