Clinical value of the systemic immune-inflammation index in patients with Crohn disease

Abstract

The systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) are emerging biomarkers that reflect the immunological and inflammatory states of an organism. The calculation formula for SII is neutrophil (N) * platelet (P)/lymphocyte (L). However, the clinical relevance of SII in Crohn disease (CD) has not yet been explored. The primary aim of this study was to investigate the associations between SII, PLR, and NLR and CD, and to compare their respective potentials in evaluating disease activity. Our retrospective study included 119 CD patients and 121 sex- and age-matched healthy individuals who visited our hospital between February 2014 and February 2023. Clinical data and laboratory indices for all participants were retrieved from the hospital’s medical record system. Disease activity in CD patients was assessed and quantified using the CD activity index. The SII was significantly higher in CD patients in comparison with healthy individuals (all P <.05). Among CD patients, males exhibited higher SII values than females, and patients with a low body mass index had higher SII values than those with a high body mass index (P <.05). SII, PLR, and NLR demonstrated numerically stronger positive correlations with CD Endoscopic Index of Severity (R = 0.298–0.370, P <.01) and Simple Endoscopic Score for CD (R = 0.309–0.382, P <.01) compared to CRP (R = 0.252, P = .009; R = 0.295, P = .002). Furthermore, multiple linear regression analysis revealed an independent association between penetrating disease and SII (beta = 0.455, t = 5.250, P <.001). The SII exhibited superior diagnostic performance for penetrating CD compared to PLR, NLR and CRP, demonstrating an area under the receiver operating characteristic (ROC) curve of 0.710. The cutoff value of SII was determined to be 1745.85, with a sensitivity of 0.615 and specificity of 0.783. We demonstrated that SII levels were significantly higher in CD patients compared to healthy individuals and were positively correlated with disease activity in CD. Furthermore, SII showed superior diagnostic performance in ruling out non CD compared to PLR, NLR and CRP.

1. Introduction

Crohn disease (CD) is a chronic inflammatory disorder affecting the entire gastrointestinal tract, with its etiology likely involving genetic, environmental, and gut microbiota factors.^[1,2] Since the mid-20th century, its incidence has risen sharply in Western countries and is now also increasing in Asian countries.^[3] Common complications of CD, including intestinal perforation, fistulas, and perianal disease, often require surgical intervention and have a significant impact on patients’ quality of life and life expectancy.^[4] Early diagnosis and timely intervention are essential to improving prognosis and survival.^[5] While endoscopy, radiologic imaging, ultrasound and laboratory markers are effective for assessing CD activity, each has notable limitations.^[6,7] Endoscopy, as an invasive and costly procedure, carries risks such as perforation, which may reduce patient adherence to follow-up.^[8] Radiologic imaging, meanwhile, exposes patients to radiation and is unsuitable for frequent short-term monitoring.^[9] The reliability of intestinal ultrasound findings is highly operator-dependent, and this modality demonstrates limited sensitivity in assessing the proximal small bowel.^[10] Although biomarkers such as fecal calprotectin and C-reactive protein (CRP) are widely used to predict and assess disease activity in CD, their sensitivity remains inadequate.^[11] Therefore, there is a critical need to identify a noninvasive, affordable, and accessible biomarker for clinical application.

The systemic immune-inflammation index (SII), first introduced by Hu et al^[12] in 2014, is a novel biomarker reflecting the immune and inflammatory status of the host.

The calculation formula for SII is neutrophil * platelet/lymphocyte.^[12] SII has been used to assess the prognosis of various malignant tumors, including colorectal cancer, hepatocellular carcinoma, lung cancer, prostate cancer, and urothelial carcinoma, among others.^[13–17] For colorectal cancer patients, the SII can serve to identify high-risk patients within the same TNM stage and predict postoperative liver metastasis.^[13,18] Furthermore, studies have demonstrated that SII is associated with poor prognosis in cardiovascular, endocrine, and autoimmune diseases.^[19–21] Elevated SII values indicate relatively high platelet and neutrophil counts alongside low lymphocyte counts, which reflect a pronounced inflammatory response in the organism.^[22] Previous research has shown that SII correlates positively with disease activity in patients with Inflammatory bowel disease (IBD), as well as with CRP and erythrocyte sedimentation rate (ESR).^[23,24] Additionally, accumulating evidence suggests that the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) may also serve as valuable biomarkers for various systemic inflammation-related diseases, with both indices demonstrating strong associations with disease activity and severity in IBD.^[25–27]

To our knowledge, there are currently limited reports on the clinical utility of the novel biomarkers SII, PLR, and NLR in CD, and comparative studies evaluating their respective clinical values remain scarce. Therefore, this study aimed to evaluate the correlations of SII, PLR, and NLR with CD, and to compare their respective potentials in disease assessment.

2. Materials and methods

2.1. Subjects of this study

This study included 119 patients with CD who attended the Gastroenterology Department at the Affiliated Hospital of Qingdao University between February 1, 2014 and February 1, 2023, of whom 106 were in the active stage and 13 were in remission. The diagnosis of CD was based on a comprehensive assessment, including clinical manifestations, laboratory tests, endoscopic evaluations, radiological imaging, and histopathological analyses. During the same period, 121 healthy individuals, matched for sex and age, were included as the control group. A detailed patient selection flowchart is provided in Figure 1.

Figure 1.

Selection process of the CD patients and healthy individuals. CD = crohn’s disease.

The exclusion criteria were as follows: other intestinal diseases, such as intestinal tuberculosis and ulcerative colitis (UC); infectious diseases, autoimmune diseases, metabolic diseases, or malignant tumors; diabetes mellitus, hypertension, cardiovascular diseases, hepatic insufficiency, or renal insufficiency; use of anti-inflammatory drugs or corticosteroids; or incomplete clinical data.

2.2. Study design

This study was conducted as a retrospective analysis. Demographic data (age and gender), clinical symptoms and signs, disease location, perianal involvement, disease behavior, colonoscopy findings, and laboratory results for all participants were retrieved from the hospital’s medical record system. The above data were accessed between November 2024 and December 2024.

Disease activity was assessed using the CD Activity Index (CDAI).^[28] A CDAI score of <150 was classified as remission; scores between 150 and 220 were classified as mild activity; scores between 220 and 450 as moderate activity; and scores >450 as severe activity.

According to the Montreal classification, disease location was categorized into 4 groups: terminal ileum (L1), colon (L2), ileocolon (L3), and isolated upper gastrointestinal tract (L4). Additionally, disease behavior was categorized into 3 types: inflammatory (B1), structuring (B2), and penetrating (B3).

2.3. Colonoscopic assessment

Endoscopic disease activity was assessed using the CD Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for CD (SES-CD).^[29,30] The CDEIS is based on 4 parameters: deep ulceration, shallow ulceration, extent of surface involvement, and extent of ulcer involvement. These parameters are evaluated at 5 sites: the terminal ileum, ascending colon, transverse colon, descending colon, and rectum. The presence or absence of stenosis is also considered, yielding scores ranging from 0 to 44.

As a simplified alternative to the CDEIS, the SES-CD provides a total score ranging from 0 to 56. It is calculated by summing the scores for each of the 5 bowel segments based on 4 criteria: ulcer area, proportion of ulcerated surfaces, proportion of bowel segments involved in the lesion, and degree of stenosis.

2.4. Laboratory evaluation

CRP, ESR, hemoglobin (Hb), neutrophil (N), platelet (P), and lymphocyte (L) counts were obtained for all participants within 1 week of colonoscopy/clinical evaluation. SII = N*P/L; PLR = P/L; NLR = N/L.

2.5. Statistical analysis

All statistical analyses were conducted using SPSS version 26.0 (Chicago). Categorical variables were expressed as counts and percentages, and differences in proportions between the 2 groups were analyzed using the chi-square test. The normality of data was assessed using the Kolmogorov-Smirnov test. Normally distributed data were presented as mean ± standard deviation, while non-normally distributed data were reported as median and interquartile range (IQR).

Comparisons between 2 groups were performed using the independent Student t test for normally distributed data and the Mann–Whitney U test for non-normally distributed data. For comparisons among multiple groups, the Kruskal–Wallis test with Bonferroni correction was employed. Spearman correlation analysis was used to assess the relationships between SII, PLR, NLR, CRP and other variables. Additionally, multiple linear regression analysis was conducted to identify factors (gender, age, BMI, CDAI, or disease location) independently associated with SII.

The diagnostic potential of the SII, PLR, NLR, and CRP in assessing disease activity was evaluated using receiver operating characteristic curves. A 2-sided P-value of <.05 was deemed statistically significant.

2.6. Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (QYFY WZLL 29242). Additionally, because this study was retrospective, the requirement for written informed consent was waived.

3. Results

3.1. Baseline characteristics of CD patients and healthy Controls

The baseline characteristics of 119 CD patients and 121 healthy individuals are detailed in Table 1. Of the CD cohort, 74 patients (72.3%) were male. B3 disease behavior was present in 13 cases (10.9%), comprising 2 internal fistulas and 11 perianal fistulas. Upper gastrointestinal tract involvement was detected in 4 patients (3.4%). Perianal involvement was observed in 19 patients (16.0%), including 8 with perianal abscesses.

Table 1.

Clinical characteristics and laboratory data of CD patients and healthy controls.

	CD (N = 119)	Controls (N = 121)	P
Gender (male/female)	74/45	76/45	.920
Age (year)	43.92 ± 17.08	44.37 ± 16.31	.836
BMI(kg/m2)	21.19 ± 3.52	24.59 ± 3.73	<.001
CDAI	252.18 (182.81–409.71)	–	–
CDEIS	10.0 (7.0–15.0)	–	–
SES-CD	12.0 (7.0–18.0)	–	–
ESR (mm/h)	21.0 (10.0–40.5)	–	–
CRP (mg/L)	11.3 (3.14–39.1)	–	–
Hb (g/L)	120.0 (105.0–135.0)	151.0 (137.0–160.0)	<.001
NLR	2.82 (1.82–4.90)	1.56 (1.21–1.91)	<.001
PLR	188.11 (135.24–311.21)	114.56 (94.47–146.64)	<.001
SII	896.43 (482.17–1791.96)	365.44 (277.52–514.33)	<.001

BMI = body mass index, CD = crohn’s disease, CDAI = Crohn disease activity index, CDEIS = Crohn disease endoscopic index of severity, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, Hb = hemoglobin, NLR = neutrophil-to-lymphocyte ratio, PLR = platelet-to-lymphocyte ratio, SES-CD = simple endoscopic score for Crohn disease, SII = systemic immune-inflammation index.

Compared to healthy individuals, CD patients demonstrated higher NLR, PLR, and SII values, alongside lower Hb levels and body mass index (BMI). These differences were statistically significant (all P <.001). In contrast, no significant differences were observed in gender or age (P >.05).

3.2. SII levels in subgroups of CD patients and healthy controls

SII levels in CD patients and healthy individuals were stratified by gender, age, and BMI, as shown in Table 2. The stratified analysis revealed that SII levels were consistently higher in the CD group compared to healthy individuals across all subgroups (all P <.05). Additionally, significant differences in SII levels were observed within the CD cohort based on gender and BMI. Male CD patients exhibited higher SII levels compared to female CD patients, and those with a BMI <18.5 kg/m² had higher SII levels than patients with a BMI ≥18.5 kg/m²(P <.05).

Table 2.

SII levels in gender, age and BMI subgroups of CD patients and healthy controls.

Group	SII (CD)	SII(Controls)	P
Gender
Male	1020.93 (513.69–1801.58) (n = 74)*	374.19 (296.41–516.36) (n = 76)	<.001
Female	727.12 (390.34–1777.97) (n = 45)	332.76 (263.38–518-02) (n = 45)	<.001
Age (year)
<30	1206.93 (716.38–1927.46) (n = 29)	449.12 (309.81–608.91) (n = 29)	<.001
30–50	896.43 (496.21–1904.91) (n = 49)	366.73 (292.27–506.06) (n = 50)	<.001
>50	626.09 (390.34–1745.85) (n = 41)	324.91 (235.64–398.48) (n = 42)	<.001
BMI(kg/m2)
<18.50	1177.33 (681.38–2443.81) (n = 26)*	279.39 (267.97–701.04) (n = 5)	.007
≥18.50	830.46 (441.25–1566.96) (n = 93)	365.57 (277.22–516.73) (n = 116)	<.001

BMI = body mass index, CD = crohn’s disease, SII = systemic immune-inflammation index.

Comparison of SII levels within CD and control groups respectively according to gender, age and BMI.

^*P <.05.

For the CD patient group, SII levels stratified by disease location, disease behavior, perianal involvement, and CDAI are presented in Table 3. Patients with penetrating CD showed higher SII levels compared to other disease behaviors (P = .042). However, no significant differences in SII levels were found among subgroups stratified by disease location or perianal involvement (P >.05). Bonferroni correction suggested that CDAI is significantly higher in L3 CD patients than in L1 (P = .001) or L2 (P = .010) (Table 4).

Table 3.

SII levels of CD patients in the stratification of disease location, disease behavior, perianal involvement and CDAI.

Group	SII (CD)	P
Disease location
L1	738.42 (377.14–1457.01)(n = 29)	.241
L2	727.12 (410.89–1830.43)(n = 27)
L3	1067.82 (544.43–2139.62)(n = 59)
L4	769.97 (347.10–1447.75)(n = 4)
Disease behaviour
B1	852.56 (415.37–1633.86)(n = 73)	.042
B2	923.03 (558.52–1438.12)(n = 33)
B3	2245.82 (640.65–7944.80)(n = 13)
Perianal involvement
Yes	1106.59 (544.43–2117.94)(n = 19)	.177
No	856.82 (468.47–1699.09)(n = 100)
Disease severity(CDAI)
Remission (<150)	511.21 (313.36–1299.98) (n = 13)	.003
Mild (150–220)	671.04 (409.96–1131.68) (n = 42)
Moderate (220–450)	1280.50 (586.44–2501.59) (n = 40)
Severe (>450)	1202.19 (758.48–2052.70) (n = 24)

BMI = body mass index, CD = crohn’s disease, CDAI = Crohn disease activity index, SII = systemic immune-inflammation index.

Table 4.

Levels of SII, PLR, NLR and CDAI in CD patients with different disease location.

	L1 (n = 29)	L2 (n = 27)	L3 (n = 59)	P
SII	738.42 (377.14–1457.01)	727.12 (410.89–1830.43)	1067.82 (544.43–2139.62)	.158
PLR	177.78 (112.48–274.69)	188.11 (138.51–296.34)	189.71 (150.35–328.71)	.381
NLR	2.59 (1.57–4.23)	2.76 (1.53–6.37)	3.04 (2.20–4.90)	.382
CDAI	195.11 (177.94–317.8)	196.67 (141.20–353.52)	346.96 (200.75–451.93)	<.001*

According to the Montreal classification, L1 = terminal ileum, L2 = colon, L3 = ileocolon.

CDAI = Crohn disease activity index, NLR = neutrophil-to-lymphocyte ratio, PLR = platelet-to-lymphocyte ratio, SII = systemic immune-inflammation index.

^*CD patients with L3 exhibited significantly higher CDAI scores compared to those with L1 (P = .001) or L2 (P = .010) by Bonferroni correction.

3.3. Correlation of SII, PLR, NLR and CRP with CD severity

Table 5 shows in detail the correlation of SII, PLR, NLR, CRP with laboratory indices, clinical and endoscopic scores in CD patients. SII, PLR, and NLR exhibited a significant inverse correlation with Hb (r = −0.408 to −0.232, P <.05), however, no significant association was observed between CRP and Hb (r = −0.110, P = .262). While SII, PLR, and NLR showed positive correlations with both ESR (R = 0.299–0.420, P <.01) and CDAI (R = 0.264–0.301, P <.01), these associations appeared weaker than those observed with CRP (R = 0.511, P <.001; R = 0.364, P <.001). Notably, in the analysis of endoscopic severity, SII, PLR, and NLR demonstrated numerically stronger positive correlations with CDEIS (R = 0.298–0.370, P <.01) and SES-CD (R = 0.309–0.382, P <.01) compared to CRP (R = 0.252, P = .009; R = 0.295, P = .002).

Table 5.

Correlations between SII, PLR, NLR, CRP and clinical/endoscopic/laboratory parameters in CD patients.

Parameter	SII		PLR		NLR		CRP
	r	P	r	P	r	P	r	P
Hb	−0.292	.001	−0.408	<.001	−0.232	.011	−0.110	.262
CRP	0.489	<.001	0.317	.001	0.444	<.001	–	–
ESR	0.420	<.001	0.299	.002	0.373	<.001	0.511	<.001
CDAI	0.270	.003	0.264	.004	0.301	.001	0.364	<.001
CDEIS	0.370	<.001	0.298	.001	0.351	<.001	0.252	.009
SES-CD	0.382	<.001	0.309	.001	0.372	<.001	0.295	.002

CD = crohn’s disease, CDAI = Crohn disease activity index, CDEIS = Crohn disease endoscopic index of severity, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, Hb = hemoglobin, NLR = neutrophil-to-lymphocyte ratio, PLR = platelet-to-lymphocyte ratio, SES-CD = simple endoscopic score for Crohn disease, SII = systemic immune-inflammation index.

3.4. Comparison of SII, PLR and NLR in CD patients with different clinical severities

Based on CDAI, CD patients were classified into 4 subgroups: 13 patients in remission, 42 patients with mildly active disease, 40 patients with moderately active disease, and 24 patients with severely active disease. SII values differed significantly among these subgroups (P = .003). Further comparisons revealed that SII values in moderately active patients were significantly higher than those in mildly active patients (P = .026) (Fig. 2A). Similarly, PLR and NLR values showed significant differences across the 4 subgroups (both P = .001) (Fig. 2B and C). Further analysis demonstrated that PLR values were significantly higher in moderately active patients compared to those in remission (P = .049) and mildly active patients (P = .004) (Fig. 2B). Additionally, NLR values were significantly elevated in patients with moderate-to-severe activity compared to those with remission-to-mild activity (P <.05) (Fig. 2C).

Figure 2.

Comparison of the SII (A), PLR (B) and NLR (C) levels between the different CD disease severity subgroups. CD = crohn’s disease, NLR = neutrophil-to-lymphocyte ratio, PLR = platelet-to-lymphocyte ratio, SII = systemic immune-inflammation index.

3.5. Comparison of the diagnostic value of SII, PLR, NLR and CRP in active CD

First, we compared SII, PLR, NLR, and CRP values between the moderate-to-severe group (n = 64) and the remission-to-mild group (n = 55) using the Mann–Whitney U test. The moderate-to-severe group demonstrated significantly higher values for SII [median (IQR): 1230.84 (609.24–2378.20) vs 626.09 (377.86–1151.22); P <.001], PLR [median (IQR): 223.73 (172.46–348.57) vs 159.40 (112.74–232.78); P <.001], NLR [median (IQR): 3.62 (2.50–6.39) vs 2.20 (1.53–3.01); P <.001], and CRP [median (IQR): 29.61 (7.91–48.33) vs 5.00 (1.63–15.58); P <.001] compared to the remission-to-mild group (Fig. 3A–D).

Figure 3.

Performance of SII, PLR, NLR and CRP in the assessment of moderate-to-severe CD. Comparison of SII (A), PLR (B), NLR (C), and CRP (D) between the remission-to-mild group (n = 55) and moderate-to-severe group (n = 64). According to the ROC curves, the CRP showed the highest diagnostic value with an AUC of 0.751 (H), and the diagnostic values for SII (E), PLR (F), and NLR (G) were comparable, with AUCs of 0.697, 0.713, and 0.708, respectively. AUC = area under the curve, CD = crohn’s disease, CRP = C-reactive protein, NLR = neutrophil-to-lymphocyte ratio, PLR = platelet-to-lymphocyte ratio, ROC = receiver operating characteristic, SII = systemic immune-inflammation index

Next, we evaluated the diagnostic performance of SII, PLR, NLR and CRP for identifying moderate-to-severe CD using receiver operating characteristic curves (Fig. 3E–H). The CRP showed the highest diagnostic value with an area under the curve (AUC) of 0.751 [cutoff value (COV): 6.79, sensitivity (SEN): 0.821, specificity (SPE): 0.612, positive predictive value (PPV): 0.708, negative predictive value (NPV): 0.750] (Fig. 3H). The diagnostic values of other 3 biomarkers were comparable. The AUCs for SII, PLR and NLR were 0.697 (COV: 1540.67, SEN: 0.453, SPE: 0.855, PPV: 0.784, NPV:0.573), 0.713 (COV: 178.46, SEN: 0.703, SPE: 0.618, PPV:0.682, NPV:0.642) and 0.708 (COV: 2.95, SEN: 0.618, SPE: 0.745, PPV:0.750, NPV:0.650), respectively (Fig. 3E–G).

3.6. Comparison of diagnostic value of SII, PLR, NLR and CRP for CD disease behavior

In terms of disease behavior, there were 73 participants with B1, 33 participants with B2 and 13 participants with B3. Notably, the penetrating group exhibited significantly higher levels of SII, PLR, NLR, and CRP compared to the nonpenetrating group [median (IQR): 2245.82 (640.65–7944.80) vs 861.16 (463.59–1580.55); 406.15 (142.19–610.03) vs 184.63 (134.36–287.27); 5.83 (2.12–13.28) vs 2.78 (1.78–4.57); 20.87 (10.33–64.77) vs 9.71 (2.72–39.22); all P <.05] (Fig. 4A–D). Among these, the SII showed the highest diagnostic value for identifying penetrating disease, with an AUC of 0.710 (COV: 1745.85, SEN: 0.615, SPE: 0.783, PPV: 0.258, NPV: 0.943) (Fig. 4E). In comparison, the AUC values for PLR, NLR and CRP were 0.681 (COV: 398.73, SEN: 0.538, SPE: 0.925, PPV: 0.467, NPV: 0.942), 0.669 (COV: 4.82, SEN: 0.615, SPE: 0.783, PPV: 0.258, NPV: 0.943) and 0.674 (COV: 5.00, SEN: 1.000, SPE: 0.359, PPV: 0.181, NPV: 1.000), respectively (Fig. 4F–H).

Figure 4.

Performance of SII, PLR, NLR, and CRP for identifying penetrating disease. Comparison of SII (A), PLR (B), NLR (C), and CRP (D) between the nonpenetrating group (n = 106) and penetrating group (n = 13). According to the ROC curve, SII (E) demonstrated the highest diagnostic value, with an AUC of 0.710, while the AUC values for PLR (F), NLR (G) and CRP (H) were 0.681, 0.669, and 0.674, respectively. AUC = area under the curve, CD = crohn’s disease, CRP = C-reactive protein, NLR = neutrophil-to-lymphocyte ratio, PLR = platelet-to-lymphocyte ratio, ROC = receiver operating characteristic, SII = systemic immune-inflammation index.

In addition, multiple linear regression analysis identified a significant independent association between penetrating disease behavior and SII (beta = 0.455, t = 5.250, P <.001). However, no independent correlations were found between SII and other factors, including gender, age, BMI, CDAI, or disease location (P >.05) (Table 6).

Table 6.

Multiple linear regression analysis with SII as the dependent variable.

	Unstandardized coefficient		Standardized coefficient	t	P-value	95% CI
	β	Standard error
Constant	1626.002	1453.682	–	1.119	.266	−1255.149 to 4507.153
Gender	−360.676	421.689	−0.076	−0.855	.394	−1196.450 to 475.098
Age	−11.834	11.849	−0.087	−0.999	.320	−35.319 to 11.651
BMI	−47.824	57.920	−0.073	−0.826	.411	−162.619 to 66.972
CDAI	2.308	1.744	0.121	1.324	.188	−1.148 to 5.763
L2	879.697	551.390	0.160	1.595	.114	−213.140 to 1972.534
L3	966.396	507.106	0.209	1.906	.059	−38.673 to 1971.464
L4	205.720	1138.578	0.016	0.181	.857	−2050.905 to 2462.346
B2	−80.622	454.061	−0.016	−0.178	.859	−980.557 to 819.313
B3	3368.975	641.729	0.455	5.250	<.001 *	2097.088–4640.861

BMI = body mass index, CDAI = Crohn disease activity index, SII = systemic immune-inflammation index.

^*Multiple linear regression analysis identified a significant independent association between penetrating disease behavior and SII (beta = 0.455, t = 5.250, P < .001).

4. Discussion

In this study, we assessed the clinical significance of SII, PLR, NLR and CRP in patients diagnosed with CD. Our findings revealed that SII levels in CD patients were significantly higher than those in healthy individuals. Among CD patients, individuals with a low BMI (<18.5 kg/m²) demonstrated higher SII levels compared to those with a high BMI (≥ 18.5 kg/m²). Additionally, penetrating CD patients exhibited elevated SII values. SII, PLR, and NLR were negatively correlated with Hb levels and positively correlated with CRP, ESR, CDAI, CDEIS, and SES-CD. Multiple linear regression analysis identified an independent association between penetrating disease behavior and SII. Furthermore, SII appears to have a higher diagnostic value in identifying penetrating disease compared to PLR, NLR and CRP.

The pathogenesis of CD involves environmental factors acting on genetically susceptible individuals, with the participation of intestinal microorganisms. This interaction disrupts intestinal immune balance, damages the intestinal mucosal barrier, and leads to persistent inflammatory injury of the intestinal mucosa.^[2] Neutrophils, lymphocytes, and platelets play crucial roles in this pathological process. During the initial phase of inflammation, neutrophils accumulate in the affected mucosa, and as the disease progresses, uncontrolled activation of neutrophils can cause severe tissue damage.^[31] The increased expression of the antiapoptotic protein A1 delays or reduces neutrophil apoptosis, contributing to the chronicity of the disease.^[32] In addition to their roles in coagulation and thrombosis, platelets also participate in the inflammatory response by releasing cytokines and chemokines.^[33,34] A study by Kapsoritakis et al reported that patients with active CD exhibited significantly higher platelet levels than those in remission and healthy controls.^[35] Furthermore, a disrupted distribution of lymphocytes in inflamed tissues has been observed, characterized by an increase in activated Th17 cells and a decrease in lymphocyte populations such as γδT and Treg cells. A reduction in intraepithelial γδT cells and an abnormal spatial distribution of T-cell subsets may contribute to CD transmural inflammation.^[36,37] Jalalvand study highlighted that patients with IBD, particularly those in the active disease stage, often show a decrease in Treg cells, which may lead to overactivation of the autoimmune response and immune system imbalance.^[38]

The SII is a novel marker of the body’s inflammatory state, calculated based on neutrophil, platelet, and lymphocyte counts.^[23] A retrospective study involving 2642 patients with rheumatoid arthritis demonstrated that elevated SII levels were associated with increased disease activity and poorer prognostic outcomes in rheumatoid arthritis.^[21] Liu et al identified high SII as an independent risk factor for acute severe pancreatitis.^[39] Moreover, Xie et al conducted a single-center study with 187 patients with UC and found that SII effectively distinguished between active and remission phases and was independently correlated with Mayo scores.^[40] In 2022, Pakoz et al reported results consistent with those of Xie.^[23] Deng et al demonstrated that SII plays a crucial role in assessing disease severity and monitoring mucosal healing in CD.^[24] Furthermore, Liu et al suggested that SII may aid in predicting the therapeutic response to infliximab in patients with CD.^[41] As noninvasive and accessible biomarkers, PLR and NLR are correlated with CRP and ESR, making them useful for distinguishing CD patients from healthy controls.^[25] Tan et al reported that elevated PLR and NLR are associated with increased disease severity in CD.^[27] Mullin et al identified a significant association between elevated NLR and PLR levels and the occurrence of major postoperative complications and reoperation in CD patients.^[42] However, to date, studies comprehensively evaluating and comparing the clinical value of SII, PLR, and NLR in CD patients remain relatively scarce.

Consistent with the findings of Liu et al, our study also demonstrated that SII levels were significantly higher in patients with CD than in healthy individuals. Additionally, stratified analyses revealed that SII levels in CD patients were consistently higher than those in the healthy population across all subgroups, including gender, age, and BMI. Notably, male CD patients exhibited higher SII values compared to female patients, which may be attributed to the higher disease activity observed in males. Gargallo-Puyuelo et al concluded that being female serves as a protective factor against perianal disease, penetrating behavior, complications, and upper gastrointestinal tract involvement.^[43]

BMI is a conventional measure of nutritional status, with a decrease in BMI indicating the presence of malnutrition. In 2002, the European Society for Parenteral and Enteral Nutrition defined a BMI of <18.5 kg/m² as malnutrition.^[44] Its clinical nutrition guidelines for IBD recommend that patients with diagnosed IBD be regularly screened and monitored for malnutrition.^[45] According to European Society for Parenteral and Enteral Nutrition statistics, 20% to 85% of patients with UC are malnourished and exhibit reduced BMI.^[46] Xie et al reported a positive correlation between higher SII levels and lower BMI values in UC patients, with significantly higher SII levels observed in patients with low and normal BMI compared to the healthy population, except in patients with high BMI.^[40] Similarly, our findings revealed that SII levels were significantly higher in CD patients compared to healthy individuals across various BMI subgroups. Furthermore, a statistically significant difference in SII levels was observed between low BMI and nonlow BMI groups of CD patients. The immune-inflammatory response is closely associated with severe intestinal mucosal damage, which can impair nutrient absorption and lead to decreased BMI.^[47,48]

Inflammatory markers (CRP and fecal calprotectin) are typically elevated in colonic CD compared to ileal CD, owing to the heightened immunostimulatory nature of the colonic mucosa.^[49] The colonic mucosa, which is abundant in TLR4 receptors, exhibits enhanced responsiveness to lipopolysaccharides derived from gut microbiota, thereby promoting IL-6 secretion and subsequent hepatic CRP production.^[50,51] In contrast, the terminal ileum is characterized by Paneth cells and α-defensins, with its inflammatory response primarily mediated through the IL-23/Th17 pathway, resulting in comparatively weaker CRP induction.^[52,53] In this study, CD patients with L3 demonstrated significantly higher CDAI scores than those with L1/L2, while L2 and L1 showed comparable values – a finding that may be attributable to the limited sample size. Notably, the SII, as a marker of systemic inflammation, remained unaffected by CD lesion location, suggesting its potential utility for cross-site comparisons to more accurately reflect the true inflammatory burden.

Currently, comparative studies on the clinical value of SII, PLR, and NLR in CD patients remain scarce. We found significant positive correlations between these 3 biomarkers and CRP, ESR, CDAI, CDEIS, and SES-CD, along with a negative correlation between SII and Hb in CD patients. Furthermore, using CDAI, we compared SII, PLR, and NLR among CD patients with varying clinical severities, which is crucial for assessing disease severity and developing treatment strategies. Notably, SII only distinguished between mild and moderate CD, while PLR distinguished between remission and moderate CD, as well as mild and moderate CD. In contrast, NLR provided more comprehensive information for differentiating between various levels of disease severity. However, these findings require further validation due to the small sample sizes in the remission and severe CD groups.

Penetration is a common complication of CD and serves as a risk factor for ongoing disease activity, higher rates of rehospitalization, and postsurgical recurrence.^[54,55] Hossne et al identified penetration as a significant risk factor for perioperative complications in CD.^[56] Additionally, Inniss et al reported that CD patients with penetrating disease exhibited a poorer response to ustekinumab treatment.^[57] In a retrospective analysis of 492 CD patients diagnosed between 1963 and 2010, Zhulina et al demonstrated that complex disease behavior (structuring and penetrating) was associated with increased CD-related mortality.^[58] Notably, no other factors were identified as predictors of penetrating behavior. In this study, SII and PLR may exhibit superior predictive value for nonpenetrating behavior in CD compared to CRP and NLR. Chen et al demonstrated that elevated platelet counts constitute an independent risk factor for fistulizing complications in CD patients.^[59] Mechanistically, platelets promote intestinal wall penetration through the release of vascular endothelial growth factor, which drives pathological angiogenesis.^[60] Similarly, neutrophils – whose counts reflect chronic intestinal inflammation – contribute to tissue remodeling and fistula development via matrix metalloproteinase-9 (MMP9)-mediated degradation of the extracellular matrix.^[61] Furthermore, reduced regulatory T-cell populations have been strongly implicated in the pathogenesis of fistulizing CD.^[61] However, CRP, as a single phase protein, has limitations such as time lag and low specificity in predicting penetrating behavior.

This study has several limitations. First, it is a single-center retrospective study with a small sample size, highlighting the need for multicenter prospective studies to validate the findings. Second, this study excluded patients using drugs such as corticosteroids that affected neutrophil, platelet, and lymphocyte counts. Therefore, the potential impact of such drugs on the indicators of this study was not considered. Lastly, the relatively small number of patients in the remission and severe groups may have introduced bias into the results.

In summary, our study demonstrated that SII levels were significantly elevated in CD patients compared to healthy individuals. CRP had a higher diagnostic value in assessing active CD. Furthermore, SII showed superior performance in ruling out nonpenetrating CD compared with PLR, NLR, and CRP, highlighting its potential as an economical, noninvasive biomarker for the assessment of penetrating CD. However, prospective studies are needed to further validate these findings.

Author contributions

Conceptualization: Jing Yan, Yonghong Xu.

Data curation: Jing Yan, Xiaojing Zhang.

Formal analysis: Jing Yan, Xiaoyu Li.

Funding acquisition: Xiaoyu Li.

Investigation: Rongkun Wang, Xiaojing Zhang, Xiaoyu Li, Yonghong Xu.

Methodology: Yonghong Xu.

Project administration: Jing Yan, Rongkun Wang.

Resources: Xiaojing Zhang, Xiaoyu Li, Jun Wu.

Software: Jing Yan, Rongkun Wang.

Supervision: Jun Wu, Yonghong Xu.

Validation: Jun Wu, Yonghong Xu.

Visualization: Jing Yan, Jun Wu.

Writing – original draft: Jing Yan.

Writing – review & editing: Yonghong Xu.