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Introduction
Since the discovery of the granulopoiesis signature in lupus, some hematological indices have been studied as markers of inflammation and prognosis. Hematological manifestations are common in systemic lupus erythematosus (SLE). Leukopenia occurs in 50-60% of SLE cases 1, and lymphopenia and neutropenia are common in SLE 2-3. Lymphopenia of less than 1500 cells/ml is the most prevalent initial laboratory abnormality in SLE, occurring more frequently than any of the preliminary criteria for its classification 4.
Hematological indices have gained importance in the study of various diseases including systemic autoimmune diseases. The neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been used as markers of inflammation and prognosis in several systemic diseases such as cardiovascular diseases, diabetes mellitus, cancer, and autoimmune diseases 5-8.
Some studies have suggested that these ratios may constitute possible inflammatory biomarkers in SLE 9-15. A meta-analysis by Wang et al. 11, NLR is significantly higher in patients with SLE than in healthy controls with a mean of 1.43 (95% CI, 0.98-1.88). A meta-analysis by Ma et al. 13, PLR was significantly higher in patients with SLE than in healthy controls, with a mean of 0.709 (95% CI, 0.58-0.838). The eosinophil/lymphocyte ratio (ELR) is also positively correlated with SLEDAI 10. In this study, we determined the association between hematological indices and other markers of inflammation and disease activity in patients with SLE.
Methodology
Prospective, observational, analytical, and cross-sectional studies included patients diagnosed with SLE according to the ACR/EULAR 2019 criteria from the Department of Rheumatology of the Hospital de Clínicas, National University of Asunción. The control group consisted of healthy individuals with no history of autoimmune pathology or current infections. This study was approved by the local ethics committee.
This study was conducted between March 2018 and December 2019. A clinical and sociodemographic questionnaire, laboratory studies including blood count, C-reactive protein (CRP), high-sensitivity C-reactive protein (hs-CRP), anti-DNAds, erythrocyte sedimentation rate (ESR), and SLEDAI measurements were performed. In our study, we grouped the patients according to their SLEDAI values into Group 1 (low activity): ≤5 points and Group 2 (moderate and high activity): ≥6 points 16. The neutrophil/lymphocyte ratio (NLR) was calculated as the absolute neutrophil count divided by the absolute lymphocyte count. The platelet/lymphocyte ratio (PLR) was calculated as the absolute platelet count divided by the absolute lymphocyte count. The eosinophil/lymphocyte ratio (ELR) was calculated as the absolute eosinophil count divided by the absolute number of lymphocytes. The monocyte/lymphocyte ratio (MLR) was calculated by dividing the absolute monocyte count by the absolute number of lymphocytes 5-10.
For quantitative variables, the mean and standard deviation were calculated. A non-parametric test (Mann-Whitney U test) was performed to compare the values of the variables of the control group with those of the SLE group. The resulting P-value is provided. For qualitative variables, Fisher’s exact test was performed to compare the distributions of the control group with those of the SLE group (both global and individual). The resulting P-value is provided. Correlation analysis was performed between quantitative variables, and the correlations between the set of hematological variables and activity were analyzed. Spearman’s correlation coefficient (non-parametric) was analyzed for each group. ROC curve analysis was performed to determine the sensitivity and specificity of NLR in predicting high SLEDAI scores. Statistical significance was defined as p<0.05. The R (4.1.2) software was used for statistical analysis.
Results
Eighty-seven patients diagnosed with SLE were included, of whom 85 % were female, with a median age of 34.9 ±12.3 years. Regarding the SLEDAI, a median of 3.7 ± 4.7 was found. Group 1 (low SLEDAI activity) included 68 patients (78%), and Group 2 (moderate and high activity) included 19 patients (21.8%) (Figure 1).
The control group consisted of 54 people, mostly women (87%), with a median age of 45.2 ±15.
Fifty-two percent of the patients had positive anti-DNA antibodies, and the median hs-CRP level was 3.5 ± 4.6. Regarding NLR, a median value of 2.4 ± 1.6 was obtained, ELR with a median value of 0.07 ± 0.09, MLR 0.07± 0.07 and PLR 155.89 ± 80.69 (Table 1).
An association was found between SLE patients and a higher NLR compared to the control group, with a median of 2.49 ± 1.63 (p=0.003); also with the PLR, with a median of 155.89 ±80.69 (p=0.0002), MLR with a median of 0.07 ± 0.07 (p=0.003), and the ESR rate in the 1st hour, with a median of 33.7 ± 23.25 (p=0.012) (Table 2).
When correlating the hematological ratios with the values of SLEDAI, CRP, hs-CRP, and ESR, a significant positive correlation was observed between the NLR values (r= 0.344, p=0.001) and SLEDAI, NLR (r=0.337, P=0.002), and PLR (r=0.422, p=0.001) regarding ESR in the 1st hour (Figure 2).
Based on the ROC curve (Figure 3 and Table 3), the best cut-off value for our patient cohort, Lupus-Paraguay (PY), capable of predicting patients with high activity is NLR values ≥ 2.283, with a sensitivity of 57.9% and specificity of 67.6% (AUC:0.66).
Figure 2 Heat map of the correlation between the hematologicalmetric indices, sledai, and acute phase reactants in patients with sle (a) and in controls (b) (n=87).
Discussion
In this study, we found that NLR was elevated in patients with SLE. NLR was significantly positively correlated with SLEDAI score, and both NLR and PLR were positively correlated with ESR. Neutrophils, lymphocytes, monocytes, eosinophils, and platelets play essential roles in the pathophysiology of inflammation 17. NLR, ELR, and PLR have been used along with other biomarkers to estimate the inflammatory activity of numerous rheumatic diseases 13-15. Several studies have demonstrated a connection between NLR and SLE activity in different groups of patients 9-13, in relation to SLEDAI, ESR, CRP, hs-CRP, and complement. In this study, we found a relationship between the SLEDAI and hs-CRP levels.
Firizal et al. 18, in a study of 112 patients with SLE, ROC analysis showed that the optimal cutoff point for NLR was 2.94 with a sensitivity and specificity of 60.71% and 76.79%, respectively. Both in the value of the cut-off point and, in the sensitivity, the results match with our work, but not in the specificity where the value found by them was significantly higher than ours. In the same way, the NLR, showed a correlation with SLE activity in different studies 9,13,14,19.
Qin et al. 9 reported that the PLR level was found to be relatively higher in SLE patients with nephritis compared to those without nephritis. This finding supports the notion that PLR can reflect disease activity in patients with SLE. Similarly, in this study, we found an association between PLR, SLEDAI, and hs-CRP. Interestingly, this relationship between NLR and PLR and inflammation in systemic autoimmune diseases is apparently not affected by differences in patient age, since this same relationship was found in juvenile SLE 20.
Regarding ELR, a positive correlation was found, but this was not statistically significant, unlike in other studies 10,21. The present study has several limitations. First, the sample size is small. Second, the relationship between the NLR and organ-specific inflammation was not analyzed. Third, the influence of disease treatment on these index values has not been studied. In conclusion, NLR is a useful and accessible biomarker for identifying elevated activity in SLE patients in the Lupus-PY cohort. This finding indicates that, like well-known and easily measurable laboratory parameters, the NLR may reflect the inflammatory response in patients with SLE. Further studies are needed to determine the associations between these hematologic indices in other populations with SLE.
