Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease that can affect multiple organs to varying degrees of severity.1 In recent years, biomarkers such as antibodies against complement C1q, interferon alpha, and B-cell stimulatory factor, as well as its family of ligands and receptors, have been proposed as markers of disease activity and organ damage.2,3 However, a lack of clinical validation, coupled with the high processing and analysis costs associated with determining them, represents a significant barrier to their introduction into routine practice.

Haematological indices, such as the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), have been suggested as useful indicators of disease activity in various autoimmune and autoinflammatory conditions. Specifically, these indices have been found to be significantly higher in patients with SLE than in healthy controls.4,5

Several studies have demonstrated the key role played by neutrophils, lymphocytes, and platelets in the pathophysiology of SLE. However, increases in NLR and PLR indices do not necessarily indicate an absolute increase in neutrophils or platelets, since neutropenia and thrombocytopenia are prevalent among these patients. These alterations are associated with immunological mechanisms, infections, splenomegaly, or the effects of immunosuppressive therapies. Conversely, lymphopenia, affecting up to 75% of patients, can be attributed to autoantibodies targeting lymphocytes, directly influencing these indices.6

Although elevated NLR and PLR indices have been observed in patients with SLE,7 more comprehensive research is needed to evaluate their diagnostic accuracy in relation to the presence and severity of the disease. This research should also assess their usefulness in identifying specific organ involvement and prognosis, particularly in Caucasian populations. Furthermore, many existing studies do not adequately control for confounding factors, such as the use of immunosuppressive therapies.

The primary objective was to evaluate the relationship between NLR and PLR in relation to disease activity, as measured by SLEDAI-2K, and organ damage, as measured by SLICC/SDI. The secondary objectives were to estimate the relationship between these indices and different clinical manifestations and mortality in SLE.

A retrospective multicentre study involving 319 patients with systemic lupus erythematosus (SLE) was conducted. All patients met at least four of the 1997 American College of Rheumatology (ACR) classification criteria.8 All patients were over 18 years of age and had been diagnosed by a rheumatologist. They were also regularly monitored in a rheumatology outpatient clinic. The study complied with the principles established in the Declaration of Helsinki. The study protocol was approved by the Ethics Committees at the Insular University Hospital of Gran Canaria, the University Hospital of the Canary Islands (Tenerife) and the Dr Negrín University Hospital of Gran Canaria.

Demographic data, disease characteristics, activity (SLEDAI-2K), damage (SLICC/SDI), and therapy were collected. Table 1 shows the demographic and clinical characteristics of the patients. Table 2 shows the different correlations of NLR and PLR with disease damage and activity.

Descriptive statistics were calculated for quantitative and qualitative variables. Normality was assessed using the Kolmogorov-Smirnov test. Depending on the type of variable, Pearson's correlation and Wilcoxon's rank sum tests were applied. Multivariate logistic and linear regression analyses were performed to explore the association between clinical and demographic characteristics and the presence of damage (SLICC/SDI) and disease activity (SLEDAI-2K). A p-value of <.05 was considered statistically significant. The analysis was performed using STATA® MP v17.0.

Of the 319 patients with lupus, 91.5% were female and had a mean age at diagnosis of 37 ± 13.5 years. Demographic, clinical, laboratory, and therapy data are summarised in Table 1.

Significant correlations were found between NLR and SLEDAI-2K-measured disease activity (p = .009), and between PLR and SLEDAI-2K (p = .032). Similarly, lymphocyte count showed a correlation with SLEDAI-2K (p = .001). No significant associations were observed between NLR and PLR and the presence of organ damage (Table 2).

With regard to serological activity, NLR was associated with hypocomplementaemia (p = .002), but not with anti-DNA antibody positivity (Table 2). Similarly, no relationships were detected between haematological indices and the different clinical manifestations of SLE at diagnosis. A trend towards statistical significance was observed between PLR and the presence of antiphospholipid syndrome (p = .073), though no association was found with the different antiphospholipid antibodies.

Finally, both NLR and PLR were associated with mortality (p = .033 and p = .028, respectively) (Table 2).

In the multivariate analysis, which was adjusted for possible confounding factors, the ratios maintained their association with disease activity according to the SLEDAI-2K, but showed no relationship with organ damage (Tables 2.1).

In this multicentre study of 319 patients with SLE, we observed that both the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) correlate significantly with clinical disease activity, as measured by the SLEDAI-2K. Furthermore, the association of absolute lymphocyte count with disease activity suggests that lymphopenia remains a relevant marker of this autoimmune disease. These results are consistent with findings from other cohorts,9–11 as well as meta-analyses,5,7 and could support the use of haematological indices as an accessible, inexpensive way of assessing SLE activity in clinical practice.

Han et al.12 demonstrated that patients with SLE have higher NLR than healthy patients, and that this ratio is associated with disease activity, as measured by SLEDAI-2K. Similarly, these authors identified an elevated NLR cut-off point of 2.73; however, these results have not been validated in prospective studies. Cho et al.13 conducted a prospective study of 290 patients with SLE and found that both NLR and PLR were associated with disease activity. In particular, NLR was related to the Systemic Lupus Erythematosus Flare Index (SFI) and to severe flare-ups, with a sensitivity of 59% and specificity of 85%.

PLR has also been associated with SLE disease activity, although less robustly. Liu et al.14 found an association between PLR and lupus nephritis compared to a group of healthy controls. In another study, PLR was only related to anti-dsDNA antibodies, but not to serum urea, serum creatinine, or 24-h urinary protein.11 In our study, NLR was correlated with hypocomplementaemia but not with anti-DNA antibody positivity. This suggests that NLR captures general inflammatory aspects while autoantibodies have a more complex dynamic.

Regarding the presence of organ damage, our study found no significant associations with the NLR and PLR indices. This result contradicts that of other studies. For example, Suszek et al.10 included 136 patients with SLE who were treated with hydroxychloroquine and glucocorticoids. They found a relationship between the presence of mucocutaneous, joint, haematological, and renal damage, and NLR and PLR. The absence of a significant relationship with organ damage in our cohort can be explained by the fact that most patients either did not present damage or had low SLICC/SDI values. Similarly, it was demonstrated that NLR and PLR primarily reflect active inflammation rather than irreversible tissue damage. However, it is important to highlight the association observed between both indices and mortality in our study. Nevertheless, the results should be interpreted with caution due to the small sample size.

Although most observations support the potential clinical application of NLR and PLR, controversies remain regarding their diagnostic and prognostic value. A significant limitation is the small number of studies conducted in Europe and America, which restricts the generalisation of these findings — especially given the reported ethnic differences in NLR values in populations without autoimmune diseases.15 Furthermore, most studies are retrospective and do not adequately adjust for common confounding factors in patients with SLE, such as cardiovascular comorbidities, infections, or immunosuppressive therapies.

Our findings suggest that NLR and PLR indices could be useful tools in assessing SLE activity. Multivariate analysis adjusted for confounding factors reaffirmed the relationship with disease activity, but not with organ damage. However, their applicability in clinical practice still needs to be confirmed by prospective studies analysing their value as independent serological biomarkers, considering the multiple factors that can modify their behaviour. In this regard, future studies should explore in greater depth how changes in neutrophil, platelet, and lymphocyte counts—and their respective proportions—are related to functional alterations in these cells, particularly in patients with different levels of activity, organ damage, and disease progression.