As a chronic inflammatory disorder involving multiple systems and organs, rheumatic disease is usually accompanied by immunological disturbances. In addition, immunosuppressive medications are often required for treatment, so such patients are prone to severe acute multiple organ failure. Patients with rheumatic diseases have a higher risk and mortality rate of admission to the intensive care unit (ICU) compared to the general population (1, 2). The mortality rate of ICU population with rheumatic diseases has been reported to be 30.5–48% (3–5), which was greater than that of the common ICU patients (1, 6). Thus, early identification for rheumatic patients at high risk of mortality is critical to improving prognosis and optimizing healthcare resource utilization.

Red blood cell distribution width (RDW), that represents erythrocyte volume heterogeneity, increases during systemic inflammation and is useful for monitoring the disease activity in autoimmune diseases (7). RDW has been demonstrated to be a powerful indicator of all-cause mortality in critically ill patients (8), and it is also related to disease activity and outcomes in multiple rheumatic diseases (9, 10). An unclear mechanism, related perhaps to inflammation response, may underlie this process (11). Like C-reactive protein (CRP), RDW may be a useful tool when it comes to distinguishing from articular inflammatory and non-inflammatory joint diseases (9). Albumin, produced by the liver, is also known as the negative acute phase reactant and represents nutritional levels as well as inflammatory status (12, 13). Lower serum albumin levels are linked to clinical prognosis among critical illness, as per recent data (14, 15).

The ratio of red blood cell distribution width to albumin (RAR) is a simple and innovate biomarker of inflammation calculated from RDW and albumin. Previous research have demonstrated that RAR can be used as an important prognostic indicator among patients with sepsis (16), cancer (17), burn surgery (18), diabetic foot ulcers (19), heart failure (20), and acute respiratory distress syndrome (21). Rheumatic diseases are primarily distinguished by persistent inflammation and immune dysregulation (22), prompting us to hypothesize a potential association between RAR and the prognosis of this population. However, the absence of pertinent studies necessitates our own investigation into the correlation between RAR and all-cause mortality among ICU patients with rheumatic diseases.

Based on MIMIC-IV database, our current study explored the correlation between RAR and all-cause mortality for critically ill patients with rheumatic diseases. In contrast to survivors, we discovered that RAR was higher in non-survivors. Kaplan–Meier analysis revealed that 90-days and 360-days cumulative survival rates gradually declined with increasing RAR. It was observed that RAR was linearly related to 90-days and 360-days mortality risk. Further analysis of Cox regression indicated that elevated RAR (> 6.07) was significantly correlated with short- and long-term mortality among critically ill patients with rheumatic diseases. To our knowledge, this is the first study on the correlation between RAR, a novel integrative biomarker, and prognosis in critically ill patients with rheumatic diseases.

The mechanisms underlying the association between elevated RAR and rheumatic disease patients admitted in ICU have not been fully elucidated. Oxidative stress in the body and systemic inflammatory response can lead to the inhibition of erythropoiesis, the promotion of erythrocyte apoptosis, the reduction of iron metabolism, the modifying of erythrocyte membranes and the altering of erythrocyte morphology (25–30). These pathological changes result in increased heterogeneity of red blood cell volume, which manifests as an elevated RDW. Although RDW has historically been used to differentiate between anemic diseases, it has also been identified in recent years as an inflammatory marker among various disorders, such as sepsis (31), rheumatoid arthritis (RA) (32), autoimmune liver diseases (33), and systemic lupus erythematosus (SLE) (34). As the most prevalent protein in plasma, serum albumin is essential for preserving the colloid osmotic pressure of plasma (35). Rheumatic diseases may involve multiple systems, including the liver, which can be damaged and result in a reduction in albumin synthesis (36, 37).It is worth noting that albumin levels decrease as the infection progresses and are linked to inflammatory response and organ failure (15). Previous research has demonstrated a significant reduction in albumin-binding function among critically ill patients suffering from sepsis or septic shock (38).

The ratio of RDW to albumin, known as RAR, provides a comprehensive representation of the acute inflammatory response in patients. When compared to individual markers such as RDW and albumin, RAR offers a more composite assessment of disease progression. It was revealed in a study involving 14,639 sepsis participants that RAR was positively related to mortality at in-hospital, 28-days, and 90-days, as well as their ICU stay and hospital stay (16). Additionally, RAR has been demonstrated to be a powerful indicator of sepsis for patients with diabetic ketoacidosis (HR: 2.9, 95% CI: 2.0–4.1, p < 0.001) (39). However, no research has examined the correlation of RAR with prognosis for critically ill rheumatic patients. Our current findings showed that RAR and mortality at 90-days and 360-days were in correlation, with higher RAR predicting a worse clinical outcome.

Presently, the SOFA score, APACHE score, and SAPS score are widely employed in the ICU to evaluate patient prognosis. However, the APACHE II score encompasses numerous indicators and is comparatively intricate. Consequently, numerous scholars have endeavored to identify cost-effective and readily available prognostic markers of disease to enhance clinical practice. The present study contributes to the existing body of literature by confirming the association between elevated RAR, a novel comprehensive inflammatory index, and unfavorable prognosis in critically ill patients with rheumatic diseases. A study conducted on patients with critical pneumonia receiving MV support demonstrated that individuals with a RAR cutoff value > 5.73 exhibited a significantly higher 28-days mortality rate compared to those with a RAR cutoff value <5.73 (AUC 0.688). Similarly, another study focusing on patients with coronavirus diseases 2019 (COVID-19) revealed that the optimal cutoff value of RAR for predicting mortality was 5.43. Consistent with these findings, the ROC curve analysis in the present study indicated that the optimal cutoff value of RAR for predicting 90-days mortality was 5.453 (AUC 0.643). Furthermore, a comparative analysis was conducted on the ROC curves of the RAR, SOFA score, and APACHEII score. The findings revealed that the RAR exhibited a similar level of prognostic predictive ability as the latter two scores. Additionally, the combination of the RAR with the two scores enhanced their prognostic predictive power.

Our research showed that the most common acute organ dysfunction for ICU rheumatic patients was sepsis (64.97%), and the incidence of sepsis was higher (79.69%) for non-survivors. These findings suggested a relationship between infection and ICU admission in patients with rheumatic diseases. A multicenter retrospective study involving ten French ICUs also confirmed similar results. The leading cause for patients with rheumatic diseases to enter ICU was sepsis, with an incidence rate of 61.6% (40). For patients with rheumatic diseases, the mortality rate was higher in hospitalized patients with infectious causes than in those with non-infectious causes (3, 6). Severe infection in SLE patients is also considered as a major cause of morbidity and mortality (41, 42). A retrospective analysis involving individuals with connective tissue disease (CTD) who were brought to the ICU due to sepsis from 2006 to 2019 showed that sepsis mortality was as high as 40.9% in patients with CTD (43). The important characteristics of rheumatic diseases are inflammation response and immune disorder (22, 44), which can be aggravated by infection, resulting in increased RDW and decreased albumin levels in the body. This could explain the conclusion of the present study in one way. The COX regression analyses performed in RA and SLE patients, respectively, yielded inconsistent conclusions. This inconsistency may be attributed to the limited sample size of SLE patients, which hindered the attainment of a statistically valid analysis. Furthermore, the differences in inflammatory processes between the two diseases may also contribute to the inconsistent findings. This needs to be verified by more large prospective studies and in-depth animal experiments.

The current study has several strengths. First, patients with rheumatism are easily overlooked in the ICU. In our research, critically ill patients with rheumatic diseases were taken as the research object to explore the correlation between RAR and all-cause mortality. Second, the sample size in our research is relatively large, and these data originate from MIMIC-IV database, a population-based, real-world study. Furthermore, RAR is a readily available and inexpensive parameter that can be applied in various clinical settings, especially in countries and regions where healthcare resources are scarce.

Despite this, certain restrictions must be taken into consideration. First, this study is a retrospective analysis, and selection bias and confounding bias will inevitably appear in this process. Furthermore, this study explored the correlation between RAR and clinical outcomes based on the initial value at ICU admission, and did not further evaluate the dynamic changes of RAR level. In addition, the MIMIC-IV database did not provide details on the specific causes of death for patients, thus our analysis was limited to all-cause mortality. Therefore, our findings are exploratory, and prospective studies with rigorous design in different settings are required to verify the conclusions of this study.

In conclusion, the current evidence suggested that elevated RAR (> 6.07) was associated with all-cause mortality at 90-days and 360-days among critically ill patients with rheumatic diseases, serving as an independent risk factor for unfavorable prognosis.

The original contributions presented in the study are included in the article/Supplementary materials, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA). The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because We had permission to access this database (certification number: 51774135; 36142713). All personal identifiers have already been deleted to afford privacy protection for participants. Consequently, this study waived consent requirements for individual patients.

LY and QS contributed to the study conception and design. JM and LZ contributed to the data analysis. LY and JM wrote the first draft of the paper. QS critically reviewed, edited, and approved the manuscript. All authors contributed to the article and approved the submitted version.