Abstract
INTRODUCTION:
Neutrophil-to-lymphocyte ratio (NLR) is a novel biomarker studied in several autoimmune diseases including inflammatory bowel disease (IBD) in adults but poorly characterized in pediatric IBD (pIBD). We aimed to primarily investigate the relationship between NLR and pIBD endoscopic disease severity. We also examined whether NLR predicted hospitalization, surgery, and therapy response by 52 weeks.
METHODS:
We used the Canadian Children IBD Network prospective inception cohort including patients < 18 years old with baseline data from 2013 to 2022. We excluded patients with concurrent diseases affecting NLR. Both Mayo endoscopic score (MES) and simple endoscopic scale for Crohn's disease (SES-CD) were dichotomized as low activity (quiescent-mild) and high activity (moderate-severe). For therapy responses, we examined year-1 steroid- and biologic-free remission. We used logistic regression for binary outcomes.
RESULTS:
A total of 580 patients with ulcerative colitis and 1,081 patients with CD were included. High NLR was associated with high-activity MES and SES-CD in both univariate and multivariable analyses (odds ratio = 1.45, 95% CI = 1.07–1.97, P value = 0.016; and odds ratio = 1.42, 95% CI = 1.04–1.94, P value = 0.026, respectively). We also calculated the best NLR cutoff point to predict MES (1.90, sensitivity = 68%, specificity = 67%, area under the curve [AUC] = 0.67, AUC 95% CI = 0.59–0.74) and SES-CD (2.50, sensitivity = 63%, specificity = 69%, AUC = 0.66, AUC 95% CI = 0.59–0.75) high activity. NLR did not predict therapy response in either ulcerative colitis or CD.
DISCUSSION:
Patients with pIBD with high baseline NLR are more probable to have worse endoscopic disease at diagnosis. This highlights NLR potential as a reliable noninvasive biomarker of disease activity. The predictive power of NLR is based mostly on neutrophils and the balance between neutrophils and lymphocytes.
KEYWORDS: Crohn's disease, ulcerative colitis, colonoscopic activity, biologic-free remission, steroid-free remission
INTRODUCTION
Inflammatory bowel disease (IBD) is a complex disease where multiple factors contribute to pathogenesis. Although the etiology of IBD is still enigmatic, environmental factors, dysbiosis, and gut pathobionts in genetically susceptible individuals contribute to IBD development (1,2). IBD starts before the age of 20 years in around 25% of cases (3), with Canada being one of the countries with the highest disease rates in children. In Canada, the most recent average incidence of pediatric-onset IBD (pIBD) is 9.68 per 100,000 children, whereas the disease prevalence in children younger than 16 years is 38.25 per 100,000 children (4).
Endoscopy remains the gold standard tool for diagnosing and classifying pIBD, which is essential for management decisions (5–8). However, it is crucial to develop noninvasive readily available and inexpensive disease markers to help guide clinical management, complement endoscopy results, and improve our understanding of disease pathogenesis. Indeed, this is identified to be one of the top 10 unanswered questions in the realm of pIBD through patient-oriented studies (9).
Although several IBD biomarkers have been studied, many of the studies were not well designed or used small samples. One widely studied biomarker is fecal calprotectin (FC), the most abundant protein found in neutrophils (10). FC can differentiate IBD from healthy individuals (11), and in a recent Crohn's disease (CD) study, FC was able to differentiate endoscopic disease severity categories. However, FC was not able to differentiate between the endoscopic ulcerative colitis (UC) activity scores measured by Mayo endoscopic score (MES) (12). Other noninvasive markers that have shown a potential to delineate patients with varying disease severity include serum seromucoid, metalloproteinase-3, C-reactive protein/albumin ratio, and transcriptional blood biomarkers such as haptoglobin, CD177, GPR84, and S100A12 (13–15). Nevertheless, many of these markers, with the caveat of FC, are expensive or not readily available for use in clinical practice.
Recently, neutrophil-to-lymphocyte ratio (NLR), a novel inflammation biomarker, was found to predict several autoimmune and neoplastic diseases (16–19). NLR mirrors the relationship between neutrophils and lymphocytes. It reflects the balance and interaction between innate and cellular immunity, which is essential to understand in the context of IBD as a chronic immune-mediated disease (20). Although several studies investigated the clinical value of NLR in IBD, most were performed in a single center using limited sample sizes, with a scarcity of studies using pediatric patients (21). In adult-onset UC, NLR predicts loss of response to infliximab and pouchitis after ileal pouch-anal anastomosis (22,23). A meta-analysis study demonstrated that NLR was able to differentiate between active vs remissive UC. However, the meta-analysis subgroup analyses showed conflicting data regarding the ability of NLR to differentiate active disease from remissive in CD but confirmed the ability of NLR to distinguish between CD and healthy controls (24).
In pediatrics, NLR with a cutoff point of 1.46 detects IBD with 86.2% sensitivity and 93.5% specificity (25). To differentiate between remission and active pIBD, NLR with a cutoff point of 2.94 has sensitivity of 77.8% and specificity of 50.0% (26). It is noteworthy that these studies defined disease activity using the pediatric UC activity index (PUCAI) and pediatric Crohn’s disease activity index (PCDAI), which rely mostly on symptom-based components. Studies have shown that clinical symptoms do not necessarily reflect the inflammation state in IBD (27,28). Consequently, using macroscopic mucosal healing as the therapeutic target is preferred (29), which is also able to predict long-term outcomes (30). Therefore, we hypothesized that NLR correlates with disease activity as defined by endoscopic scores. We sought also to investigate the ability of NLR to predict complications such as hospitalization and the need for surgery and one-year therapy responses in a large pediatric cohort of patients suffering from IBD.
METHODS
Ethics
The study was conducted according to the principles of the Declaration of Helsinki. All the participating centers obtained the approval of the local Research Ethics Board.
Study population
This multicenter study used data collected through Canadian Children IBD Network, a national prospective inception cohort with longitudinal data on patients from 13 Canadian academic pIBD centers. The diagnosis of IBD was made based on the clinical decision of the treating physician using ileocolonoscopy, gastroduodenoscopy, histopathology, and laboratory results, following the Porto criteria (31).
Exclusion criteria
For the purpose of this study, we excluded patients with concurrent conditions that could affect NLR value, if diagnosed within a year of receiving an IBD diagnosis. These included autoimmune diseases, neoplasms, chronic inflammation, and thyroid dysfunction. Nevertheless, patients with extraintestinal manifestations of IBD, including IBD-associated axial arthritis, skin or eye manifestations, autoimmune hepatitis, primary sclerosing cholangitis, or pancreatitis, were not excluded. Patients with incomplete laboratory work, endoscopy results, or therapy data were excluded from the respective analysis.
Data and outcomes definitions
Data were gathered through standardized case report forms filled prospectively and by reviewing electronic medical records to record the patients' clinical data. Of the recorded data, we included the age and year of diagnosis, sex, baseline laboratory results (erythrocyte sedimentation rate, C-reactive protein, albumin, complete blood count, and FC), disease severity scores (PUCAI (32) and PCDAI (33)), and baseline colonoscopic severity scores (MES for UC (34) and simple endoscopic score for CD [SES-CD] (35)). Baseline laboratory test results were collected within a window of 2 weeks before or after the diagnostic endoscopy and before the start of any IBD treatment. We calculated NLR by dividing the absolute neutrophils count by the absolute lymphocyte count from the complete blood count differential.
The primary outcomes for correlation of NLR were baseline MES for the UC cohort and SES-CD for the CD cohort. We dichotomized MES into 2 categories: low activity (MES 0 and 1) and high activity (MES 2 and 3). Similarly, SES-CD was dichotomized as low activity (SES-CD ≤ 6), which includes patients with quiescent or mild SES-CD and high activity (SES-CD > 6) (36). As SES-CD underestimates disease severity for ileal-only CD (37), patients with L1-only Paris classification (38) were excluded from the analysis for the primary outcome. Secondary outcomes for both UC and CD were hospitalization during follow-up after diagnosis, hospitalization at any time point including presentation, surgery at any time point (including perianal surgery), first-year steroid-free remission, and first-year biologic-free remission. Only patients with at least one year of follow-up after diagnosis were included in the latter 2 secondary outcomes. Steroid-free remission was defined as achieving remission by 52 weeks after starting medical treatment without the need for steroids, including for induction of remission. Biologic-free remission was defined as achieving remission by 52 weeks after starting medical treatment, without the need for biologics. Remission was defined as PUCAI or PDCAI < 10 for UC and CD, respectively. We also analyzed the correlation between the NLR and the endoscopic activity dichotomized as quiescent disease vs any inflammation for both UC and CD. Please note that we use the term “high endoscopic activity” to refer to the primary outcome definition meaning moderate and severe colonoscopic disease activity.
Statistical analysis
For statistical analysis, we used STATA/BE 18.0 for Windows (64-bit x86-64). The Shapiro-Wilk test was used to test normality of continuous data. Non-normally distributed data were reported as the median and interquartile range (IQR). Univariate and multivariate logistic regression were used to examine correlations with binary outcomes. Univariate and multivariable simple linear regression were used with continuous dependent and independent variables. Only variates significant in univariate analyses were included in multivariable models. The multivariable models were adjusted to the year of diagnosis and the presence of extraintestinal manifestations of IBD. A P value < 0.05 was considered significant. Receiver operating characteristic curves were graphed to analyze the area under the curve (AUC) for diagnostic models. We used the Youden index (39) to calculate the NLR cutoff point with the best sensitivity and specificity possible.
RESULTS
Cohort characteristics
We identified 1,744 patients with IBD in the Canadian Children IBD Network cohort: 602 had UC (including IBD-unclassified favoring UC), and 1,142 had CD (including IBD-unclassified favoring CD). A total of 83 patients were excluded for having concomitant diseases (Figure 1). A total of 580 patients with UC and 1,081 patients with CD were included in our study. Patients were diagnosed between 2013 and 2022. The median age at diagnosis in years was 13 for both UC and CD (IQR = 9.92–15.33 and 10.75–14.9, respectively). Although there was no difference in the sex proportions in the UC cohort (male = 50%), the CD cohort had a higher proportion of males (63%). Most of the patients with UC and CD (83.01% and 88.15%, respectively) had high-activity endoscopic disease at diagnosis. During the first year of follow-up, 67% of the UC cohort needed steroids, whereas 41.55% required biologic therapy. By contrast, in the CD cohort, 43.98% needed steroids, whereas 64.19% were placed on biologic therapy during the first year of follow-up.
Figure 1.
Study design. CD, Crohn's disease; CIDsCaNN, Canadian Children IBD Network; IBD, inflammatory bowel disease; NLR, neutrophil-to-lymphocyte ratio; SES-CD, simple endoscopic scale for CD; UC, ulcerative colitis.
It is noteworthy that at diagnosis, patients with UC had a slightly lower NLR than in CD (median (n) = 2.34 (340), IQR = 1.64–3.55, vs median (n) = 2.79 (648), IQR = 1.98–4.09, respectively) (Table 1). Using the individual MES scores, there was a stepwise increase in the NLR medians with the increase of the MES disease activity. This relationship was statistically significant using the Mann–Whitney U analysis (Figure 2a), apart from MES 0 was not different from MES 1 or 2, most likely due to the limited sample size (n = 7) and the high interobserver variability nature of MES scores especially in the lower scores (40). When comparing patients with low vs high baseline colonoscopic activity in both UC and CD, neutrophil cell counts were significantly higher with high activity (Table 2). Moreover, the median lymphocytic cell count was lower with high activity, albeit not significant. Regarding FC, our cohort did not show a statistical difference in FC value between low and high colonoscopic inflammation in either UC or CD. However, there was a high rate of missing values in FC compared with other laboratory values.
Table 1.
CIDsCaNN cohort characteristics
| UC (n = 580) | CD (n = 1,081) | |||
| Median/% (n) | IQR | Median/% (n) | IQR | |
| Year of diagnosis | 2013–2021 | 2013–2022 | ||
| Age at diagnosis (mo) | 156 (577) | 119–184 | 156 (1,078) | 129–179 |
| Follow-up duration (mo) | 32 (580) | 17–53 | 32 (1,076) | 17–52 |
| PUCAI (at presentation) | 55 (471) | 35–65 | ||
| PUCAI (1 yr after treatment) | 0 (453) | 0–10 | ||
| PCDAI (at presentation) | 35 (413) | 22.5–47.5 | ||
| PCDAI (1 yr after treatment) | 2.5 (531) | 0–10 | ||
| Laboratory test results at baseline | ||||
| Hemoglobin | 111 (467) | 94–125 | 111 (899) | 100–122 |
| ESR | 25 (400) | 13–42.5 | 36 (761) | 21–54 |
| CRP | 3.6 (226) | 1–15.6 | 26.9 (403) | 9.3–63.2 |
| Albumin | 37 (446) | 31–42 | 34 (869) | 29–39 |
| Platelets | 381 (463) | 306–483 | 432 (894) | 349–533 |
| WBCs | 9.6 (345) | 7.4–11.9 | 8.75 (655) | 6.9–10.9 |
| Neutrophils | 5.2 (340) | 3.855–7.43 | 5.4 (650) | 4–7.31 |
| Lymphocytes | 2.2 (341) | 1.73–2.95 | 1.975 (648) | 1.5–2.5 |
| Fecal calprotectin | 1,322.5 (103) | 722–2,100 | 1,685.25 (310) | 916–2,343 |
| NLR | 2.34 (340) | 1.64–3.55 | 2.79 (648) | 1.98–4.09 |
| Sex (male:female) | 290:290 | 699:411 | ||
| MES (at presentation) | ||||
| 0 | 1.35% (7/518) | |||
| 1 | 15.64% (81/518) | |||
| 2 | 43.24% (224/518) | |||
| 3 | 39.77% (206/518) | |||
| SES-CD continuous (at presentation) | 16 (658) | 11–23 | ||
| SES-CD categorical (at presentation)a | ||||
| Quiescent | 5.47% (36/658) | |||
| Mild | 6.38% (42/658) | |||
| Moderate | 38.45% (253/658) | |||
| Severe | 49.70% (327/658) | |||
| Surgery at any time | 8.10% (47/580) | 10.18% (110/1,081) | ||
| Admission at any time including presentation | 50.52% (293/580) | 39.59% (428/1,081) | ||
| Admission during follow-up | 27.41% (159/580) | 17.67% (191/1,081) | ||
| Extraintestinal manifestations | ||||
| Oligoarthritic | 3/580 | 16/1,081 | ||
| Polyarthritis | 2/580 | 10/1,081 | ||
| Enthesitis | 5/580 | 7/1,081 | ||
| Dactylitis | — | 3/1,081 | ||
| Sacroiliitis | — | 15/1,081 | ||
| Erythema nodosum | 3/580 | 36/1,081 | ||
| Pyoderma gangrenosum | — | 2/1,081 | ||
| Autoimmune hepatitis | 3/580 | 2/1,081 | ||
| Primary sclerosing cholangitis | 21/580 | 3/1,081 | ||
| Uveitis | 6/580 | 2/1,081 | ||
| Pancreatitis | 9/580 | 8/1,081 | ||
| Therapy during the 1st year | ||||
| Biologics | 42.50 (241/567) | 64.19 (683/1,064) | ||
| Steroid | 68.61 (389/567) | 43.98 (468/1,064) | ||
| 5-ASA | 80.42 (456/567) | 18.89 (201/1,064) | ||
| Antibiotics | 17.81 (101/567) | 27.07 (288/1,064) | ||
| EEN | 10.76 (61/567) | 39.19 (417/1,064) | ||
CD, Crohn's disease; CIDsCaNN, Canadian Children Inflammatory Bowel Disease Network; EEN, enteral nutrition; IQR, interquartile range; MES, Mayo endoscopic score; NLR, neutrophil-to-lymphocyte ratio; PCDAI, pediatric Crohn’s disease activity index; PUCAI, pediatric ulcerative colitis activity index; SES-CD, simple endoscopic scale for CD; UC, ulcerative colitis; WBC, white blood cell.
SES-CD categories: quiescent (0–2), mild (3–6), moderate (7–15), and severe≥ 16.
Figure 2.
Baseline NLR and Mayo endoscopic score at diagnosis in the ulcerative colitis cohort. (a) A box plot of the natural log of NLR according to the different MES scores. There is a statistically significant stepwise increase in the NLR with increasing the MES scores. (b) ROC curves of the unadjusted baseline NLR and albumin predictions of the baseline binary MES. (c) ROC curve of the full logistic regression model predicting baseline binary MES. The model consists of NLR and albumin adjusted to the presence of extraintestinal manifestations of inflammatory bowel disease and year of diagnosis. MES, Mayo endoscopic score; NLR, neutrophil-to-lymphocyte ratio; ROC, receiver operating characteristic.
Table 2.
Mann–Whitney U analysis of the laboratory test result difference between low- and high-activity groups in both pediatric UC and CD
| UC | CD | |||||||||
| Low-activity MES (n = 88) | High-activity MES (n = 430) | P | Low-activity SES-CD (n = 78) | High-activity SES-CD (n = 580) | P | |||||
| Median (n) | IQR | Median (n) | IQR | Median (n) | IQR | Median (n) | IQR | |||
| NLR | 1.74 (51) | 1.35–2.33 | 2.44 (263) | 1.65–3.64 | 0.0002 | 2.09 (48) | 1.64–2.85 | 2.89 (366) | 2.01–4.21 | 0.0002 |
| Hemoglobin | 117 (69) | 101–128 | 109 (367) | 93–124 | 0.0528 | 119 (69) | 107–127 | 111 (520) | 99.5–122 | 0.0026 |
| ESR | 19.5 (60) | 8.5–39 | 27 (317) | 14–43 | 0.0679 | 28 (58) | 12–40 | 37.5 (454) | 21–57 | 0.0004 |
| CRP | 2.45 (36) | 0.5–5.85 | 5 (179) | 1.2–20.3 | 0.0139 | 15.1 (35) | 3–40.5 | 27.05 (246) | 8.8–65.5 | 0.0441 |
| Albumin | 41 (68) | 36.5–44 | 36 (351) | 30–41 | 0.0001 | 38.5 (66) | 32–41 | 34 (505) | 30–38.1 | 0.0087 |
| Platelets | 364 (67) | 296–470 | 387 (365) | 309–489 | 0.3469 | 380 (69) | 314–473 | 438 (515) | 359–553 | 0.0028 |
| WBCs | 7.8 (52) | 6.6–10.35 | 9.7 (267) | 7.6–12.3 | 0.0035 | 8.2 (47) | 7.1–9.2 | 9.1 (373) | 7.2–11.1 | 0.0441 |
| Neutrophils | 4.49 (51) | 3.31–5.8 | 5.4 (263) | 3.94–8 | 0.0001 | 4.985 (48) | 3.97–5.97 | 5.6 (367) | 4.1–7.4 | 0.0711 |
| Lymphocytes | 2.53 (51) | 1.89–3.05 | 2.2 (264) | 1.7–2.925 | 0.0701 | 2.205 (48) | 1.8–2.7 | 1.985 (366) | 1.5–2.45 | 0.0083 |
| Fecal calprotectin | 1,191.3 (13) | 502.9–1,530 | 1,339.1 (79) | 777.3–2,100 | 0.2323 | 1,526.5 (26) | 332.9–2,888 | 1731 (161) | 928.3–2,720 | 0.3275 |
CD, Crohn's disease; IQR, interquartile range; MES, Mayo endoscopic score; NLR, neutrophil-to-lymphocyte ratio; SES-CD, simple endoscopic scale for CD; UC, ulcerative colitis; WBC, white blood cell.
p values in bold are statistically significant.
NLR is associated with baseline MES in UC
In univariate logistic regression, both high NLR and low albumin were correlated with high MES activity (odds ratio [OR] = 1.59, 95% CI = 1.21–2.11, P value = 0.001, and OR = 0.88, 95% CI = 0.84–0.93, P value<=0.0001, respectively) (Table 3). Although higher white blood cell (WBC) count was significantly correlated with higher colonoscopic activity, it was not included in the multivariable model because of collinearity with NLR. The best NLR cutoff point was 1.90 with sensitivity = 68% and specificity = 67% (AUC = 0.67, 95% CI = 0.59–0.74) (Figure 2b). We were not able to investigate whether NLR can predict MES 0 vs any higher MES because of the small number of participants with MES 0 in our cohort (n = 7).
Table 3.
Univariate and multivariable logistic regression of the relationship between baseline laboratory test results in pediatric UC and baseline Mayo endoscopic score
| Univariate | Multivariable without PUCAI | Multivariable with PUCAI | |||||||
| OR | 95% CI | P | OR | 95% CI | P | OR | 95% CI | P | |
| NLR | 1.59 | 1.21–2.11 | 0.001 | 1.45 | 1.07–1.97 | 0.02 | 1.38 | 1.02–1.88 | 0.04 |
| Hemoglobin | 0.99 | 0.98–1.001 | 0.13 | — | — | — | |||
| ESR | 1.01 | 0.99–1.02 | 0.44 | — | — | — | |||
| CRP | 1.02 | 0.996–1.04 | 0.11 | — | — | — | |||
| Albumin | 0.88 | 0.84–0.93 | <0.0001 | 0.90 | 0.85–0.96 | 0.001 | 0.94 | 0.88–1.003 | 0.06 |
| Platelets | 1.001 | 0.999–1.003 | 0.22 | — | — | — | — | — | — |
| WBCs | 1.14 | 1.035–1.26 | 0.009 | — | — | — | — | — | — |
| Neutrophils | 1.03 | 0.98–1.08 | 0.22 | — | — | — | — | — | — |
| Lymphocytes | 1.02 | 0.95–1.20 | 0.60 | — | — | — | — | — | — |
| Fecal calprotectin | 1.0004 | 1.00–1.001 | 0.21 | — | — | — | — | — | — |
| PUCAI | 1.05 | 1.04–1.06 | <0.0001 | — | — | — | 1.04 | 1.02–1.05 | <0.0001 |
| Extraintestinal manifestations | 0.95 | 0.52–1.73 | 0.87 | 0.66 | 0.27–1.60 | 0.35 | 0.86 | 0.34–2.19 | 0.75 |
| Year of diagnosis | 0.96 | 0.84–1.11 | 0.58 | 1.11 | 0.88–1.44 | 0.35 | 1.09 | 0.84–1.41 | 0.51 |
NLR, neutrophil-to-lymphocyte ratio; OR, odds ratio; PUCAI, pediatric ulcerative colitis activity index; UC, ulcerative colitis; WBC, white blood cell.
p values in bold are statistically significant.
Both NLR and albumin remained significant in the multivariable model (OR = 1.45, 95% CI = 1.07–1.97, P value = 0.016, and OR = 0.90, 95% CI = 0.85–0.96, P value ≤ 0.001, respectively) (Table 3). NLR remained significant even after adding the symptom-based score PUCAI to the model (Table 3). We adjusted the model for the year of diagnosis and the presence of extraintestinal manifestations of IBD. The adjusted model (without PUCAI) had a higher AUC than the NLR alone (AUC = 0.74, 95% CI = 0.66–0.81) (Figure 2c).
NLR is associated with baseline SES-CD in CD
Similar to UC, higher NLR was associated with higher SES-CD score at diagnosis as a continuous variable in both univariate (t-statistic = 5.03, r2 = 0.06, P value < 0.0001) (Figure 3a) and multivariable (t-statistic = 3.43, model r2 = 0.32, P value = 0.001) simple linear regression. When NLR was tested against SES-CD as a binary outcome, higher NLR was correlated with high SES-CD activity in both univariate and multivariable logistic regression (multivariable OR = 1.42, 95% CI = 1.04–1.94, P value = 0.026) (Table 4). When the symptom-based score PCDAI was added to the model, NLR was not significantly associated with SES-CD, although it kept the same trend (Table 4).
Figure 3.
Baseline NLR and SES-CD score at diagnosis in the CD cohort. (a) A scatter plot with a fitted line showing a directly proportional relationship between baseline NLR and baseline SES-CD score. (b) ROC curves of the unadjusted baseline NLR, hemoglobin, ESR, albumin, and platelet predictions of the baseline binary SES-CD score. (c) ROC curve of the full logistic regression model predicting baseline binary SES-CD score. The model consists of NLR, hemoglobin, ESR, albumin, and platelets adjusted to the presence of extraintestinal autoimmune manifestations of inflammatory bowel disease and year of diagnosis. CD, Crohn's disease; ESR, erythrocyte sedimentation rate; NLR, neutrophil-to-lymphocyte ratio; SES-CD, simple endoscopic scale for CD; ROC, receiver operating characteristic.
Table 4.
Univariate and multivariable logistic regression of the relationship between baseline laboratory test results in pediatric CD and baseline SES-CD score
| Univariate | Multivariable without PCDAI | Multivariable with PCDAI | |||||||
| OR | 95% CI | P | OR | 95% CI | P | OR | 95% CI | P | |
| NLR | 1.48 | 1.16–1.89 | 0.002 | 1.42 | 1.04–1.94 | 0.03 | 1.24 | 0.87–1.77 | 0.24 |
| Hemoglobin | 0.98 | 0.96–0.99 | 0.01 | 1.01 | 0.98–1.03 | 0.59 | 1.04 | 0.996–1.08 | 0.07 |
| ESR | 1.02 | 1.01–1.03 | 0.001 | 1.02 | 1.004–1.04 | 0.02 | 1.00 | 0.97–1.03 | 0.95 |
| CRP | 1.01 | 0.999–1.02 | 0.08 | — | — | — | — | — | — |
| Albumin | 0.94 | 0.91–0.98 | 0.002 | 0.96 | 0.91–1.01 | 0.13 | 1.08 | 0.97–1.21 | 0.15 |
| Platelets | 1.002 | 1.00–1.004 | 0.02 | 0.999 | 0.996–1.002 | 0.56 | 1.00 | 0.99–1.004 | 0.64 |
| WBCs | 1.13 | 1.004–1.26 | 0.04 | — | — | — | — | — | — |
| Neutrophils | 1.003 | 0.96–1.04 | 0.90 | — | — | — | — | — | — |
| Lymphocytes | 0.97 | 0.93–1.01 | 0.19 | — | — | — | — | — | — |
| Fecal calprotectin | 1.000058 | 1.00–1.0003 | 0.60 | — | — | — | — | — | — |
| PCDAI | 1.03 | 1.01–1.05 | 0.015 | — | — | — | 1.08 | 1.03–1.14 | <0.0001 |
| Extraintestinal manifestations | 1.67 | 0.74–3.75 | 0.21 | 0.90 | 0.28–2.89 | 0.85 | 3.03 | 0.34–27.06 | 0.32 |
| Year of diagnosis | 1.02 | 0.91–1.15 | 0.70 | 0.97 | 0.75–1.26 | 0.85 | 0.97 | 0.70–1.35 | 0.88 |
CD, Crohn's disease; NLR, neutrophil-to-lymphocyte ratio; OR, odds ratio; PCDAI, pediatric Crohn’s disease activity index; SES-CD, simple endoscopic scale for CD; WBC, white blood cell.
p values in bold are statistically significant.
We sought also to test whether NLR can differentiate between quiescent disease vs any inflammation including mild. Higher NLR was significantly associated with any colonoscopic inflammation in univariate logistic regression (OR = 1.43, 95% CI = 1.02–2.002, P value = 0.04), and it kept the same trend in the multivariable logistic regression, but it lost the statistical significance (Supplementary Table 1, http://links.lww.com/CTG/B273).
Youden index calculated cutoff point for NLR to predict high SES-CD activity (moderate and severe) was 2.50 with a 63% sensitivity, 69% specificity, AUC = 0.66, AUC 95% CI = 0.59–0.75. When the receiver operating characteristic was plotted for the whole multivariable model (without PCDAI), it showed AUC of 0.72 (95% CI = 0.63–0.81) (, ).
NLR does not predict secondary outcomes
In UC, there was no association between baseline NLR and either steroid- or biologic-free remission in univariate logistic regression (OR = 0.91, 95% CI = 0.77–1.06, P value = 0.23, and OR = 0.91, 95% CI = 0.81–1.03, P value = 0.14, respectively) ( Tables 5 and 6). Similarly for CD, NLR did not predict either steroid- or biologic-free remission in univariate logistic regression (OR = 0.97, 95% CI = 0.88–1.06, P value = 0.47, and OR = 0.91, 95% CI = 0.79–1.05, P value = 0.20, respectively) (Tables 5 and 6). Interestingly, NLR was not associated with hospitalization during follow-up for both UC and CD (Supplementary Table 7, http://links.lww.com/CTG/B273). In addition, it did not predict the need for surgery for either UC or CD (Supplementary Table 8, http://links.lww.com/CTG/B273).
Table 5.
Univariate logistic regression of the relationship between baseline laboratory test results in pIBD and 1st-year steroid-free remission
| UC | CD | |||||
| OR | 95% CI | P | OR | 95% CI | P | |
| NLR | 0.91 | 0.77–1.06 | 0.23 | 0.97 | 0.88–1.06 | 0.47 |
| Hemoglobin | 1.01 | 1.001–1.02 | 0.04 | 1.004 | 0.99–1.01 | 0.42 |
| ESR | 0.99 | 0.97–0.999 | 0.04 | 1.001 | 0.99–1.01 | 0.85 |
| CRP | 0.98 | 0.96–1.003 | 0.09 | 1.00 | 0.995–1.004 | 0.95 |
| Albumin | 1.09 | 1.05–1.14 | <0.0001 | 1.01 | 0.98–1.03 | 0.51 |
| Platelets | 0.998 | 0.996–0.999 | 0.01 | 1.00 | 0.999–1.001 | 0.86 |
| WBCs | 0.86 | 0.78–0.94 | 0.001 | 0.99 | 0.94–1.04 | 0.62 |
| Neutrophils | 1.02 | 0.99–1.04 | 0.145 | 0.997 | 0.97–1.02 | 0.84 |
| Lymphocytes | 1.06 | 1.00–1.13 | 0.051 | 0.995 | 0.95–1.04 | 0.85 |
| Fecal calprotectin | 1.00 | 0.999–1.0002 | 0.18 | 1.0001 | 1.00–1.0001 | 0.31 |
CD, Crohn's disease; NLR, neutrophil-to-lymphocyte ratio; OR, odds ratio; pIBD, pediatric inflammatory bowel diseases; UC, ulcerative colitis; WBC, white blood cell.
p values in bold are statistically significant.
Table 6.
Univariate logistic regression of the relationship between baseline laboratory test results in pIBD and 1st-year biologics-free remission
| UC | CD | |||||
| OR | 95% CI | P | OR | 95% CI | P | |
| NLR | 0.91 | 0.81–1.03 | 0.138 | 0.91 | 0.79–1.05 | 0.201 |
| Hemoglobin | 1.01 | 1.00–1.02 | 0.129 | 1.01 | 1.00–1.03 | 0.056 |
| ESR | 0.99 | 0.98–1.002 | 0.108 | 0.99 | 0.98–1.003 | 0.191 |
| CRP | 0.98 | 0.96–0.995 | 0.01 | 0.999 | 0.992–1.01 | 0.711 |
| Albumin | 1.06 | 1.03–1.10 | <0.0001 | 1.07 | 1.03–1.11 | <0.0001 |
| Platelets | 0.999 | 0.998–1.001 | 0.232 | 0.999 | 0.997–1.00 | 0.076 |
| WBCs | 0.98 | 0.93–1.03 | 0.322 | 0.93 | 0.85–1.02 | 0.111 |
| Neutrophils | 0.99 | 0.96–1.01 | 0.238 | 0.98 | 0.94–1.03 | 0.415 |
| Lymphocytes | 0.99 | 0.93–1.05 | 0.651 | 0.997 | 0.94–1.06 | 0.928 |
| Fecal calprotectin | 1.00 | 0.999–1.0001 | 0.202 | 1.00001 | 1.00–1.0002 | 0.902 |
CD, Crohn's disease; NLR, neutrophil-to-lymphocyte ratio; OR, odds ratio; pIBD, pediatric inflammatory bowel diseases; UC, ulcerative colitis; WBC, white blood cell.
P values in bold are statistically significant.
DISCUSSION
Our study investigated the association between NLR and several clinically relevant outcomes in pIBD. We analyzed the correlation between NLR and macroscopic inflammation as assessed by colonoscopy at the time of diagnosis, as well as first-year steroid- and biologic-free remission, the need for hospitalization, and the need for surgery. Our study suggests that NLR correlates mostly with colonoscopic disease activity; patients with higher NLR exhibit a higher degree of macroscopic inflammation at colonoscopy (moderate and severe scores). NLR remains an independent predictor in multivariable analyses. In the difference between groups analysis, pIBD with higher colonoscopic scores had significantly higher neutrophil and lower lymphocyte counts. This study extends the previously reported importance of total WBC counts in predicting outcomes in children with severe UC. Using the PROTECT cohort of children with UC (n = 427), boosted classification and regression trees identified total WBC count as an important predictor for clinical and mucosal measures for severe UC (41).
We are also reporting the best NLR cutoff points for clinical use, correlating with macroscopic disease severity in both UC and CD (1.90 and 2.50, respectively). Although the AUC for the NLR was not high enough alone, it markedly improved by adding other blood biomarkers to the adjusted models. This provides an opportunity to develop a fairly accurate model using readily available low-cost blood tests.
In contrast to endoscopy scores, NLR was not well associated with the need for admission, surgery, or therapy response. A possible explanation for the lack of association between NLR and hospitalization is the disconnect between symptoms and tissue inflammation (27), whereas the former can be a major driver for deciding on admission.
Our data signify the imbalance between innate and cellular immunity in pIBD. Interestingly, a population-based study reported that patients with high normal NLR had less diverse gut microbiota and an abundance of Bacteroides eggerthii (42), factors known to be associated with developing IBD (43,44). It also highlights the potential role of neutrophils at this acute stage of the disease. Despite the known role of innate immunity in IBD, neutrophils seem to be understudied compared with lymphocytes in the context of IBD. For instance, our team has found that patients with CD experience high genetic expression of A20 in their terminal ileum coupled with low levels of the A20 protein (45). As A20 functions mainly in the myeloid cells including neutrophils, this signifies a dysregulated innate inflammatory process (46). In fact, a recent study reported that patients with UC with high IL-22, which controls the neutrophil chemokines CXC family, suffered from higher histologic grade and therapy resistance (47). Genetic studies have shown that pediatric patients with CD who have neutrophils with nonsense nicotinamide adenine dinucleotide phosphate mutations had low-ROS activity with more severe inflammation (48). Several proteomics reports have also linked neutrophil-related proteins to IBD disease severity and treatment resistance (49).
Our results suggest that the role of neutrophils in IBD should be probed further. We also highlight the opportunity for developing a prognostic model for pIBD comprised easily accessed blood markers including NLR.
Our study has several strengths. The national, multicenter prospective design with the large sample size boosts the study's statistical power. To the best of our knowledge, this is the largest study investigating NLR in the context of both adult IBD and pIBD (21). In addition, we have a well-characterized inception cohort followed prospectively with high data quality. We performed the analysis by studying NLR from different angles including disease severity, complications, and therapy response providing a holistic overview. Moreover, we took precautions to mitigate the risk of NLR confounders such as concurrent diseases and using laboratory test results before starting immunosuppressive medications avoiding the pitfalls of other studies (50).
There are inevitable limitations to our study, given the observational design. Observational studies are known for their high probability of confounding and bias. However, as we are exclusively studying NLR in pediatric patients, it is natural that our cohort has a low rate of concurrent diseases, and those with other known conditions were excluded. This leads to a low level of confounding in our assessment of NLR in the context of IBD. In addition, our database has a high missing rate of FC, which prevented us from having a reliable assessment of the interaction between NLR and FC values in IBD.
High NLR at diagnosis is strongly associated with high baseline endoscopic severity in pIBD. This mirrors the dysregulated inflammatory state in pIBD and highlights a potential role of neutrophils in the early disease process. NLR is not associated with clinical complications such as therapy response, admission rate, or surgical interventions. This makes NLR a useful, noninvasive marker of inflammation in patients with pIBD.
CONFLICTS OF INTEREST
Guarantor of the article: Eytan Wine, MD, PhD.
Specific author contributions: B.A.: conceived and designed the analysis, performed the analysis, and wrote the paper. R.B.: revised the analysis design and reviewed and edited the paper draft. H.H., K.J., D.R.M., C.D., A.O., J.D., W.E., E.C., M.S., J.C., N.A., A.G., and T.W.: data acquisition, approved methodology, and reviewed and edited the paper draft. E.W.: data acquisition, approved methodology, results interpretation, funding acquisition, supervised the work, and reviewed and edited the paper draft.
Financial support: CIDsCaNN is funded through The CH.I.L.D foundation, BC, Canada.
Potential competing interests: HQH served as an advisory board member and speaker for AbbVie. PCC has received consulting fees from AbbVie, Janssen, Ferring, and Merck; honoraria from AbbVie and Amgen, investigator-initiated research support from AbbVie and Janssen; and educational grants from Janssen, Amgen, Takeda, and Viatris. KJ has served as an advisory board member for AbbVie, Janssen, Amgen, Merck, Viatris, and McKesson Canada, is a member of AbbVie and Janssen Speaker's bureau, and has received investigator-initiated research support from Janssen. DRM is cofounder and shareholder of MedBiome Inc. CD served as an advisory board member and speaker for AbbVie, Organon, and Janssen. AO has served on an advisory board for AbbVie, Janssen, Pfizer, and Eli-Lilly; has received investigator-initiated research support from AbbVie; and has received educational grants from AbbVie and Janssen. JD served as an advisory board member and speaker for AbbVie, as well as an advisory board member for Janssen, Amgen, and Mylan. WEM served as an advisory board member and speaker's panel for AbbVie. EC has received an educational grant and speaker fees from AbbVie and Pfizer and consulting fees from Alimentiv Inc. and Sanofi. MS received an honorarium from Sanofi for an advisory board in Nov. AMG reports consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Lilly, Merck, and Pfizer; speaker fees from AbbVie, Janssen, and Nestle; investigator-initiated research support from AbbVie. Thomas D. Walters has received grants from AbbVie and Ferring; honoraria from AbbVie and Pfizer; and served as an advisory board member for AbbVie, Janssen, and Pfizer. EW reports personal fees from AbbVie, Janssen, Nestle Health Sciences, BioJamp, Pfizer, and Mead Johnson Nutrition. None of these disclosures are directly related to this work. The remaining authors of this study have no conflict of interest to disclose.
Study Highlights.
WHAT IS KNOWN
✓ Fecal calprotectin is widely used non-invasive biomarker to differentiate between inflammatory bowel disease and healthy cases.
✓ Neutrophil-to-lymphocyte (NLR) is a new biomarker representing the balance between innate and acquired immunity.
✓ High NLR predicts loss of response to infliximab in adult-onset ulcerative colitis.
WHAT IS NEW HERE
✓ Baseline NLR higher than 1.9 is a risk factor for severe endoscopic disease activity in pediatric-onset ulcerative colitis at diagnosis.
✓ Baseline NLR higher than 2.5 is a risk factor for severe endoscopic disease activity in pediatric-onset Crohn's disease at diagnosis.
✓ In ulcerative colitis, NLR discrimination between low and high disease activity is driven by neutrophils. In Crohn's disease, it is driven by lymphocytes.
TRANSLATIONAL IMPACT
✓ We are the showing the great significance of neutrophils in pediatric-onset ulcerative colitis pathophysiology, a component that was not studied enough compared to the role of lymphocytes and acquired immunity.
Supplementary Material
Footnotes
SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/CTG/B273
REFERENCES
- 1.Alipour M, Zaidi D, Valcheva R, et al. Mucosal barrier depletion and loss of bacterial diversity are primary abnormalities in paediatric ulcerative colitis. J Crohns Colitis 2016;10(4):462–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Zaidi D, Huynh HQ, Carroll MW, et al. Gut microenvironment and bacterial invasion in paediatric inflammatory bowel diseases. J Pediatr Gastroenterol Nutr 2020;71(5):624–32. [DOI] [PubMed] [Google Scholar]
- 3.Rosen MJ, Dhawan A, Saeed SA. Inflammatory bowel disease in children and adolescents. JAMA Pediatr 2015;169(11):1053–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Benchimol EI, Bernstein CN, Bitton A, et al. Trends in epidemiology of pediatric inflammatory bowel disease in Canada: Distributed network analysis of multiple population-based provincial health administrative databases. Am J Gastroenterol 2017;112(7):1120–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Shaoul R, Day AS. An overview of tools to score severity in pediatric inflammatory bowel disease. Front Pediatr 2021;9:615216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 1: Ambulatory care—an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;67(2):257–91. [DOI] [PubMed] [Google Scholar]
- 7.Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 2: Acute severe colitis—an evidence-based consensus guideline from the European Crohn's and Colitis Organization and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;67(2):292–310. [DOI] [PubMed] [Google Scholar]
- 8.Mack DR, Benchimol EI, Critch J, et al. Canadian association of gastroenterology clinical practice guideline for the medical management of pediatric luminal Crohn's disease. J Can Assoc Gastroenterol 2019;2(3):e35–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Grant A, Crane M, Laupacis A, et al. Engaging patients and caregivers in research for pediatric inflammatory bowel disease: Top 10 research priorities. J Pediatr Gastroenterol Nutr 2019;69(3):317–23. [DOI] [PubMed] [Google Scholar]
- 10.Chang MH, Chou JW, Chen SM, et al. Faecal calprotectin as a novel biomarker for differentiating between inflammatory bowel disease and irritable bowel syndrome. Mol Med Rep 2014;10(1):522–6. [DOI] [PubMed] [Google Scholar]
- 11.Walsham NE, Sherwood RA. Fecal calprotectin in inflammatory bowel disease. Clin Exp Gastroenterol 2016;9:21–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Crawford E, Gestrich C, Malay S, et al. Association of fecal calprotectin with endoscopic and histologic activity in pediatric inflammatory bowel disease. JPGN Rep 2021;2(4):e129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Iwańczak B, Ruczka M, Matusiewicz M, et al. Correlation between biomarkers (calprotectin, seromucoid, metalloproteinase-3 and CRP) and clinical and endoscopic activity of ulcerative colitis in children. Adv Med Sci 2020;65(2):259–64. [DOI] [PubMed] [Google Scholar]
- 14.Glapa-Nowak A, Szczepanik M, Banaszkiewicz A, et al. C-reactive protein/albumin ratio at diagnosis of pediatric inflammatory bowel disease: A retrospective multi-center study. Med Sci Monitor 2022;28:e937842. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Planell N, Masamunt MC, Leal RF, et al. Usefulness of transcriptional blood biomarkers as a non-invasive surrogate marker of mucosal healing and endoscopic response in ulcerative colitis. J Crohns Colitis 2017;11(11):1335–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Soliman WM, Sherif NM, Ghanima IM, et al. Neutrophil to lymphocyte and platelet to lymphocyte ratios in systemic lupus erythematosus: Relation with disease activity and lupus nephritis. Reumatol Clin 2020;16(4):255–61. [DOI] [PubMed] [Google Scholar]
- 17.Russo A, Russano M, Franchina T, et al. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and outcomes with nivolumab in pretreated non-small cell lung cancer (NSCLC): A large retrospective multicenter study. Adv Ther 2020;37(3):1145–55. [DOI] [PubMed] [Google Scholar]
- 18.Motomura T, Shirabe K, Mano Y, et al. Neutrophil–lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol 2013;58(1):58–64. [DOI] [PubMed] [Google Scholar]
- 19.Aziz B, Roberts SB, Lytvyak E, et al. Elevated neutrophil/lymphocyte ratio (NLR) one-year post-diagnosis is associated with decreased liver transplant-free and overall survival in PBC. In: The Liver Meeting Digital Experience™. AASLD, 2020. [Google Scholar]
- 20.Müller I, Munder M, Kropf P, et al. Polymorphonuclear neutrophils and T lymphocytes: Strange bedfellows or brothers in arms? Trend Immunol 2009;30(11):522–30. [DOI] [PubMed] [Google Scholar]
- 21.Langley BO, Guedry SE, Goldenberg JZ, et al. Inflammatory bowel disease and neutrophil–lymphocyte ratio: A systematic Scoping review. J Clin Med 2021;10(18):4219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Nishida Y, Hosomi S, Yamagami H, et al. Neutrophil-to-lymphocyte ratio for predicting loss of response to infliximab in ulcerative colitis. PloS One 2017;12(1):e0169845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Nishida Y, Hosomi S, Yamagami H, et al. Novel prognostic biomarkers of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis: Neutrophil-to-lymphocyte ratio. PLoS One 2020;15(10):e0241322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Fu W, Fu H, Ye W, et al. Peripheral blood neutrophil-to-lymphocyte ratio in inflammatory bowel disease and disease activity: A meta-analysis. Int Immunopharmacol 2021;101(Pt B):108235. [DOI] [PubMed] [Google Scholar]
- 25.Şimşek-Onat P, Hizarcioglu-Gulsen H, Ergen YM, et al. Neutrophil-to-lymphocyte ratio: An easy marker for the diagnosis and monitoring of inflammatory bowel disease in children. Dig Dis Sci 2023;68(1):233–9. [DOI] [PubMed] [Google Scholar]
- 26.Zahmatkesh A, Sohouli MH, Hosseini SME, et al. The role of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in the diagnosis and severity of inflammatory bowel disease in children. Eur J Pediatr 2023;182(9):4263–70. [DOI] [PubMed] [Google Scholar]
- 27.Hoekman DR, Diederen K, Koot BGP, et al. Relationship of clinical symptoms with biomarkers of inflammation in pediatric inflammatory bowel disease. Eur J Pediatrics 2016;175(10):1335–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Carman N, Tomalty D, Church PC, et al. Clinical disease activity and endoscopic severity correlate poorly in children newly diagnosed with Crohn's disease. Gastrointest Endosc 2019;89(2):364–72. [DOI] [PubMed] [Google Scholar]
- 29.Rutgeerts P, Vermeire S, Van Assche G. Mucosal healing in inflammatory bowel disease: Impossible ideal or therapeutic target? Gut 2007;56(4):453–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Shah SC, Colombel JF, Sands BE, et al. Mucosal healing is associated with improved long-term outcomes of patients with ulcerative colitis: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2016;14(9):1245–55.e8. [DOI] [PubMed] [Google Scholar]
- 31.IBD Working Group of the European Society for Paediatric Gastroenterology Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: Recommendations for diagnosis--the Porto criteria. J Pediatr Gastroenterol Nutr 2005;41(1):1–7. [DOI] [PubMed] [Google Scholar]
- 32.Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: A prospective multicenter study. Gastroenterology 2007;133(2):423–32. [DOI] [PubMed] [Google Scholar]
- 33.Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr 1991;12(4):439–47. [PubMed] [Google Scholar]
- 34.Vashist NM, Samaan M, Mosli MH, et al. Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis. Cochrane Database Syst Rev 2018;1(1):CD011450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Daperno M, D'Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: The SES-CD. Gastrointest Endosc 2004;60(4):505–12. [DOI] [PubMed] [Google Scholar]
- 36.af Björkesten C-G, Nieminen U, Turunen U, et al. Surrogate markers and clinical indices, alone or combined, as indicators for endoscopic remission in anti-TNF-treated luminal Crohn's disease. Scand J Gastroenterol 2012;47(5):528–37. [DOI] [PubMed] [Google Scholar]
- 37.Koutroumpakis E, Katsanos KH. Implementation of the simple endoscopic activity score in Crohn's disease. Saudi J Gastroenterol 2016;22(3):183–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011;17(6):1314–21. [DOI] [PubMed] [Google Scholar]
- 39.Youden WJ. Index for rating diagnostic tests. Cancer 1950;3(1):32–5. [DOI] [PubMed] [Google Scholar]
- 40.Hart L, Chavannes M, Lakatos PL, et al. Do you see what I see? An assessment of endoscopic lesions recognition and description by gastroenterology trainees and staff physicians. J Can Assoc Gastroenterol 2020;3(5):216–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Mack DR, Saul B, Boyle B, et al. Analysis of using the total white blood cell count to define severe new-onset ulcerative colitis in children. J Pediatr Gastroenterol Nutr 2020;71(3):354–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Yoon H-Y, Kim HN, Lee SH, et al. Association between neutrophil-to-lymphocyte ratio and gut microbiota in a large population: A retrospective cross-sectional study. Sci Rep 2018;8(1):16031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.De Cruz P, Kang S, Wagner J, et al. Association between specific mucosa-associated microbiota in Crohn's disease at the time of resection and subsequent disease recurrence: A pilot study. J Gastroenterol Hepatol 2015;30(2):268–78. [DOI] [PubMed] [Google Scholar]
- 44.Lucke K, Miehlke S, Jacobs E, et al. Prevalence of Bacteroides and Prevotella spp. in ulcerative colitis. J Med Microbiol 2006;55(Pt 5):617–24. [DOI] [PubMed] [Google Scholar]
- 45.Zaidi D, Huynh HQ, Carroll MW, et al. Tumor necrosis factor α-induced protein 3 (A20) is dysregulated in pediatric Crohn disease. Clin Exp Gastroenterol 2018;11:217–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Matmati M, Jacques P, Maelfait J, et al. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet 2011;43(9):908–12. [DOI] [PubMed] [Google Scholar]
- 47.Pavlidis P, Tsakmaki A, Pantazi E, et al. O32 the Interleukin 22//Neutrophil Axis is Associated With Treatment Resistance in Ulcerative Colitis. BMJ Publishing Group, 2022. [Google Scholar]
- 48.Denson LA, Jurickova I, Karns R, et al. Clinical and genomic correlates of neutrophil reactive oxygen species production in pediatric patients with Crohn's disease. Gastroenterology 2018;154(8):2097–110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Fabian O, Bajer L, Drastich P, et al. A current state of proteomics in adult and pediatric inflammatory bowel diseases: A systematic search and review. Int J Mol Sci 2023;24(11):9386. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Düzenli T, Köseoğlu H, Akyol T. NLR and PLR as novel prognostic biomarkers of mucosal healing in ulcerative colitis patients treated with anti-TNF. Inflamm Bowel Dis 2020;26(9):e103. [DOI] [PubMed] [Google Scholar]