Osteoarthritis (OA) is an age-related joint condition impacting articular cartilage and the overall joint structure, causing joint pain, swelling, stiffness, joint deformity, and significant functional limitations, often leading to high disability. The main pathological features included cartilage deterioration, bone resorption, and osteophyte formation (1). OA is becoming increasingly prevalent globally, with substantial impacts on various health outcomes in the US and globally (2). According to data from the National Health Interview Survey, approximately 14 million Americans suffer from symptomatic knee osteoarthritis (KOA) (3). As one of the most common chronic illnesses, OA significantly affects both the physical and mental wellbeing of individuals, while also imposing a substantial financial and medical burden (4). Individuals diagnosed with OA experience a heightened risk of both all-cause and cardiovascular mortality compared to the general population (5, 6). The importance of the management of OA as part of the care of patients with multiple chronic diseases cannot be overlooked, given its impact on disability and functional limitations, as well as high all-cause and cardiovascular mortality rates (7). Therefore, this study intends to provide strategies for the long-term management of patients with arthritis by investigating the correlation between simple and easily accessible biomarkers and mortality in OA and to provide a key reference for the development of targeted interventions in the future.

Low-grade chronic inflammation is believed to be essential in the development of OA, despite its exact pathophysiology remaining unclear (8). In OA, the innate immune system plays a critical role in sustaining persistent, low-grade inflammation (8). Local joint inflammation can directly harm the joint, aggravate the severity of joint symptoms, and increase the loss of cartilage (9). Furthermore, systemic inflammation stimulates local joint inflammation, ultimately resulting in OA (10). Previous research has demonstrated that a close relationship between nutritional status indicators like albumin and body mass index (BMI) and the prognosis of OA patients (11–13). A meta-analysis found that obesity not only increases the risk of osteoarthritis (OA) but also contributes to disease progression and complications, including mortality, particularly when related to cardiovascular comorbidities. The high BMI is a leading factor in OA-related mortality and overall disease burden (14). Albumin level is a useful indicator of nutritional status in clinical populations (15). Low serum albumin was associated with increased mortality and several additional major perioperative complications after total knee arthroplasty for OA (16). Metabolic syndrome and obesity are well-known risk factors for osteoarthritis likely due to increased joint load and the promotion of chronic systemic inflammation (8). Hence, both inflammation and nutritional status impact the prognosis of OA patients. Consequently, the use of a single indicator to assess inflammation or nutritional status for prognosis evaluation may not be comprehensive. There is a critical need for novel predictive indicators that simultaneously consider inflammation and nutritional status to provide a thorough prognosis evaluation for OA patients. This study aims to identify new predictive markers that concurrently evaluate inflammation and nutritional status to comprehensively assess the outcome of OA patients.

The advanced lung cancer inflammation index (ALI) is an innovative composite measure that combines indicators of inflammation and nutritional status by considering parameters such as albumin, BMI, and the neutrophil-to-lymphocyte ratio (NLR). Initially developed to assess the outcome of lung cancer patients, ALI has been expanded for use in various other malignancies like esophageal, colorectal, pancreatic, and gastric cancers (17–22). Due to its capability to comprehensively evaluate both inflammation and nutritional status, ALI's application can be extended to chronic inflammatory conditions such as hypertension, diabetes, heart failure, stroke, and even rheumatoid arthritis (23–27). The systemic immune-inflammation index (SII) is a novel composite marker of systemic inflammation that incorporates neutrophil, lymphocyte, and platelet counts to reflect both pro-inflammatory and anti-inflammatory responses. Initially, it was designed to project longevity and the return of cancer (28, 29). Nonetheless, it is currently uncertain how the ALI and SII relate to the risk of mortality in OA patients.

The study represented a pioneering investigation that explores the associations between the innovative integrated inflammatory and nutritional status markers ALI and SII, and the mortality rates among patients with OA.

This is a large sample study aimed at providing easy and accessible monitoring markers for the long-term management of OA and providing evidence-based evidence for policy makers and clinicians. Based on a sizable cohort, this investigation was the first to explore the connections between ALI and SII and cardiovascular as well as all-cause mortality in OA patients. An increase in ALI was associated with reduced all-cause and cardiovascular mortality after multivariate adjustments. On the other hand, there was a strong correlation between an increase SII and increased cardiovascular and all-cause mortality. The data also revealed a J-shaped non-linear association between SII levels and all-cause mortality, as well as an L-shaped non-linear link between ALI levels and all-cause mortality. These results highlight the significance of ALI and SII in assessing the risk and predicting the prognosis of osteoarthritis (OA) patients. Furthermore, ROC analysis confirmed the predictive capability of ALI and SII in forecasting survival outcomes in OA patients. The AUC values for predicting all-cause mortality at 3-, 5-, 10-, and 15-years were 0.8072, 0.7996, 0.8262, and 0.8566 for ALI, and 0.8026, 0.7998, 0.8248, and 0.8549 for SII, respectively.

Patients with OA experience higher all-cause death rates than the general population, especially if they have a history of cardiovascular disease, which is a major risk factor (31). Recent evidence suggests that OA increases the risk of developing CVD (32, 33). While OA was traditionally believed to result only from cartilage deterioration causing joint damage, a more modern perspective emphasizes the role of both systemic and local inflammation in causing cartilage damage (34). OA is now understood as a joint disease involving inflammation of the synovium (synovitis), with inflammatory cell infiltration being a key characteristic (35–37). Additionally, synovitis in OA is associated with more severe joint symptoms, greater cartilage loss, reduced mobility, and higher radiographic grades (38, 39). Obesity and metabolic syndrome are significant modifiable risk factors for both the onset and advancement of OA (40, 41).

As an index integrating inflammation and nutrition, the prognostic value of ALI has been demonstrated in patients with various types of cancer (17, 19, 21). Previous research has established ALI as a reliable marker for predicting outcomes in operable non-small cell lung cancer patients (42). Recent studies have indicated the utility of ALI in assessing prognosis and the protective effects in patients with rheumatoid arthritis (27), which is consistent with our findings. The L-shaped non-linear link between ALI levels and all-cause mortality in OA patients can be explained from several perspectives. Firstly, the NLR plays a crucial role. High levels of neutrophils indicated non-specific inflammation, while low levels of lymphocytes indicated impaired immune function (43). Therefore, a higher NLR may reflect immune activity during chronic inflammation (44). In OA, the inflammation is typically chronic and low-grade, involving primarily innate immune responses with some adaptive involvement (45). The infiltration of immune cells into the synovial membrane leads to synovitis in the early stages of OA. Neutrophils are the first immune cells to post the synovium following joint damage, promoting tissue degradation through neutrophil elastase (NE) action, osteophyte formation, and the production of inflammatory cytokines and chemokines (46). Meanwhile, lymphocytes also accumulate in the synovium with impaired T and B cell function observed in OA patients compared to healthy individuals, indicating a dysfunctional immune response that may contribute significantly to OA pathogenesis (47–49). Secondly, serum albumin serves as a widely used marker for assessing nutritional status. Research has shown higher levels of serum albumin in OA patients (50). Evidence from a Mendelian randomization (MR) study supports that high levels of retinol and albumin may have a preventive impact on the incidence of osteoarthritis (12). Serum albumin has been implicated in pain reduction and effective OA management by promoting anti-inflammatory prostaglandin production, assisting in inflammation resolution, supporting cartilage healing, and aiding in symptom improvement (51). Low albumin levels may predict poorer health outcomes due to its role as a marker for systemic inflammation and nutritional status, which are crucial factors in managing OA and its comorbidities, such as cardiovascular diseases (52). Thirdly, obesity has been linked to unfavorable outcomes in OA patients. Enhanced BMI significantly increases the risk of developing radiographic and clinical hand OA, as indicated in recent meta-analyses (14, 53). Obesity is a major cause of OA, driven by multiple factors beyond biomechanical changes. Additionally, adipose tissue induces the production of inflammatory mediators and cartilage degradation factors, which contribute to cartilage deterioration and the progression of OA (54, 55). A study on elderly patients revealed that obesity not only poses a risk for OA but also for cardiovascular disease (13). Research also suggested that extreme BMIs—both low and high—are linked to worse outcomes, including higher mortality (56).

The SII has been seen associated with higher mortality rates in individuals with various diseases (57, 58). Osteoarthritis is becoming regarded as a low-grade inflammatory condition that can be impacted by platelets. Elevated platelet levels, which frequently reflect systemic inflammation, are associated with OA severity and may imply a higher risk of mortality, particularly from cardiovascular problems, which are common in OA patients (59). There is a growing understanding of the significant role platelets play in inflammatory and immune responses. Platelet activation results in increasing immune responses, contributing to the degradation of cartilage and bone in OA (60). Platelet counts outside the normal range (either low or high) predicted increased all-cause and cardiovascular mortality in the general population and the elderly, which may explain the J-shaped association between SII and all-cause mortality of OA (61). The SII integrates three distinct types of inflammatory cells, demonstrating their interconnected impacts and cumulative influence. The approach avoids the limitations of single blood cell measures, which can be influenced by factors affecting cell volume, thereby providing a more comprehensive insight into the overall inflammatory condition. Based on the results, ALI and SII are expected to be predictors for risk stratification in patients with osteoarthritis. Our results showed that elevated ALI levels (>32.23) and lower SII values (< 991.43) are associated with consistently lower mortality rates among OA patients. Therefore, more attention and management should be strengthened for this population. The study revealed that the relationships between ALI, SII and mortality outcomes in individuals with OA varied by subgroup and were not totally consistent. In terms of all-cause events, the association with lower ALI levels and higher SII values was most pronounced in individuals aged 20–65 years, males, former smokers, and current drinkers. This could be explained by the higher prevalence of OA in females compared to and in older individuals compared to younger ones (62). Notably, the inflammatory and nutritional status of patients with osteoarthritis changes over time, and these changes may lead to anti-inflammatory and pro-inflammatory imbalances, comorbidities, and increased resistance to medications (63). Therefore, dynamic monitoring of ALI and SII and assessing their impact on OA mortality may offer deeper insights.

This research has several important implications. Firstly, an important advantage of this research is the use of a substantial, nationwide cohort of US people that was tracked over time. Secondly, we enhanced the robustness of our results by conducting extensive subgroup and sensitivity analyses. Particularly, our findings highlight the prospective value of the ALI and SII as predictive factors for assessing the likelihood of death in OA patients. These variables, which can be quite easily obtained from CBC, liver function tests, and basic body measurements without additional expense, could assist healthcare professionals in identifying OA patients at a heightened risk of mortality, enabling targeted interventions to reduce risks. In order to lessen confounding effects, we included total cholesterol and HDL as factors since hyperlipidemia is a risk factor for OA.

Nonetheless, there are several limitations. Firstly, the impact of dynamic changes in ALI and SII on the mortality rate of OA were not evaluated in this study. Secondly, while we adjusted for the majority of possible variables, residual confounding due to unmeasured factors may still be present. Genetic predisposition, psychological stress, and occupational factors can all influence inflammatory nutritional status, but could not be adjusted in our study. The effects of these confounding factors should be attended to in future database development and clinical studies to improve the accuracy of the model estimates. Thirdly, potential bias could have arisen due to the reliance on self-reported OA diagnoses by patients. The concordance rate between self-reported OA and clinically well-defined OA was 81%, so the OA diagnosis can be confirmed by combining clinical assessment and imaging data, such as bone density and digital radiography. Fourthly, the data extracted from the NHANES database are mainly from household interviews and questionnaires, then there may be a selection bias by excluding individuals with severe disability who may not participate in NHANES. Therefore, it is imperative to validate our discoveries in varied cohorts and explore the fundamental mechanisms further.

In conclusion, our research showed that lower ALI levels and higher SII values, reflecting increased systemic inflammation and poor nutritional status, are independently associated with higher risks of all-cause and cardiovascular mortality in US adults with osteoarthritis. There was a J-shaped non-linear link between SII values and all-cause mortality and an L-shaped non-linear relationship between ALI levels and all-cause mortality in OA patients. However, to better understand the complex interactions between inflammatory and nutritional biomarkers and survival outcomes in people with OA, more research is necessary.