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Correlation of anemia status with worsening bowel damage as measured by Lémann Index in patients with Crohn's disease

Digestive and Liver Disease, In Press, Corrected Proof, Available online 2 March 2016, Available online 2 March 2016

Abstract

Background

There is evidence that anemia in Crohn's disease (CD) is a predictor of disease severity.

Aim

To evaluate if patterns of anemia over time showed correlation with aggressive disease trajectory, as characterized by change in Lémann Index (LI), which is a metric that quantifies bowel damage.

Methods

CD patients with 5 year (y) follow-up from a prospective registry were included. LI was calculated from the first (LI1) and last (LI2) clinical encounters. The change in score (LI2–LI1) or the Delta LI (DLI) was recorded. Patterns of anemia, healthcare utilization and disease activity scores were analyzed.

Results

A total of 389 CD patients with 5 y follow-up formed the study population [median age 40 y (IQR: 31–53); 57.3% female; median disease duration 12 y (IQR: 6–20.5), overall surgical exposure 69%]. Patients with anemia had significantly higher LI1, LI2, DLI and also significantly higher healthcare utilization and indices of disease activity, than patients without anemia (p < 0.001). CD patients with anemia for any duration during the study had OR of 2.15 (95% CI 1.29–3.57, p = 0.003) for worsening bowel damage over the 5 y.

Conclusion

Based on a longitudinal analysis of CD patients, anemia status over time shows significant correlation with increasing Lémann index and aggressive disease trajectory.

Keywords: Anemia, Crohn's disease, Lémann Index.

1. Introduction

Crohn's disease (CD) is a subtype of inflammatory bowel disease (IBD) that shows a progressive relapsing-remitting course. (1) In long standing disease, the ongoing underlying inflammatory process leads to continued structural bowel damage and development of strictures and/or fistulas, which often require surgical treatment [1], [2], and [3]. Severe or disabling CD is defined based on the impact of the disease on patient (symptoms, quality of life, etc.), the inflammatory burden, and the disease course, including structural damage [4]. The Lémann Index (LI) is a new tool that allows quantification of cumulative bowel damage based on the presence and extent of stricturing and penetrating lesions and history of surgical resection [5]. Higher scores and rapid increases in scores portend aggressive disease trajectories with marked disability [6].

Anemia is the most common extra-intestinal manifestation of CD, with a significant impact on patients’ quality of life as well as on disease course and costs [7] and [8]. In a recent European meta-analysis the prevalence of anemia among CD patients was 27% and active disease was more often associated with anemia [9]. In a cohort study, low hemoglobin was found to be an independent predictor for more rapid occurrence of the first CD complication or CD related surgery [10]. Our recent evaluation of a longitudinally evaluated IBD cohort showed that patients with anemia required significantly higher health care and had higher indices of disease activity, as well as worse average quality of life, than patients without anemia [11]. This suggests its role as a potential marker of severe and disabling disease but, as far as we are aware, there is no other published information on the possible association between anemia and bowel damage in CD patients.

The aim of our study was to investigate if the presence and duration of anemia in longitudinally followed CD patients correlates with a clinical pattern of aggressive/disabling disease, as characterized by the change in Lémann Index.

2. Patients and methods

A consented, prospective, longitudinal natural history registry containing data on 2300 patients with CD and ulcerative colitis, maintained at a tertiary adult IBD center was utilized to perform this observational study. Patients with a definitive CD diagnosis according to established criteria and with regular follow up between January 1, 2009 and December 31, 2013 were identified. Regular follow up was defined as having at least one IBD clinic visit in each year (y). Among them, those who had undergone at least two CD related diagnostic imaging tests, including endoscopic and radiologic imaging, at least three months apart within the period of interest, were included. Patients with established CD of less than 3 month duration or those who had never undergone clinical evaluation or diagnostic testing at our IBD center prior to January 1, 2009 were excluded. Also, patients who had undergone CD related surgery during the 5 y follow up, without CD related diagnostic imaging tests both preceding and following the surgery were excluded.

2.1. Data acquisition

For all patients’ details regarding demographics, disease characteristics, including Montreal classification [12], hospitalizations during the study and surgical history were extracted from the registry. Disease activity and quality of life as evaluated by Harvey Bradshaw Index (HBI) [13] and Short Inflammatory Bowel Disease Questionnaire (SIBDQ) [14] respectively at each IBD clinic visit were tracked. Laboratory data including biochemical markers of inflammation [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] and hemoglobin (Hb) measurements were recorded using electronic medical record based searches. Treatment related details, such as the use of steroids, immunomodulators (methotrexate, azathioprine, 6-mercaptopurine), anti-tumor necrosis factor (TNF) agents (infliximab, adalimumab, certolizumab), and iron supplementation (oral or intravenous) were also prospectively recorded. For the analysis, variables under biochemical markers and medications were tabulated using a scale that ranged from 1 to 5. A value of 1 implied abnormal biomarker in one or more measurements in a single year or one or more prescriptions for an agent in a single year, 2 indicated abnormal values in one or more measurements in two out of five years or one or more prescriptions in two out of the five years and so forth. Based on our laboratory's arbitrary cut off, we considered an ESR value >20 mm/hr and a CRP value >0.8 mg/dL elevated.

2.2. Evaluation of anemia

Anemia was defined based on the World Health Organization (WHO) criteria (Hb < 13 g/dL in men and Hb < 12 g/dL in non-pregnant women) [15]. The study cohort was divided into three groups according to anemia status during the study, with group A composed of patients without anemia, group B having patients with anemia for one or two (consecutive or not) years and group C comprising patients with anemia for three (consecutive or not) or more years. Hematopoietic response, considered as an increase of ≥2 g/dL in Hb is a measure utilized in assessing treatment of anemia which has been validated in IBD [16]. We dichotomized patients in group C as having persistent or recurrent anemia, based on absence or presence of hematopoietic response with iron supplementation respectively.

2.3. Calculation of Lémann Index

Calculation of LI was done using the Microsoft Excel based calculator devised by Pariente et al. [5]. Relevant information was gathered by reviewing reports of all available CD related diagnostic imaging tests (endoscopic and radiologic) that were performed within a 3 month window. LI was calculated twice for each patient, first (LI1) using the earliest available diagnostic tests during period of follow up and second (LI2) with the last available diagnostic tests. Change in LI (LI2–LI1) was designated as Delta Lémann Index (DLI) and was used to stratify patients into three distinct categories of disease evolution: improvement (DLI < 0), no change (DLI = 0) or deterioration (DLI > 0).

2.4. Statistical analysis

Normality of data distribution was evaluated using the Kolmogorov–Smirnov test. Normally distributed variables are presented as mean ± SD and nonparametric data as median [inter-quartile range (IQR)]. Difference between groups was evaluated using Student's t test for parametric continuous data and Mann Whitney U test and Kruskal Wallis test for nonparametric continuous data. Chi squared analysis was used for contingency tables. Univariate analysis was used to assess the correlation of trajectory of deterioration (DLI > 0) with parameters that are routinely used to gauge disease activity (HBI, SIBDQ, ESR, CRP), along with anemia status. Covariates showing p value <0.1 were used for the multivariate logistic regression analysis. Potential confounders were adjusted for and the increase in LI or DLI > 0 which signifies worsening bowel damage was selected as the dependent variable. All analyses were performed using 19.1 SPSS statistical software (SPSS, Chicago, USA). p values <0.05 were considered statistically significant.

2.5. Ethical considerations

The study was approved by the University of Pittsburgh's Institutional Review Board on 6/30/2014 (PRO14050636). Enrollment was done using informed consent and voluntary withdrawal and all study material was de-identified and maintained confidential.

3. Results

We found 1098 CD patients in the IBD registry; with 430 having regular follow up between January 1, 2009 and December 31, 2013. In total, 41 patients met the exclusion criteria and Fig. 1 details the patients’ flow within the study with numbers and reasons for exclusion. Finally, 389 patients were included in the analysis and their baseline demographic and clinical characteristics [median age 40 y (IQR: 31–53); 57.3% female; median disease duration 12 y (IQR: 6–20.5), overall surgical exposure 69%] are outlined in Table 1.

gr1

Fig. 1 Schematic representation of study population selection.

Table 1 Demographic and clinical characteristics of Crohn's disease patients (n = 389) included in the study.

Characteristic n (% or IQR)
Females, n (%) 223 (57.3)
Age (years), median (IQR) 40 (31–53)
Caucasian ethnicity, n (%) 377 (97)
Active/former smoker, n (%) 184 (47.3)
Age at diagnosis (years), median (IQR) 26 (19–34)
Disease duration (years), median (IQR) 12 (6–20.5)
Disease location (as per Montreal classification [5]), n (%)
 L1 (ileal) 95 (24.4)
 L2 (colonic) 81 (20.8)
 L3 (ileocolonic) 210 (54)
 L4 (isolated upper digestive) 3 (0.8)
Disease behavior (as per Montreal classification [5]), n (%)a
 B1 (non stricturing, non penetrating) 161 (41.4)
 B2 (stricturing) 157 (40.4)
 B3 (penetrating) 98 (25.2)
 P (perianal disease) 86 (22.1)
CRS prior to study, n (%) 267 (68.6)
CRS during the study, n (%) 151 (38.8)
LI1, median (IQR) 8.3 (0.8–12)
LI2, median (IQR) 8.3 (1.5–17.7)
Months between LI1 and LI2, median (IQR) 42 (33–51)
DLI, median (IQR) 0 (0–2.9)
5 y SIBDQ, median (IQR) 51 (42.1–59)
5 y HBI, median (IQR) 3.7 (1.9–6.9)

a Some patients had showed more than one disease behavior pattern during their course prior to study.

n: number of patients; IQR: interquartile range; BMI: Body Mass Index; CRS: Crohn's disease related surgery; LI1: Lémann Index 1; LI2: Lémann Index 2; DLI: Delta Lémann Index; SIBDQ: Short Inflammatory Bowel Disease Questionnaire; HBI: Harvey Bradshaw Index; y: years.

One hundred fifty three CD patients (39.3%) were without anemia throughout the study period (group A), 143 CD patients (36.8%) had anemia for 1–2 years (group B) and 93 patients (23.9%) had anemia for ≥3 years (group C). Average Hb across 5 years was significantly different across the 3 groups (median 14 vs. 12.6 vs. 11.1 in groups A, B, and C respectively; p < 0.001). Iron supplementation at any time was administered to 125 patients (97 oral and 28 intravenous) and was more frequent in group C patients (p < 0.001) compared to the other groups. Among patients of group C, 22 (23.7%) had persistent anemia and 71 (76.3%) had recurrent anemia.

Sex, age, age at disease onset, disease duration, smoking status and disease characteristics as per Montreal Classification were not significantly different across the three groups as shown in Table 2. Patients in group C were noted to have a significantly lower BMI (p = 0.018) compared to group A. Patients in group B and C had significantly higher rates of CD related surgical exposure both prior to and during the study when compared to patients in group A (p value for all parameters <0.001).

Table 2 Characteristics of Crohn's disease patients in relation to the status of anemia.

Group Aa Group Bb Group Cc p valued p valuee p valuef
Patients, n (%) 153 (39.3) 143 (36.8) 93 (23.9) NA NA NA
Females, n (%) 83 (54.2) 87 (60.8) 53 (56.9) 0.517 0.694 0.152
Age (y), median (IQR) 43 (35–54) 40 (30–53) 40 (31–52) 0.252 0.21 0.128
BMI (kg/m2), median (IQR) 25.83 (23–29) 24.5 (22–28) 24.2 (22–28) 0.042g 0.018g 0.069
Active/Former smoker, n (%) 73 (47.7) 67 (46.9) 44 (47.3) 0.989 1 0.487
Age at onset (y), median (IQR) 27 (20–36) 25 (19–31) 23 (17–34) 0.163 0.082 0.151
Disease duration (y), median (IQR) 12 (7–20) 11 (6–19) 12 (6–21) 0.669 0.804 0.363
Disease location, n (%)
 L1 (ileal) 38 (24.8) 36 (25.2) 21 (22.6) 0.892 0.759 0.526
 L2 (colonic) 36 (23.6) 24 (16.8) 21 (22.6) 0.321 1 0.097
 L3 (ileocolonic) 79 (51.6) 81 (55.9) 50 (53.8) 0.614 0.693 0.193
 L4 (isolated upper GI) 0 2 (1.4) 1 (1) 0.361 0.378 0.233
Disease behavior, n (%)h
 B1 (non stricturing, non penetrating) 71 (46.4) 53 (37.1) 37 (39.8) 0.248 0.354 0.065
 B2 (stricturing) 55 (35.9) 64 (44.8) 38 (40.9) 0.302 0.498 0.077
 B3 (penetrating) 30 (19.6) 41 (28.7) 27 (29) 0.124 0.119 0.046g
 P (perianal disease) 29 (19) 34 (23.8) 23 (24.7) 0.476 0.334 0.192
CRS prior to study, n (%) 84 (54.9) 107 (74.8) 76 (81.7) <0.001g <0.001g <0.001g
CRS during study, n (%) 26 (16.9) 66 (46.2) 59 (63.4) <0.001g <0.001g <0.001g
5 y Hb, (g/dL), median (IQR) 14 (13.4–14.8) 12.6 (12–13.2) 11.1 (10.2–11.9) <0.001g <0.001g <0.001g
LI1, median (IQR) 3.2 (0–8.6) 8.3 (1.3–12.7) 8.3 (2.3–19.4) <0.001g <0.001g <0.001g
LI2, median (IQR) 8.3 (0–9.9) 9.6 (3.5–20.6) 12 (6.5–34.2) <0.001g <0.001g <0.001g
Months between LI1 and LI2, median (IQR) 32 (40–52) 32 (43–51) 35 (45–52) 0.5 0.268 0.778
DLI, median (IQR) 0 (0–0.9) 0.5 (0–4.8) 1.7 (0–8) <0.001g <0.001g <0.001g
ESR elevation (/5 y), median (IQR) 0 (0–1) 1 (0–2) 2 (1–4) <0.001g <0.001g 0.001g
CRP elevation (/5 y), median (IQR) 0 (0–1) 1 (0–2) 1 (0–3) <0.001g <0.001g <0.001g
5 y ESR, median (IQR) 14 (9.6–20.1) 26 (21.4–31.1) 41 (37.4–46.5) <0.001g <0.001g <0.001g
5 y CRP, median (IQR) 0.8 (0.6–1) 2.1 (1.8–2.4) 6.3 (4.8–10) <0.001g <0.001g <0.001g
5 y SIBDQ, median (IQR) 54 (46.5–62) 51 (44–58) 43 (36–54) <0.001g <0.001g 0.012g
5 y HBI, median (IQR) 3 (1.5–4.8) 4 (2–6.9) 6 (2.8–9.2) <0.001g <0.001g 0.005g
Hospitalizations, median (IQR) 0 (0–1) 1 (0–2) 2 (1–6) <0.001g <0.001g <0.001g
Steroid use (/5 y), median (IQR) 0 (0–1) 0 (0–2) 2 (0–3) <0.001g <0.001g 0.001g
Immunomodulator use (/5 y), median (IQR) 0 (0–4) 2 (0–5) 2 (0–4) 0.051 0.032g 0.045g
Anti-TNF use (/5 y), median (IQR) 0 (0–2) 2 (0–3) 2 (0–3) 0.003g 0.026g 0.001g
Iron supplementation, n (%) 24 (15.7) 51 (35.7%) 50 (53.8%) <0.001g <0.001g <0.001g

a Patients without anemia.

b With anemia for 1–2 years.

c With anemia for ≥3 years.

d For Kruskal Wallis test across 3 groups.

e For Mann Whitney U test comparing groups A and C.

f For Mann Whitney U test comparing groups A and B.

g Significant.

h Some patients had showed more than one disease behavior pattern during their course prior to study

n: number of patients; IQR: interquartile range; BMI: Body Mass Index; CRS: Crohn's disease related surgery; LI1: Lémann Index 1; LI2: Lémann Index 2; DLI: Delta Lémann Index; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; SIBDQ: Short Inflammatory Bowel Disease Questionnaire; HBI: Harvey Bradshaw Index; IBD: inflammatory bowel disease; GI: gastrointestinal; y: years; NA: not applicable; TNF: tumor necrosis factor.

For the entire cohort, the median LI1 was 8.3 (IQR 0.8–12), median LI2 was 8.3 (IQR 1.5–17.7) and the median DLI was 0 (IQR 0–2.9) as shown in Table 1. The median interval between LI1 and LI2 was 42 months (IQR: 33–51). CD patients in group B and C had significantly higher LI1, LI2 and DLI compared to patients in group A (for all parameters p < 0.001) (Table 2). Patients were further stratified based on DLI into subgroups as showing improving (1: DLI < 0), stable (2: DLI 0) or worsening (3: DLI > 0) structural damage. Most patients in the cohort showed worsening gut destruction (47.8%) during the 5 years, which was mostly secondary to surgical resection, followed by development of ileal strictures or perianal fistulas; while 35.2% showed stable disease and 17% experienced improvement in bowel damage. A significantly greater proportion of patients in group C (63.4%) fell under subgroup 3 compared to group A (33.3%) and B (53.1%), which indicates rapid continued bowel destruction in this set of patients (p < 0.001) (Fig. 2). Among CD patients with persistent or recurrent anemia (group C), 59.1% and 64.8% had worsening gut damage respectively as shown in Table 3. The interval over which DLI was calculated was not significantly different across the 3 groups (Table 2).

gr2

Fig. 2 Crohn's disease damage trajectories over 5 years characterized by Delta Lémann Index (DLI) and patterns of anemia. DLI was calculated by subtracting the first Lémann Index from the second Lémann Index with a score >0 signifying increased damage, a score of 0 signifying no additional damage and a score <0 signifying improvement. Annual patterns of anemia were categorized as no anemia (0 years), 1–2 years, and >3 years over the 5 year period.

Table 3 Disease trajectory as characterized by Delta Lémann Index in Crohn's disease patients in relation to anemia status.

Group Aa
n = 153
Group Bb
n = 143
Group Cc p value
Recurrent
n = 71
Persistent
n = 22
Total
n = 93
Improvement
DLI < 0
33 (21.6%) 18 (12.6%) 11 (15.5%) 4 (18.2%) 15 (16.1%) <0.001d
Stable
DLI = 0
69 (45.1%) 49 (34.3%) 14 (19.7%) 5 (22.7%) 19 (20.4%)
Deterioration
DLI > 0
51 (33.3%) 76 (53.1%) 46 (64.8%) 13 (59.1%) 59 (63.4%)

a Patients without anemia.

b With anemia for 1–2 years.

c With anemia for ≥3 years.

d Significant.

n: number, DLI: Delta Lémann Index.

CD patients in groups B and C were also found to have significantly higher rates of hospitalizations and more frequent elevations in biochemical markers (ESR, CRP) (for all parameters p < 0.001) compared to patients in group A (Table 2). Patients in group A had significantly lower 5 year average HBI scores compared to patients in group B (p = 0.005) and C (p < 0.001), and significantly higher 5 year SIBDQ scores compared to group B (p = 0.012) and C (p < 0.001) respectively. The proportion of patients with five year average HBI > 4, implying active disease, was significantly different across groups A, B and C respectively (32.7% vs. 46.2% vs. 62.4%; p < 0.001). Concerning the use of IBD medications, patients of group B and C had significantly higher use of steroids (p value for both <0.001), immunomodulators (p = 0.045 and p = 0.032, respectively) and anti-TNF agents (p = 0.001 and p = 0.026, respectively), over the 5 years, when compared to group A (Table 2).

On univariate analysis worsening bowel damage showed notable association with average HBI [OR = 1.09 (95% CI 1.03–1.15), p = 0.0023], average SIBDQ [OR = 0.97 (95% CI 0.95–0.99), p = 0.001], ESR [OR = 1.14 (95% CI 0.99–1.31), p = 0.054] and CRP elevation [OR = 1.42 (95% CI 1.21–1.68), p < 0.001]. In addition, trajectory of deterioration showed significant association with presence of anemia of any duration [OR = 2.67 (95% CI 1.75–4.08), p < 0.001], anemia ≥3 y [OR = 2.31 (95% CI 1.43–3.73), p = 0.001] and with persistent anemia ≥3 y duration [OR = 1.62 (95% CI 0.68–3.88), p < 0.001]. On multivariate logistic regression analysis, after adjustment, median CRP elevation [OR = 1.41 (95% CI 1.13–1.74), p = 0.002] and anemia of any duration [OR = 2.15 (95% CI 1.29–3.57), p = 0.003] were the only variables noted to be significantly associated with progressive LI and damage as seen in Table 4.

Table 4 Determinants of worsening bowel damage (Delta Lémann Index >0) in Crohn's disease patients in the multivariate logistic regression analysis.

Independent variables OR (95% CI) p
ESR elevation (/5 y) 0.85 (0.7–1.03) 0.089
CRP elevation (/5 y) 1.41 (1.13–1.74) 0.002a
5 y SIBDQ 0.99 (0.97–1.01) 0.353
5 y HBI 1.05 (0.98–1.12) 0.193
Anemia of any duration during study 2.15 (1.29–3.57) 0.003a
Anemia ≥3 y 1.32 (0.73–2.38) 0.357

a Significant.

OR: odds ratio; CI: confidence intervals; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; SIBDQ: Short Inflammatory Bowel Disease Questionnaire; HBI: Harvey Bradshaw Index; y: years.

4. Discussion

In this study we found that patients with CD and anemia, particularly those with persistent or recurrent anemia had significantly higher Lémann Index scores and more rapid increases in LI over longitudinal follow up, along with significantly higher health care utilization, higher indices of disease activity and lower average quality of life, than patients without anemia. Moreover, the presence of anemia together with persistent CRP elevation is independently correlated with the worsening bowel damage.

There is evidence that surrogate markers of CD severity (use of more potent medications, hospitalizations and surgeries) correlate with greater health care utilization and expenditure along with lower quality of life [3], [17], and [18]. Previous indices devised to assess severity or disabilities in CD have focused more on functional rather than the structural aspects of disease complications [19] and [20]. LI is the first instrument that measures cumulative structural bowel damage and thus evaluates long term disability independent of fluctuations in disease activity [5]. It is a longitudinal tool, with each point in a plot of serial measurements representing total bowel damage thus far and a line joining each point depicting disease evolution over time [21]. As seen in prior cohorts, LI escalates with disease duration, thus indicative of accumulating damage [5], [6], and [22]. Rate of change in LI with time may be used to stratify patients’ disease into aggressive, indolent or treatment responsive types [6].

The presence of anemia has been found to be associated with several clinical and laboratory measures of CD activity [23], [24], and [25]. In a recent report a low hematocrit served as an independent predictor for shorter time to occurrence of CD related complication or surgery. In addition, sustained anemia in this cohort was associated with higher frequency of complications [10]. Our prior study that included 245 CD patients showed that anemia status was significantly correlated with higher health care utilization, greater disease activity as measured by clinical activity indices (HBI) and biochemical markers (CRP and ESR), and lower quality of life scores as measured by SIBDQ [11]. Our current study with a higher number of CD patients finds similar strong association of anemia status with a more disabling disease course.

In addition, in the present study we find for the first time that anemia status is independently significantly correlated with bowel damage as depicted with the recently developed and evaluated Lémann Index. CD patients with anemia also had significantly higher rate of change in LI, or the DLI over 5 years compared to patients without anemia. These findings highlight the role of anemia as a marker for aggressive disease and a possible contributing factor in disease progression. Among parameters that are currently used as measurements and biomarkers to gauge disease activity, persistent CRP elevation and anemia of any duration during the study raised the odds for trajectory of deterioration by 1.41 and 2.15 times respectively.

The frequent elevation of biochemical markers and the higher disease activity index scores seen in patients with anemia (groups B and C) suggests ongoing underlying mucosal inflammation, which leads to worsening damage and this is reflected in higher DLI. These patients had significantly higher use of aggressive therapies including immunomodulators, anti-TNF agents and surgeries during the study. Despite these measures and iron supplementation the persistence of anemia in this group could be multifactorial in etiology and possibly secondary to extensive mucosal injury, inadequate iron repletion, and co-existence of anemia of chronic disease or could have been intervention related causes such as intestinal resection related nutritional deficiencies and possible myelosuppressive effects of immunomodulators. Our recent analysis of anemia in CD patients showed that despite one year of therapy with anti-TNF agents, often the anemia status remains unimproved [26]. The significantly lower BMI among patients with anemia ≥3 y also suggests malnourishment, which poses challenges to treatment.

Based on these results the presence of anemia and especially of persistent/recurrent anemia could be considered to portend aggressive disease and might have a role in guiding treatment strategies. Characterization of the type of anemia and instituting appropriate treatment, both for anemia and IBD, is essential in these patients. Further prospective case controlled studies might reveal if treatment of anemia alone has the potential to influence disease course. Future studies could also incorporate endoscopic data in relation to anemia status in CD patients to precisely ascertain bowel damage.

Our study has several strengths but also has a few limitations. Firstly, since the study was conducted at a tertiary level center, referral bias and the inclusion of patients with more aggressive disease may be involved, thus affecting generalizability of the findings to the general CD population. Secondly, due to unavailability of complete data regarding iron status, we were unable to differentiate iron deficiency related anemia from anemia of chronic disease, which often co-exist in this population and influence treatment [27]. Thirdly, due to the retrospective nature of the evaluation, follow-up clinic visits and diagnostic testing did not follow a standardized protocol with regards to timing or choice of modality, and were performed at varying stages of the patients’ disease. Although the developers of LI have suggested that abdomino-pelvic MRI is the possible preferred single modality for index calculation [5], in our study we employed the available cross-sectional imaging (mainly computed tomography scans) and endoscopic diagnostic tests. While all these factors could have affected the precision of scores, it reflects the practicality of incorporating LI assessment in clinical settings. Also, we chose to lay focus on the change in LI or the DLI rather than the absolute values for our analysis to mitigate such differences. Fourthly, while healthcare utilization, anemia, disease activity and quality of life assessment spanned across 5 years, DLI ranged a shorter interval and this has the potential to misclassify patients. However, since all surgical procedures had been captured by the DLI intervals and because scores are most strongly influenced by surgeries alone [5], conducting association analysis was deemed reasonable.

In summary, anemia status in CD patients shows strong associations with worse clinical outcomes. The presence of persistent/recurrent anemia is associated with higher Lémann index scores that directly portend greater bowel damage. Patients with anemia show a 2.15 times higher risk for rapid progression in Lémann index compared to patients without anemia. Pending validation in other population based cohorts, anemia status could potentially serve as a biomarker for aggressive and disabling course in Crohn's disease.

Conflict of interest

Ioannis Koutroubakis has served on the consulting/advisory board for Abbvie and MSD. Miguel Regueiro has served as a consultant for Abbvie, Janssen, Shire, Takeda, and UCB.

David Binion has served on the Consulting/Advisory board for Abbvie, Janssen, Cubist, Salix, Steering committee FDA Safety Board UCB Pharma, Grant support from Janssen.

The remaining authors disclose no conflicts.

Funding

Ioannis Koutroubakis was supported by a sabbatical salary of Medical Faculty University of Crete, Greece. Michael Dunn and David G. Binion were supported by a Grant W81XWH-11-2-0133 from the US Army Medical Research and Materiel Command.

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Footnotes

a Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, USA

b Division of Gastroenterology, Hepatology & Nutrition, Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, USA

Corresponding author at: Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, 200 Lothrop Street PUH Mezzanine Level C Wing, Pittsburgh, PA 15213, USA. Tel.: +1 412 926 6091.

This work was presented at the American College of Gastroenterology conference on October 20th, 2015 at Honolulu, Hawaii.