Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the accumulation of autoantibodies. It often manifests with the involvement of multiple systems and organs (1). Untreated or improperly managed SLE can cause irreversible, life-threatening organ damage. Lupus nephritis (LN), a chronic kidney disease, is one of the most common and serious organ complications of SLE, affecting about 60% of patients (2, 3). Main clinical manifestations include proteinuria, gross/microscopic hematuria, casts in the urine, impaired renal function. The main challenge in early SLE diagnosis is that delays can result in missed opportunities for effective treatment. Renal biopsy is a commonly used and reliable technique for diagnosing LN. However, this invasive procedure itself causes certain trauma to patients, making the timing of its use an urgent issue to solve clinically. Several international standards are established for assessing SLE disease activity, including the systemic lupus erythematosus disease activity index (SLEDAI-2K), systemic lupus activity measure (SLAM), and the British Isles lupus assessment group scale (BILAG), with SLEDAI-2K being the most widely used. However, clinical laboratory indicators such as urine protein levels, anti-dsDNA antibodies, complement level, creatinine (CREA), and blood urea nitrogen (BUN) have limitations and are relatively low in sensitivity and specificity, and cannot accurately distinguish between active and chronic kidney injury promptly (4, 5). Studies have shown that certain inflammatory factors and chemokines, such as TWEAK, MCP-1, NGAL, OPG, Lipocalin-2, IP-10, and CXCL-16, are involved in the pathogenesis of lupus nephritis. These factors could potentially be biomarkers for lupus nephritis, but their expression levels are influenced by various factors, including genetics, environment, and immune status (6). Therefore, novel non-invasive biomarkers are urgently needed to predict disease activity and the onset of nephritis. Ideally, these biomarkers will demonstrate significant and specific changes in the early stages of the disease, and thus evaluating the progression.

Systemic inflammation response index (SIRI) is a highly sensitive marker of inflammation across various diseases, calculated from monocytes and neutrophil-lymphocyte ratio including cancer, cardiovascular disease, and infection (7, 8). Systemic immune-inflammation index (SII), derived from platelet counts and neutrophil-lymphocyte ratio, along with SIRI, provides a more comprehensive representation of the immune-inflammatory condition. In addition, neutrophils, lymphocytes, and platelets are important components of the inflammatory response, which contributes to the progression of many autoimmune diseases (9, 10). Expressing these hematological indicators as ratios or indices enhances their predictive value (9, 11). SII and SIRI combine multiple blood routine parameters, enabling a more comprehensive assessment of the immune-inflammatory status and facilitating a more accurate evaluation of SLE disease activity. In contrast, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are non-specific inflammatory markers, and their levels can be influenced by various factors such as age, gender, and physiological state, which may lead to deviations in assessing SLE disease activity.

SII and SIRI are derived from various ratios and counts of immune cells, including neutrophils, lymphocytes, and platelets. These cells are essential for immune responses and often change in autoimmune diseases. Neutrophils typically increase during inflammation and infection, contribute to tissue damage by releasing reactive oxygen species and proteolytic enzymes. In SLE, neutrophils can form neutrophil extracellular traps (NETs), worsening inflammation and tissue injury (12). Lymphocytes, particularly T cells and B cells, are important to adaptive immune response. Dysregulated lymphocyte function and proliferation can lead to the production of autoantibody and sustained inflammation. The counts and ratios of lymphocytes may indicate the level of immune activation and autoimmunity in SLE patients (13). Monocytes, which differentiate into macrophages and dendritic cells in tissues, are essential for phagocytosis and cytokine production. Monocyte levels elevated in inflammatory conditions like SLE, contributing to tissue damage and chronic inflammation (14). Platelets are involved in inflammation and hemostasis. Their activation can cause vascular damage and intensify inflammatory responses. In SLE, increased platelet counts or activation may be associated with disease activity and organ involvement (15).

In recent years, the use of inflammatory biomarkers for the identification and prognosis of immune system diseases has become a hot research topic. However, the association between SIRI and SII with SLE disease activity and LN has been rarely studied. This study aims to investigate the relationship between SIRI and SII with disease activity and LN in SLE patients. By assessing these indicators, we seek to evaluate the disease progression of SLE and provide a solid basis for deciding the need for invasive testing.

In patients with SLE, extensive inflammatory responses can lead to multi-organ system damage (17, 18), affecting the central nervous system, hematologic system, skin, musculoskeletal system, lungs, and kidneys. Among these, kidneys are the most affected, with approximately 40%-60% of SLE patients have renal dysfunction (2, 19). LN typically occurs within the first five years of SLE diagnosis (20–22). Previous studies have demonstrated that systemic inflammation in SLE is characterized by elevated markers such as the NLR and PLR, both of which have predictive value (AUC_NLR: 0.715, AUC_PLR: less than 0.7, predicting SLE) (11, 23–26). Han et al. (27) reported significantly higher NLR levels in LN patients compared to those without LN. Compared to established markers like NLR and PLR, the SII and SIRI have been less studied, especially in SLE and LN. Our study showed that SII had the largest AUC (AUC: 0.6775, 95% CI: 0.6020 - 0.7531) for predicting LN, higher than NLR (AUC: 0.5982, 95% CI: 0.5167 - 0.6797) and PLR (AUC: 0.6567, 95% CI: 0.5779 - 0.7355). However, the area under the ROC curve for SII was relatively low, so multiple biomarkers should be combined to improve diagnostic and predictive accuracy and clinical utility. Unlike the previous findings by Ozdemir A et al. (28) (NLR was a better marker than SII in predicting SLE and LN), and Gambichler T et al. (29) (SII was significantly increased in SLE patients but was not useful in managing SLE clinically), the reasons for the discrepancies may be due to sample differences (age, race, disease severity) and methodological differences (diagnostic tools, data collection and statistical analysis). These novel inflammatory markers are advantageous due to their simplicity, non-invasiveness, and high sensitivity and specificity, making them effective in identifying kidney damage.

SLE is a complex, multifactorial disease with an unclear etiology. Several factors (genetic, immunologic, endocrine, and environmental) can influence the responses and functions of T and B lymphocytes, as well as innate immune cells via different pathways. Abnormal responses of T cells to autoantigens can lead to cytokine imbalances, including decreased IL-2 and increased IL-17, resulting in tissue inflammatory responses (30, 31). B cells, activated via cytokine interactions with T cells, produce autoantibodies that can infiltrate tissues directly or as immune complexes (IC). This process triggers complement activation, neutrophil activation, and cytokine production, all of which contribute to tissue inflammatory damage. Furthermore, innate immune cells, influenced by pathogenic factors, produce cytokines (such as interferon-α) or interact directly with lymphocytes, significantly promoting tissue inflammatory damage (32). Therefore, inflammation is a critical element in the pathogenesis of SLE. Clinically, SIRI and SII provide comprehensive insights into the inflammatory status of patients by combining multiple blood cell counts, which allows for a more subtle assessment compared to single markers like CRP and ESR. Our study revealed that SII and SIRI values in SLE patients (N = 189) were greater than those in healthy control group (N=91). The SII and SIRI levels in the LN group were higher than those in the non-LN group and healthy control group (all p< 0.001). The ROC curve analysis showed that SII and SIRI are reliable predictors of disease activity and LN. Logistic regression analysis further identified that SII and SIRI are risk factors for LN (OR_SIRI: 5.363, 95% CI: 1.931 - 14.893, OR_SII: 1.005, 95% CI: 1.002 - 1.007), with higher SII and SIRI levels correlating with increased LN risk. Compared to other indicators such as CRP, ESR, C3, and C4, SII and SIRI have greater predictive value. Moreover, after controlling for confounding factors, SIRI (0.56 < SIRI ≤ 1.00 and SIRI > 1.90) and SII (294.5 < SII ≤ 502.9) remained independent predictors of LN.

CREA and BUN rise as renal function declines in SLE patients, which is consistent with our study. Accelerated ESR indicates increased RBC aggregation, seen in vascular inflammation and tissue necrosis, and may increase in SLE patients (33). Dyslipidemia, with elevated TC, TG, LDL-C and decreased HDL-C, is associated to autoimmune diseases like SLE and rheumatoid arthritis, promoting inflammation and autoimmunity (34, 35). In SLE patients, dyslipidemia mainly shows as elevated TG, LDL-C, and decreased HDL-C (36). The complement system, with over 30 proteins, involves activation pathways related to SLE inflammation and tissue damage, especially the classical pathway (37). Low C3 and C4 levels are useful diagnostic markers for SLE (38). In this study, we found that SII and SIRI had a non-significant positive correlation with C3. The possible reason for this is that during periods of inflammation, the body's immune system is activated, and the complement system, as a part of it, plays a regulatory and enhancing role in the immune response. When inflammatory markers are elevated, they are often accompanied by increased levels of complement proteins such as C3. The SLEDAI-2K is a weighted index used to evaluate disease activity in SLE (16). Higher SLEDAI-2K scores indicate more affected tissues and organs. Patients with SLE-LN and high disease activity often experience renal involvement, suggesting that higher SLEDAI-2K scores are associated with an increased risk of renal involvement. Our study observed a trend of rising SII and SIRI with increasing SLEDAI-2K scores (rSII=0.23, p<0.05; rSIRI=0.22, p<0.05), consistent with the findings of Ergun, M C (39) (r=0.186; p<0.05), indicating a strong correlation between SII, SIRI, and SLE disease activity. These suggest that SII and SIRI may be more reflective of disease activity in SLE patients.

SII and SIRI are recently identified inflammatory markers mainly used for predicting the development and prognosis of tumors (40–43). These markers also play a significant role in predicting the progression of inflammatory diseases such as cardiovascular diseases and chronic obstructive pulmonary disease (COPD) (44–47). However, their application in SLE and LN is rarely studied. We demonstrated that elevated SII and SIRI values were associated with more severe systemic inflammatory responses and a higher likelihood of developing SLE, with SII showing a significant predictive value. Additionally, the median SII levels were lower in Class III LN pathology compared to Class IV, suggesting potential clinical significance in the stratification of LN risk.

This study has certain limitations. First, as a small-sample, single-center retrospective study without long-term clinical observation, we cannot establish the causal relationship between SII, SIRI, and disease activity or LN. To fully understand the predictive and prognostic value of SII and SIRI in SLE and LN, prospective studies with larger samples and long-term follow-up are necessary. In addition, our study population consisted of hospitalized SLE patients, which might represent more severe cases compared to outpatients. We excluded patients with incomplete SLE disease activity assessments, which might cause discrepancies. Larger, multi-center, prospective studies are needed to evaluate the clinical application value of SII and SIRI.

In conclusion, SII and SIRI levels are closely related to disease activity and LN in SLE patients. SII and SIRI may serve as predictive factors for LN diagnosis and as potential biological indicators for assessing disease progression. Additionally, the simplicity, cost-effectiveness, and non-invasiveness make them easy to popularize and important for early diagnosis and disease activity assessment in SLE and LN.