Abstract
Background
Inflammatory bowel disease (IBD) is associated with alterations of the innate and adaptive immune systems. Monocytes respond to inflammation and infection, yet the relationship between monocytosis and IBD severity is not fully understood. We aimed to characterize the prevalence of monocytosis in IBD and the association between monocytosis and disease severity and IBD-related health care utilization.
Methods
We used a multiyear, prospectively collected natural history registry to compare patients with IBD with monocytosis to those without monocytosis, among all patients and by disease type.
Results
A total of 1290 patients with IBD (64.1% with Crohn disease; 35.9% with ulcerative colitis) were included (mean age 46.4 years; 52.6% female). Monocytosis was found in 399 (30.9%) of patients with IBD (29.3% with Crohn disease; 33.9% with ulcerative colitis). Monocytosis was significantly associated with abnormal C-reactive protein level and erythrocyte sedimentation rate, anemia, worse quality of life, active disease, and increased exposure to biologics (all P < 0.001). Compared with patients without monocytosis, patients with monocytosis had a 3-fold increase in annual financial health care charges (median: $127,013 vs. $32,925, P < 0.001) and an increased likelihood of hospitalization (adjusted odds ratio [AOR], 4.5; P < 0.001), IBD-related surgery (AOR, 1.9; P = 0.002), and emergency department (ED) use (AOR, 2.8; P < 0.001). Patients with monocytosis had a shorter time to surgery, hospitalization, and ED visit after stratifying by disease activity (all P < 0.05).
Conclusions
Patients with IBD with monocytosis, regardless of disease type, are at increased risk for worse clinical outcomes, hospitalization, surgery, and ED use. Peripheral monocytosis may represent a routinely available biomarker of a distinct subgroup with severe disease.
Keywords: monocytosis, inflammatory bowel disease, biomarker, severity
INTRODUCTION
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn disease (CD), is a heterogeneous group of immune-mediated chronic disorders of the gastrointestinal tract with significant morbidity.1 Within UC and CD, the clinical phenotypes are heterogeneous with different disease trajectories, outcomes, and variable response to therapy.2, 3 Recent advances in IBD therapies offer new and evolving therapeutic strategies to control inflammation with the goal of preventing future costly complications. Given the diversity of IBD phenotypes and the range of disease severity, the challenge of identifying high-risk patients who will benefit most from aggressive therapy remains a major focus of research.
Biomarkers of disease severity and clinical course are continuously evolving. Identifying biomarkers associated with disease severity is essential to guiding our clinical practice and offering personalized treatment for each patient. Various clinical factors including young age (mean age 45.2), eosinophilia, perianal disease, use of steroids for the first flare, smoking, and extensive ileal disease are correlated with severe disease in patients with CD.4-6 Similarly, in UC, disease extent (ie, extensive colitis) and younger age have been associated with poor prognosis.5
Although clinical information is readily available, it cannot explain the overall heterogeneity of IBD. There has been a recent effort to repurpose routine laboratory values as predictors, including C-reactive protein (CRP), anemia, and components of the complete blood count (CBC) and differential.6-11 Monocytes are a subset of circulating white blood cells and play a significant role in innate immunity.12, 13 In inflammatory conditions such as IBD, rheumatoid arthritis, and atherosclerosis, monocytes are recruited from the bone marrow to the blood, through which they will traffic to the peripheral tissues where they are stimulated by cytokines or microbial molecules to differentiate into macrophages and dendritic cells.12, 13 These cells are responsible for the production of cytokines and chemokines that contribute to the inflammatory cascade.12-14
There is evidence that peripheral monocytes from patients with IBD are phenotypically altered in comparison to those from healthy control patients.15, 16 However, there are a few studies that have evaluated peripheral monocytosis as a biomarker of clinical disease severity. It has been suggested that monocytosis is associated with disease activity in patients with UC, but it has not been examined in CD.17, 18 We hypothesized that all patients with IBD with any absolute monocytosis over a multiyear time period have worse clinical outcomes compared with patients with IBD without monocytosis. The aims of this study were to determine the association between monocytosis and disease severity and to define the relationship between monocytosis and health care utilization in both UC and CD.
MATERIALS AND METHODS
Study Design and Patient Population
For this study, we utilized a consented longitudinal IBD research registry at a tertiary care center. The University of Pittsburgh Medical Center research registry prospectively enrolls patients with diagnoses of IBD, based on clinical, laboratory, imaging, and endoscopic findings and established criteria, which has been discussed in detail.19 Briefly, the IBD research registry generates research data from the electronic health record. Regularly curated data include all demographic, laboratory, prescription, health care utilization (ie, telephone calls, emails, clinic visits, emergency department (ED) visits, hospitalizations, surgeries, endoscopic procedures), radiography, clinical disease activity scores, and health-related quality of life scores information, and all standard data entry fields in the electronic medical record.19 The University of Pittsburgh Medical Center IBD Research Registry was utilized as the data source for all participants in this study.
The study period included 6 calendar years, from January 2010 to December 2015. Eligible patients were required to have at least 1 CBC with differential and a minimum of 4 years of clinical follow-up between 2010 and 2015, defined as 1 phone call, email, or office visit to the Digestive Disorders Clinic in each calendar year. Patients were excluded from the study if they had <4 years of clinical follow-up, indeterminate colitis, or unclassified disease type. Monocytosis was defined as an absolute monocyte count above the upper limit of normal for each specific laboratory reference occurring at any point during the study period to account for variation in standardized normal ranges between regional laboratories. Patients with at least 1 occurrence of an elevated monocyte count formed the monocytosis group, and all other patients with IBD were included as the control patients. Repeated laboratory draws were not prospectively planned at defined intervals but rather were the result of routine patient care.
Data Collection
For all patients in the study, data included baseline demographics of age, race, sex, relationship status, and employment status. Data specific to IBD included disease type (CD or UC), duration of the disease, and extent and behavior at diagnosis using the Montreal classification.3 Medication exposures were assessed using prescription data and were categorized as exposure per year. Medication categories consisted of immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), anti-tumor necrosis factor (anti-TNF) agents (infliximab, adalimumab, certolizumab pegol, and golimumab), 5-aminosalicylic acid agents, and systemic steroids. Health care utilization was assessed by year using the total number of IBD clinic visits, ED visits, hospital admissions, telephone calls, endoscopies, and radiologic studies, and the need for an IBD-related surgery during the 6-year study period. Health care utilization was also quantified by the 6-year total financial charges, which included charge data for all obtained health care services including but not limited to gastrointestinal care. Financial charges included both inpatient and outpatient charges but did not include pharmacy charges because prescription charges are independent of the health care system.
For logistic regression analyses, we dichotomized certain health care utilization metrics as “ever occurring” over the study period (yes/no). We assessed IBD disease activity using inflammatory biomarkers and clinical disease activity indices. Inflammatory biomarkers included CRP and erythrocyte sedimentation rate (ESR), which were transformed into annual categorical dichotomous variables if they were flagged as elevated using local laboratory reference values. Disease activity scores were collected prospectively at outpatient visits using the Harvey-Bradshaw Index for CD and the Ulcerative Colitis Activity Index for UC.20,21 Active disease was defined as a mean Ulcerative Colitis Activity Index score ≥4 or mean Harvey-Bradshaw Index scores ≥5 during the study period. The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) was prospectively collected at outpatient visits to estimate participants’ health-related quality of life.22 Mean disease activity and quality-of-life scores were calculated on an annual basis and over the entire study period.
Statistical Analysis
Normally distributed continuous variables are presented as mean with standard deviation, and nonparametric continuous and count variables are presented as median with interquartile ratio (IQR). To compare between monocytosis groups we used the Student t test for normally distributed continuous variables and the Wilcoxon rank sum test for nonparametric continuous variables. Categorical variables were presented as proportions and compared between groups using the χ 2 test or the Fisher exact test as appropriate. We evaluated monocytosis in all patients with IBD and repeated the analyses within the disease-specific subgroups because existing literature suggests that monocytosis may have a differential ability between UC and CD.18
To evaluate the association between monocytosis and health care outcomes, we used univariable and multivariable logistic regression. Variables relating to disease severity and inflammation on univariable analysis with P < 0.10 were included in multivariable logistic regression models. Health care outcomes were dichotomized as “ever occurring” within the 6-year study period. In an effort to further understand the relationship between monocytosis and health care utilization, we performed a time-to-event analysis. Time zero was defined as the first event of monocytosis for the monocytosis group and the first CBC for the control group. Participants were followed until the event of their first surgery, hospitalization, and ED visit occurred or on December 31 of their last year of documented clinical follow-up. Time to first hospitalization, surgery, or ED visit was analyzed separately and not as a composite outcome. We excluded events (ED visit, hospitalization, or surgery) occurring within the 2 weeks immediately after CBC to avoid confounding of acute or co-occurring events. The last documented clinical follow-up was defined as a telephone encounter, email, or office visit occurring within a calendar year. The difference in survival functions was assessed using the log-rank test and the stratified log-rank test to control for active disease. Survival curves were graphically represented by Kaplan-Meier survival curves. All statistical tests were evaluated with an alpha = 0.05 and were completed in StataSE (version 14, StataCorp, College Station, TX).
Ethical Considerations
All participants were enrolled in the IBD Research Registry using informed consent. The IBD Research Registry (protocol number 0309054) and the current analysis (protocol number PRO17030588) were both approved by the University of Pittsburgh Institutional Review Board.
RESULTS
Study Cohort
A total of 1290 patients with IBD were included in the study, 827 (64.1%) with CD and 463 (35.9%) with UC. The mean age of the study participants was 46.4 ± 15.0 years, and just over half were female (52.6%; Table 1). The majority were White and had no previous history of tobacco use (Table 1). Monocytosis was found in 399 (30.9%) patients. In the majority of those patients (86.5%), monocytosis was identified in a single year of the study period.
TABLE 1.
Demographics of Patients With IBD Included in the Study
| Total N = 1290 | Monocytosis n = 399 | No Monocytosis n = 891 | Monocytosis vs No Monocytosis P | CD P | UC P | |||
|---|---|---|---|---|---|---|---|---|
| CD n = 242 | UC n = 157 | CD n = 585 | UC n = 306 | 0.083 | ||||
| Demographics | ||||||||
| Age, y (mean ± SD) | 46.4 ± 15.0 | 43.9 ± 14.1 | 47.1 ± 16.9 | 45.9 ± 14.7 | 49.0 ± 14.7 | 0.046* | 0.079 | 0.199 |
| Female, % | 52.6 | 50.8 | 35.7 | 58.3 | 51.6 | <0.001* | 0.049* | 0.001* |
| BMI, mean ± SD | 26.8 ± 5.8 | 26.8 ± 6.2 | 27.1 ± 5.5 | 26.3 ± 5.6 | 27.5 ± 5.8 | 0.644 | 0.323 | 0.468 |
| Race/ethnicity, % | 0.085 | 0.392 | 0.041* | |||||
| White | 96.0 | 96.3 | 91.1 | 96.9 | 96.4 | |||
| Black | 2.3 | 3.3 | 3.8 | 2.1 | 1.0 | |||
| Other or unknown | 1.8 | 0.4 | 5.1 | 1.0 | 2.6 | |||
| Hispanic/Latino | 0.5 | 0.8 | 0.0 | 0.3 | 0.7 | |||
| Smoking status, % | 0.052 | 0.078 | 0.168 | |||||
| Current smoker | 6.4 | 5.2 | 10.7 | 6.7 | 2.9 | |||
| Past smoker | 35.2 | 33.6 | 40.5 | 37.1 | 28.1 | |||
| Never smoker | 57.6 | 61.3 | 47.5 | 55.6 | 67.7 | |||
| Unknown | 0.9 | 0.0 | 1.2 | 0.7 | 1.3 | |||
| Disease characteristics | ||||||||
| Disease, y, mean ± SD | 18.1 ± 10.1 | 17.6 ± 9.1 | 16.1 ± 10.2 | 19.8 ± 10.8 | 16.6 ± 9.1 | 0.014* | 0.015* | 0.296 |
| Prior IBD surgery, % | 35.0 | 45.5 | 18.5 | 44.8 | 16.7 | 0.919 | 0.860 | 0.627 |
| CD location, % | -- | |||||||
| Ileal (L1) | -- | 27.2 | -- | 30.0 | -- | -- | 0.451 | |
| Colonic (L2) | 21.0 | 20.5 | 0.883 | |||||
| Ileocolonic (L3) | 51.3 | 50.8 | 0.895 | |||||
| Upper GI (L4) | 4.0 | 4.5 | 0.749 | |||||
| CD behavior, % | ||||||||
| Inflammatory (B1) | -- | 40.6 | -- | 43.8 | -- | -- | 0.416 | -- |
| Stricturing (B2) | 36.2 | 39.4 | 0.403 | |||||
| Penetrating (B3) | 28.1 | 21.1 | 0.034* | |||||
| Perianal disease, % | -- | 22.3 | 15.6 | -- | 0.026* | -- | ||
| UC extent, % | 0.007* | |||||||
| Proctitis (E1) | -- | -- | 7 (4.1) | -- | 17 (5.2) | -- | -- | |
| Left-sided (E2) | 37 (21.6) | 113 (34.2) | ||||||
| Extensive (E3) | 102 (59.7) | 154 (46.7) | ||||||
| Disease activity | ||||||||
| Elevated CRP, % | 665 (51.6) | 175 (72.3) | 111 (70.7) | 257 (43.9) | 122 (39.9) | <0.001* | <0.001* | <0.001* |
| Elevated ESR, % | 480 (37.2) | 135 (55.8) | 86 (54.8) | 166 (28.4) | 93 (30.4) | <0.001* | <0.001* | <0.001* |
| Anemia, % | 687 (53.3) | 177 (73.1) | 101 (64.3) | 278 (47.5) | 131 (42.8) | <0.001* | <0.001* | <0.001* |
| HBI | -- | 4.3 (5.0) | -- | 2.5 (4.0) | -- | -- | <0.001* | -- |
| UCAI | -- | -- | 3.2 (5.3) | -- | 2.0 (3.3) | -- | -- | 0.001* |
| Quality of life | ||||||||
| SIBDQ (median [IQR]) | 55.2 (16.1) | 49.7 (17.0) | 55.0 (15.7) | 55.8 (16.5) | 57.8 (12.7) | <0.001* | <0.001* | 0.041* |
| Medication use, % | ||||||||
| Biologics | 597 (46.3) | 168 (69.4) | 64 (40.8) | 300 (51.3) | 65 (21.2) | <0.001* | <0.001* | <0.001* |
| Immunomodulators | 701 (54.3) | 151 (62.4) | 73 (46.5) | 344 (58.8) | 133 (43.5) | 0.385 | 0.338 | 0.534 |
| Systemic steroids | 736 (57.1) | 166 (68.6) | 121 (77.1) | 288 (49.2) | 161 (52.6) | <0.001* | <0.001* | <0.001 |
| 5-ASAs | 632 (49.0) | 77 (31.8) | 126 (80.3) | 201 (34.4) | 228 (74.5) | 0.365 | 0.482 | 0.168 |
| Health care utilization (median [IQR]) | ||||||||
| ED visits (n, %) | 678 (52.6) | <0.001* | <0.001* | <0.001* | ||||
| Hospitalizations (n, %) | 626 (48.5) | <0.001* | <0.001* | <0.001* | ||||
| Surgeries, (n, %) | 274 (21.2) | 108 (44.6) | 4.0 (3.0) | 121 (20.7) | 4.0 (3.0) | <0.001* | <0.001* | 0.001* |
| Endoscopies | 4.0 (2.0) | 4.0 (3.0) | 28 (17.8) | 4.0 (3.0) | 17 (5.6) | <0.001* | <0.001* | <0.001* |
| Radiologic studies | 5.0 (10.0) | 11.0 (17.0) | 8.0 (15.0) | 4.0 (8.0) | 3.0 (7.0) | <0.001* | <0.001* | <0.001* |
| Clinic visits | 8.0 (8.0) | 11.0 (11.0) | 9.0 (8.0) | 7.0 (7.0) | 6.0 (7.0) | <0.001* | <0.001* | 0.001* |
| Telephone calls | 17.0 (21.0) | 28.0 (33.0) | 20.0 (21.0) | 15.0 (19.0) | 13.5 (17.0) | <0.001* | <0.001* | <0.001* |
| Financial charges ($USD) | 50,743.01 (153,012.90) | 161,827.90 (373,035.00) | 216,396.00 ([95,400.65) | 37,736.00 (129,610.30) | 24,619.00 (48,177.75) | <0.001* | <0.001* | <0.001* |
5-ASAs indicates 5-aminosalicylic acids; BMI, body mass index; SD, standard deviation.
Among all patients with IBD, monocytosis was associated with younger age (45.2 vs. 47.0 years; P = 0.05) and male sex (55.1% vs 44.0%; P < 0.001). There was no difference between patients with monocytosis and control patients regarding smoking status and history of IBD-related surgery before 2010. Monocytosis was associated with shorter disease duration (16.9 vs 18.6 years; P = 0.01). Although not statistically significant, there was a trend of monocytosis occurring more in patients with UC (29.3% of CD, 33.9% of UC; P = 0.08; Table 1).
Having monocytosis was associated with increased serum biomarkers of inflammation, including ever having an elevation of CRP (71.7% vs 42.5%; P < 0.001) or ESR (55.4% vs 29.1%; P < 0.001). Monocytosis was associated with increased exposure to biologics (58.2% vs 41.9%; P < 0.001) and systemic steroids (71.9% vs 28.1%; P < 0.001) but was not associated with immunomodulator (56.1% vs 53.5%) or 5-aminosalicylic acid agent exposure (50.9% vs 48.2%; Table 1). Among all patients with IBD, monocytosis was significantly associated with worse quality-of-life scores (average SIBDQ score, 50.0 vs 54.1; P < 0.001). Monocytosis was associated with increases across all health care utilization measures over the study period, including an increased proportion of patients requiring hospitalization (75.4% vs 36.5%; P < 0.001) or an ED visit (74.2% vs 42.9%; P < 0.001). Of those with monocytosis, 34.1% had at least 1 surgery during the study period, compared to 15.5% of the patients without monocytosis (P < 0.001). Monocytosis was associated with more endoscopies (median [IQR], 4 [3] vs 4 [3]), radiologic studies (10 [16] vs 4 [9]), clinic visits (10 [10] vs 7 [6]), and telephone encounters (24 [28] vs 15 [19]; all P < 0.001; Table 1). Overall financial health care charges (over 6 years) occurring in the study period were significantly greater in the monocytosis group (median [IQR], $127,014 [354,062] vs. $32,925 [106,262], P < 0.001). After multivariable analysis controlling for demographics, inflammatory measures, steroids, and disease activity, patients with monocytosis remained significantly associated with an increased likelihood of hospitalization (adjusted odds ratio [AOR], 4.49), surgery (AOR, 1.85), and ED use (AOR, 2.80; Table 2) compared with those without monocytosis.
TABLE 2.
Multivariate Logistic Regression Analysis of Monocytosis
| Odds Ratio | 95% CI | AOR | 95% CI | |
|---|---|---|---|---|
| IBD* | ||||
| Hospitalization | 5.35 | (4.10-6.98) | 4.49 | (3.10-6.50) |
| Surgery | 2.82 | (2.14-3.72) | 1.85 | (1.27-2.73) |
| ED | 3.83 | (2.95-4.97) | 2.80 | (2.02-2.89) |
| CD† | ||||
| Hospitalization | 5.31 | (3.74-7.53) | 3.42 | (2.06-5.71) |
| Surgery | 3.09 | (2.24-4.27) | 1.77 | (1.12-2.79) |
| ED | 3.71 | (2.66-5.19) | 2.58 | (1.64-4.04) |
| UC‡ | ||||
| Hospitalization | 6.29 | (4.11-9.61) | 6.52 | (3.47-12.25) |
| Surgery | 3.69 | (1.95-6.98) | 1.96 | (0.78-4.93) |
| ED | 4.17 | (2.74-6.34) | 3.54 | (2.03-6.18) |
*Multivariable logistic regression adjusted for sex, age, disease type, disease duration, biologic exposure, systemic steroid exposure, abnormal ESR, abnormal C-reactive protein, anemia, and active disease as determined by Ulcerative Colitis Activity Index and Harvey-Bradshaw Index scores.
†Multivariable logistic regression adjusted for sex, age, disease duration, biologic exposure, systemic steroid exposure, abnormal ESR, abnormal C-reactive protein, anemia, penetrating CD behavior, perianal disease, and mean Harvey-Bradshaw Index disease activity score.
‡Multivariable logistic regression adjusted for sex, age, disease duration, biologic exposure, systemic steroid exposure, abnormal ESR, abnormal C-reactive protein, anemia, left-sided colitis, extensive colitis, and mean Ulcerative Colitis Activity Index score.
CI indicates confidence interval.
CD
Patients with CD with monocytosis had more penetrating disease behavior and perianal disease compared to those without monocytosis (P < 0.05; Table 1). There was no association between monocytosis and disease location in patients with CD. Similar to the entire cohort of patients with IBD, there was a significantly higher proportion of patients with CD with monocytosis exposed to biologics (69.4% vs 51.3%) and systemic steroids (68.6% vs 49.2%) as compared with patients with CD without monocytosis (Table 1). Patients with CD with monocytosis were more likely to ever have an abnormal CRP and ESR and to have anemia over the study period (all P < 0.001; Table 1). The CD clinical activity scores and mean SIBDQ scores were significantly worse in these patients. Health care utilization was increased in patients with CD with monocytosis compared with those without monocytosis across all measured health care utilization categories, and a larger proportion of patients with CD with monocytosis required surgery (44.6% vs 20.7%) compared with those without monocytosis (Table 1). Finally, overall financial health care charges were significantly greater in patients with CD with monocytosis (median, $161,827 vs $37,736; P < 0.001) than in patients with CD without monocytosis (Table 1).
Patients with CD with monocytosis were 3.4 times as likely as those without monocytosis to require any hospitalization, 2.6 times as likely to use the ED, and 1.8 times as likely to have surgery over the study period, after adjusting for significant covariates (Table 2). In the time-to-event analysis, patients with CD with monocytosis had a significantly shorter time to first hospitalization, surgery, and ED visit (Fig. 1), all of which remained significant after stratifying for active disease (ED, hospitalization: P < 0.001; surgery: P = 0.031).
FIGURE 1.
ED, hospitalization, and surgery-free survival of patients with IBD with monocytosis and those without, separated by event and disease type. Dashed line represents patients with IBD with monocytosis and solid line represents all other patients without monocytosis. A and B, ED-free survival. C and D, Hospitalization-free survival. E and F, Surgery-free survival from 2 weeks after first monocytosis or CBC.
UC
Approximately one-third of patients with UC had monocytosis over the study period. Monocytosis was associated with the extent of UC (P < 0.01; Table 1). Patients with UC with monocytosis were significantly more likely to have an abnormal CRP or ESR, and to ever have anemia (Table 1). These patients were also more likely to be exposed to biologics (40.8% vs 21.2%; P < 0.001) and to require systemic steroids at any time during the study period (77.1% vs 52.6%; P < 0.001; Table 1). Patients with UC with monocytosis had worse mean disease activity scores and a poorer mean SIBDQ score (Table 1). They had significantly increased health care utilization, including ED visits, hospitalizations, endoscopies, total radiologic studies, outpatient clinic visits, and telephone encounters (all P < 0.01; Table 1). In addition, patients with UC with monocytosis were also more likely to require IBD-related surgery at any time over the study period (17.8% vs 5.6%; P < 0.001; Table 1). Finally, overall financial health care charges were significantly greater in patients with UC with monocytosis (median, $216,396 vs $24,619; P < 0.001) than in patients with UC without monocytosis (Table 1).
In UC, patients with monocytosis were 6.5 times as likely to require hospitalization and 3.5 times as likely to use the ED, after adjusting for significant covariates including steroid use and inflammatory markers (Table 2). In the time-to-event analysis, patients with UC with monocytosis had a significantly shorter time to first hospitalization, surgery, and ED visit (Fig. 1), which remained significant after stratifying for active disease (all P < 0.001).
DISCUSSION
In this study, we found that approximately one-third of patients with IBD had an elevation in their monocyte count over a 6-year observation period. Monocytosis was associated with an aggressive disease pattern requiring biologics and steroids, poor quality of life, and dramatically increased health care utilization over the study period in both patients with CD and patients with UC.
Established markers of aggressive disease and severity including age, perianal and penetrating disease in CD, and extensive disease in UC were significantly more common in the monocytosis group than in the nonmonocytosis group. We also found that patients with monocytosis in UC and CD had a significantly higher use of steroids and biologics. Monocytosis could be a result of steroid exposure,23, 24 but monocytosis is not likely a result of anti-TNF exposure because anti-TNF treatment has been shown to cause monocytopenia.25-27 Beyond medications, monocytosis was also associated with abnormal CRP, ESR, and anemia, suggesting that this finding is more likely related to overall disease severity and the need for aggressive therapy.
To address the concern for monocytosis as a marker of inflammation and not necessarily a marker of severity in IBD, we controlled for any abnormal inflammatory biomarkers of CRP and ESR over the 6-year time period when evaluating health care utilization. Monocytosis remained independently associated with primary clinical outcomes, including surgery in CD, after adjusting for confounding variables including CRP, which has been shown to associate with surgical risk within subgroups of patients with IBD patients.9, 10 Monocytosis was uniformly predictive of health care utilization after adjusting for active disease in the time-to-event analysis, suggesting that peripheral monocytosis could be used as a biomarker of impending disease severity or health care utilization, but these results require additional prospective validation. In addition, a comparison of the cost and utility of the landscape of inflammatory markers available would be of clinical interest.
Monocytes and other white blood cell subtypes have been studied in other inflammatory diseases such as atherosclerosis and rheumatoid arthritis and have been found to play a role as biomarkers by predicting therapy response or disease severity.28, 29 We have shown that an elevated monocyte count at a point in time is associated with disease activity, similar to earlier studies.17, 18, 30 However, there are no prior studies looking at the role of peripheral blood monocytes as a multiyear prognostic biomarker in patients with IBD, including both CD and UC.
Components of the white blood cell differential have recently gained attention as potential biomarkers for prognosis and chronic inflammatory disease management. This development is true for treatment selection in asthma, where biologic agents have been linked to peripheral blood eosinophilia.31 Studies have explored eosinophilia in the population of patients with IBD and have found that it is a biomarker of multiyear severity.6 Such attempts to repurpose routine laboratory results (ie, components of the white blood cell differential) prompted our exploration of peripheral blood monocytosis as a potential biomarker of severity in IBD and the work presented in this article. Although we show an association with disease severity over time, the mechanisms for this association are still unclear. Monocytes are important in innate immune function, infection, and inflammation, and monocyte and macrophage numbers in the blood pool and inflamed tissues are linked.12 Interestingly, although monocytes and macrophages are critically important for inflammatory response and eventual tissue repair, in the context of ischemic heart disease animal models the oversupply of inflammatory monocytes in the blood can actually impair healing.12, 32 The monocytosis we observed in patients with IBD may be similarly skewed toward inflammatory rather than reparative monocytes and may similarly impair healing at the site of inflammation. Although studies have shown that monocyte and macrophage polarization is important in models of IBD,33, 34 the peripheral monocytosis phenotypes within patients with CD and UC have yet to be fully characterized. A few studies have evaluated ex vivo characteristics of peripheral blood mononuclear cells and shown alterations in glucocorticoid receptors and inflammatory cytokine production in comparison with results from healthy control patients.35, 36 Overall, the innate immune system has been widely implicated in the susceptibility and pathogenesis of IBD, and expanding the characterization of peripheral monocyte populations in patients with IBD may further elucidate our understanding of inflammatory mechanisms in IBD disease activity.37-39
Our study is limited by its retrospective design in a single tertiary referral center, which may limit generalizability. All patients included were part of an IBD research registry, which is susceptible to participation bias. This is an observational study utilizing electronic medical records and is thus prone to confounding variables and data capture limitations associated with medical records research. It is also difficult to address the temporal association between monocytosis and disease severity using an observational data structure. This is not an inception cohort because the majority of patients present to the tertiary care clinic with a known history of IBD. Therefore, it is uncertain how the biomarker of monocytosis would relate to disease severity in newly diagnosed patients with IBD.
Despite the inherent limitations, this is the first study examining monocytosis as a marker of multiyear disease severity in both UC and CD. The potential biomarker of monocytosis offers the advantage of being low-cost and routinely available in medical practice, which makes clinical translation into community settings increasingly feasible. This study also carries the advantage of including a large cohort of patients over a multiyear observation period in a real-world setting. Moving to multiyear data allows for analyzing disease patterns over time. In addition, although this study was located at a tertiary care center, the research registry captures data regionally and includes all care occurring at >20 affiliated hospitals and 500 clinics in the health care system in the surrounding communities.
CONCLUSIONS
Monocytosis occurs in a subset of patients with IBD and is associated with severe disease and increased health care utilization over a multiyear time period. Patients with IBD with monocytosis are at an increased risk for worse clinical outcomes. Future research is necessary to determine whether monocytosis can be used as a prospective prognostic marker of unplanned care or whether it can predict response to therapy.
ACKNOWLEDGMENTS
We acknowledge the faculty, staff, and most important the generosity of our patients who continue to make this research feasible.
Glossary
Abbreviations
- anti-TNF
anti-tumor necrosis factor
- AOR
adjusted odds ratio
- CBC
complete blood count
- CD
Crohn disease
- CRP
C-reactive protein
- ED
emergency department
- ESR
erythrocyte sedimentation rate
- IBD
inflammatory bowel disease
- IQR
interquartile range
- SIBDQ
Short Inflammatory Bowel Disease Questionnaire
- UC
ulcerative colitis
Author contributions: Drafting of the manuscript: Anderson, Click, Cherfane. Analysis and interpretation of data: Anderson, Click, Ramos-Rivers, Koutroubakis, Binion. Study concept and design: Anderson, Cherfane, Click, Binion. Acquisition of data: Schwartz, Barrie, Dunn, Hashash, Cherfane, Ramos-Rivers, Proksell, Johnston, Dueker, Babichenko, Tang, Binion. Administrative support: Binion, Dunn, Ramos-Rivers. Critical revision of the manuscript: Anderson, Koutrobakis, Click, Cherfane. Study supervision: Binion. All authors read and approved the final manuscript.
Supported by: Alyce Anderson was supported by a National Institutes of Health training grant (TL1TR001858). Michael Dunn reports support from W81XWH-11-2-0133 from the U.S. Army Medical Research and Materiel Command. David Binion reports support from W81XWH-17-1-0556 from the U.S. Department of Defense. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR001858. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflicts of interest: David Binion has served as a consultant for Janssen, AbbVie, Synthetic Biologics, and UCB Pharma. Benjamin Click has served as a consultant for Takeda and TARGET PharmaSoulutions and on the speakers’ bureau for Takeda. All remaining authors report no conflicts of interest.
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