Ulcerative colitis (UC) is a relapsing and remitting mucosal inflammation often restricted to the colon and rectum, which may be associated with dysregulated immune response (1). The highest incidence and prevalence of UC is 4.6 per 100,000 person-years and 57.3 per 100,000 persons in Eastern Asia, respectively (2). Patients with active UC always suffer from embarrassing and painful symptoms, such as fecal incontinence, abdominal pain, bloody diarrhea, arthritis, and fatigue, and tend to develop poorer psychosocial outcomes than those with inactive UC (3). Active UC is usually classified into mild, moderate, and severe according to the recommendation by the international guideline (4). Generally, severe UC can bring more negative impact on the patient's quality of life, social and psychological wellbeing, healthcare resource utilization (5), and prognosis than mild-moderate UC (6, 7). Early medications can avoid the progression from mild-moderate to severe UC (7). 5-aminosalicylic acid (5-ASA) is the first-line choice of medication for patients with UC diagnosed within the first year (8). Usually, patients with severe UC are not well responsive to 5-ASA, leading to the use of corticosteroids, immunosuppressants, and biologics (9–12). Therefore, it is a clinical priority to identify patients who require more aggressive treatment to reach clinical remission.

In 1955, Truelove and Witts (13) established their criteria to explore the efficacy of cortisone medications in patients with UC. Currently, the Truelove and Witts criteria have been the cornerstone of assessing the severity of UC. However, it still has several potential limitations. The most critical limitation is that the definitions of improvement and worsening are ambiguous (14), as well as that of moderate UC. In 1987, Schroeder et al. (15) further developed the Mayo score by combining clinical symptoms, laboratory tests, and endoscopic findings. Despite one of the most commonly used scores for the severity of UC, it contains endoscopic procedures, which may be invasive, expensive, and time-consuming. Recently, the partial Mayo score (PMS) has been increasingly recognized, because it can properly discriminate this disease based on stool frequency, rectal bleeding, and physician's global assessment, but does not contemplate endoscopic data (16–18). However, the requirement of clinician's subjective evaluation of patient's symptoms remains its potential drawback (19).

Erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) are two traditional serologic biomarkers and are usually used for monitoring the disease course of UC, but their sensitivity and specificity are unsatisfactory (20). Recently, several integrated indexes have been used for the assessment of infective, acute, and critical diseases, including neutrophil-to-lymphocyte ratio (NLR) (21), platelet-to-lymphocyte ratio (PLR) (22), systemic immune-inflammation index (SII) (23), neutrophil-to-platelet ratio (NPR) (24), platelet-to-albumin ratio (PAR) (25), CRP-to-albumin ratio (CAR) (26), and CRP-to-lymphocyte ratio (CLR) (27). Notably, they are non-invasive and easier to use at a low cost. Thus, the purpose of this study is to determine the accuracy of inflammatory indexes for diagnosing active UC and severe UC and identifying the response to 5-ASA medication.

The present study has compared the value of seven inflammatory indexes, including NLR, PLR, SII, NPR, PAR, CAR, and CLR, at baseline for assessing the activity of UC, the severity of UC, and response to 5-ASA, and found that SII had the greatest predictive value for active UC, CLR for severe UC, and CAR for non-response to 5-ASA.

Systemic immune-inflammation index (SII) was originally developed as an independent predictor of recurrence and survival for patients with hepatocellular carcinoma after surgery (23). Recently, it has also been demonstrated that SII level was higher in patients with UC than in healthy control groups and that SII level was positively associated with disease activity in patients (32) with UC. Similarly, our study found that the SII level was significantly correlated with the activity of UC. Moreover, SII had a better diagnostic capability for active UC than other inflammatory indexes. This finding may be attributed to the fact that immunity and inflammation are crucial for the occurrence of UC (1) and SII is calculated as neutrophil counts multiplied by platelet counts and divided by lymphocyte counts (23).

First, in a healthy human body, although 1-2 × 10¹¹ neutrophils are generated every day in the bone marrow (33), chemokine receptors, including CXCR4 and CXCR2, may maintain a delicate balance of neutrophil counts by mediating the retention of neutrophils in the bone marrow and their mobilization to peripheral blood (34, 35). In patients with active inflammatory bowel disease (IBD), there are significantly increased interleukin-17A (IL-17A) levels in inflamed mucosa that promote the transcription of granulocyte colony-stimulating factor in bone marrow (36), thereby inhibiting and activating the expression of CXCR4 binding ligands and CXCR2 binding ligands, respectively. As a result, increased neutrophils are released from the bone marrow into the peripheral blood (37). Therefore, patients with active IBD often have peripheral neutrophilia (38).

Second, lymphocytes, such as Th1 cells, Th17 cells, and B cells, can produce pro-inflammatory cytokines and activate intestinal proteases leading to mucosal damage (39), and are accumulated in the inflamed lamina propria of IBD (40, 41). In patients with active IBD, lymphocytes are accumulated from the peripheral blood into the inflamed intestine, which eventually results in peripheral lymphopenia (39).

Third, platelets are produced from long cytoplasmic processes fragmentation of megakaryocyte in the extravascular marrow space (42). Patients with IBD have elevated levels of thrombopoietin and IL-6, which are involved in megakaryocytic maturation (43). Moreover, in patients with IBD, the platelets in the peripheral blood are active and can spontaneously aggregate with increased susceptibility to proaggregating agents (44). Thus, patients with active UC often have peripheral thrombocytosis (45). Additionally, platelet counts are more strongly associated with the activity of UC than the severity of UC. Platelet counts in peripheral blood are markedly increased in patients with active UC compared with inactive UC (45), but not correlated with the Ulcerative Colitis Colonoscopic Index of Severity, which has an excellent overall assessment of endoscopic severity (46).

C-reactive protein-to-lymphocyte ratio (CLR) was originally developed as a novel index to predict the major morbidity after esophagogastric cancer resection (27). To our knowledge, only Con et al. explored the role of CLR for assessing the dynamic response to infliximab salvage treatment and predicting the risk of subsequent colectomy in patients with UC (47). Similarly, our study found that CLR had a better capability to predict the severity of UC than other inflammatory indexes. This finding may be attributed to the fact that CLR is calculated as CRP levels divided by lymphocyte counts (27). CRP, the most important acute-phase protein, is produced almost exclusively by hepatocytes in response to stimulation by IL-6, IL-1β, and tumor necrosis factor α. In the presence of an acute-phase inflammation or infection, CRP levels are increased dramatically. Contrarily, CRP levels are quickly decreased when inflammation is effectively treated (48). CRP alone can be used to predict the severity of active UC (49). Additionally, CRP levels are more strongly associated with the severity of UC than the activity of UC (50).

C-reactive protein-to-albumin ratio (CAR) was originally developed to predict the outcome of patients from acute medical ward (26). Gibson et al. (51) detected the predictive value of CAR to steroid response in patients with acute severe UC aiming to select patients who need early rescue treatment (51). Similarly, our study found that CAR had a better capability to predict the response to 5-ASA than other inflammatory indexes. This finding may be attributed to the fact that CAR is calculated as CRP levels divided by albumin levels (26). First, CRP levels are significantly correlated with the proportion of corticosteroid use in patients (52) with Crohn's disease. Corticosteroids, as rescue medications, are usually used in patients who are not well responsive to 5-ASA (9, 10). Second, albumin levels can reflect the nutritional status of patients (53) with UC and are correlated significantly with the clinical severity of UC (54). Moreover, an in vitro study suggested a strong interaction between 5-ASA and human serum albumin (55). In a mouse model of UC, 5-ASA conjugated with human serum albumin was found to show a significant therapeutic effect (56). Thus, albumin levels may influence the therapeutic effect of 5-ASA for UC.

The present study had several limitations. First, it was conducted at a single center with a relatively small sample size of total patients and a very small sample size of patients in the non-response group, probably compromising the statistical analyses presented. Second, the external validity of our findings was lacking. Third, endoscopy was not performed by the same expert at our hospital, so endoscopic assessment might be a bit inconsistent. Fourth, this study was retrospective and cross-sectional, where CRP and albumin levels were not routinely tested in our patients. Moreover, there were some damages in the inpatient information system, leading to the lack of details of two patient's medical records. Fifth, only a few patients were treated with corticosteroids or biologics in our study. Therefore, we cannot evaluate the correlation between inflammatory indexes and response to corticosteroids or biologics.

In conclusion, SII, CLR, and CAR have higher diagnostic performance than other inflammatory indexes for active UC, severe UC, and response to 5-ASA, respectively. Dynamic changes of these inflammatory indexes along with activity and severity of UC should be further explored. Moreover, future studies should also evaluate the association between these inflammatory indexes and mucosal severity of UC.

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

The studies involving human participants were reviewed and approved by Ethical Committee of General Hospital of Northern Theater Command. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

XQ: conceptualization. HL and XQ: methodology. HL, ZB, and XQ: formal analysis and writing–original draft. HL, ZB, GC, and XQ: data curation. HL, ZB, QW, GC, YZ, XG, and XQ: writing–review and editing. XG and XQ: supervision. All authors have made an intellectual contribution to the manuscript and approved the submission.

YZ received funding supported by the Natural Science Foundation of Liaoning Province (No. 2019-ZD-1058).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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