Abstract
Background
Anti-tumor necrosis factor (TNF) agents are an important component of inflammatory bowel disease (IBD) treatment but data on their influence on anemia, a frequent complication of IBD is limited. The aim of this study was to evaluate the effect of anti-TNF agents on hemoglobin (Hb) levels in a large IBD cohort.
Methods
Prospectively collected demographic, clinical, laboratory and treatment data from IBD patients who started anti-TNF treatment at a tertiary referral center during the years 2010–2012 were analyzed. Follow-up data including disease activity scores (Harvey-Bradshaw Index or ulcerative colitis activity index), quality of life scores [short IBD questionnaire (SIBDQ)] completed at each visit, and laboratory data were analyzed. Data from the year of anti-TNF initiation (year 0) and the following year (year 1) were compared.
Results
A total of 430 IBD patients (324 with Crohn’s disease, 51.6% females) started anti-TNF treatment. The prevalence of anemia and median Hb levels did not change between year 0 and year 1. Median SIBDQ was significantly improved at year 1 (p=0.002). IBD patients with anemia had significantly higher median Hb levels at year 1 compared to year 0 (p=0.0009). Hematopoietic response (increase of Hb ≥2 g/dL) was observed in only 33.6 % of the 134 anemic IBD patients, despite iron replacement being administered in 126 anemic patients (oral 77 %). Improvement in Hb levels was independently significantly correlated with change of CRP levels (p=0.04) and immunomodulators use (p=0.03).
Conclusion
Anemia remains a significant manifestation of IBD one year after treatment with anti-TNF agents.
Keywords: anemia, anti-TNF, biologics, Crohn’s disease, ulcerative colitis
Introduction
Anemia is the most common systemic complication and/or extraintestinal manifestation of inflammatory bowel disease (IBD) emerging in more than one third of the patients (1–3). Anemia can significantly impair quality of life, negatively impact work and school productivity (4) and at a health economic level, it can significantly increase the cost of care (5). Understanding the pathophysiology of anemia in IBD has increased in recent years, which has been paralleled by new therapeutic strategies for iron supplementation. However, despite the widespread use of potent anti-inflammatory therapies and proper iron supplementation, anemia in IBD may recur and measures for its prevention and effective maintenance of iron stores have been suggested (6).
The tumor necrosis factor-α (TNF-α) inhibitors infliximab, adalimumab and certolizumab pegol have been proven to be safe and effective in the treatment of chronic inflammatory diseases and they play a key role in the management of moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC). It has been demonstrated that mucosal healing, often considered the optimal mucosal therapeutic response, achieved by anti-TNF treatment leads to decreased hospitalizations and surgeries in IBD patients (7). Anemia treatment in IBD is directed at both the underlying mucosal inflammation (i.e. the cause of the anemia) as well as blood loss, but the data on the long-term effect of anti-TNF agents on anemia in IBD is limited. There is evidence suggesting that TNF inhibition improves anemia in other chronic inflammatory diseases outside of the gastrointestinal tract. Anti-TNF treatment has been found to have a significant impact on hemoglobin levels in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis (8–10). Anemia in these chronic inflammatory diseases is usually characterized as anemia of chronic disease (ACD) in comparison with IBD where the most common type of anemia is iron deficiency anemia (IDA) although ACD often coexists (6).
We sought to characterize the long-term effect of TNF-α inhibition on anemia in IBD patients using data from a prospective, longitudinal, natural history registry at a tertiary referral center.
Patients and methods
The characteristics of the consented, prospective, longitudinal, natural history registry of patients with IBD at University of Pittsburgh Medical Center have been previously described (11). This registry includes demographic, clinical, endoscopic, pathological, radiological, laboratory, and other clinical data of enrolled patients and is updated routinely through Information Technology support. De-identified longitudinal data were used in the analysis from patients with definitive IBD diagnosis according to established criteria. Patients who started treatment with an anti-TNF agent (being without anti-TNF treatment the previous year) during a 3-year period from January 1, 2010 to December 31, 2012 were included. Prospectively collected demographic, clinical and laboratory data from clinic visits was utilized. Additional information was obtained with electronic medical record based computer searches and manual confirmation of information. Complete blood count data, disease activity scores, biochemical markers of inflammation and anemia, and patterns of medication use were prospectively monitored in all patients. Disease location and behavior in CD and extent of bowel involvement in UC was classified according to the Montreal classification (12). The disease activity was also prospectively evaluated using clinical activity scores such as Harvey-Bradshaw index (HBI) for CD (13) and ulcerative colitis activity index (UCAI) for UC (14). Prospectively collected health-related quality of life as measured by the validated short IBD questionnaire (SIBDQ) (15) was also analyzed. The median scores of HBI, UCAI, and SIBDQ as well as of CRP and ESR of the measurements for the year of anti-TNF initiation (year 0) and the following year (year 1) were calculated and used in the analysis. Both minimum and median levels of consecutive Hb measurements per year were evaluated.
Anemia was defined as Hb <13 g/dL in men and Hb <12 g/dL in non-pregnant women based on World Health Organization (WHO) criteria (16). Patients with Hb <10 g/dL, irrespective of gender were considered to have severe anemia. Improvement of anemia was considered any increase of Hb levels and hematopoietic response the increase of Hb ≥2 g/dL. The use of any increase of Hb as a criterion has the limitation of including minimal changes in Hb levels but it has value since it reflects median values of several measurements. Hematopoietic response has been used as a criterion in the treatment of anemia and has been validated in IBD patients (17). Similarly any drop of median Hb levels was evaluated and a special focus was placed on the development of anemia or a drop of Hb≥2g/dL both of which were considered significant. IBD patients with persistent anemia after one year despite treatment were investigated for other causes of anemia (celiac disease, hemolytic anemia and bone marrow dyscrasia). Information on iron supplementation during the study period for anemic patients was searched in the electronic records. Proportions of patients treated for anemia at the time of the evaluation with oral or intravenous (IV) iron were recorded.
Statistical analysis
Data is presented either as mean±SD for continuous, normally distributed variables or as median and range for nonparametric data. The Kolmogorov-Smirnov test was used to evaluate distribution normality. Differences between groups were evaluated using Student’s t test for parametric continuous data and Mann–Whitney U test for nonparametric continuous data. Data from contingency tables was analyzed using chi-squared analysis. Correlation with Spearman’s rho (r) was used for assessing the relationship between the change in Hb levels (year 1 – year 0) and biomarkers or disease activity indices. A logistic regression analysis was used to adjust for potential confounders. In the final model, the dependent variable was the improvement (any improvement) of Hb levels between year 0 and year 1, and the covariates were those with significance <0.1 in the univariate analysis. Tests were two-sided and P values <0.05 were considered statistically significant.
Ethical Considerations
The University of Pittsburgh’s Institutional Review Board approved enrollment and participation of the patients in the research registry (PRO12110117).
Results
A total of 430 IBD patients (324 CD, 106 UC) met inclusion criteria. Anti-TNF treatment administered to these patients included infliximab in 239 patients, adalimumab in 180 patients and certolizumab pegol in 33 patients. Twenty-two IBD individuals started a second anti-TNF agent during the same year. Demographic and clinical data of the IBD patients included in the study are presented in Table 1. Among them 352 patients continued anti-TNF treatment after 1 year with complete laboratory and follow-up data available which were analyzed. Seventy eight patients had stopped the anti-TNF treatment due to failure to response or side effects and these patients were excluded from the analysis. The assessment of changes in Hb levels and prevalence of anemia in year 0 and year 1 was done in the group of the 352 patients.
Table 1.
Demographic and clinical characteristics of inflammatory bowel disease patients included in the study
| Diagnosis | CD | UC | Total IBD |
|---|---|---|---|
| Number (%) | 324 (75.3) | 106 (24.7) | 430 (100) |
| Median age (years, IQR) | 40.0 (28.0–49.0) | 42.0 (31.0–56.0) | 41.0 (30.0–52.0) |
| Gender (females, %) | 176 (54.3) | 46 (43.4) | 222 (51.6) |
| Smoking (yes, %) | 147 (45.4) | 40 (37.7) | 187 (43.5) |
| Median disease duration (years, IQR) | 14.0 (9–20) | 9.0 (6–16.5) | 12.0 (8–19) |
| Montreal classification for UC (data on 49 patients) | |||
| Proctitis (E1, N %) | 1 (2.0) | ||
| Left sided colitis (E2, N %) | 17 (34.7) | ||
| Extensive colitis (E3, N %) | 31 (63.3) | ||
| Montreal classification for CD (data on 152 patients) | |||
| Inflammatory (B1, N %) | 54 (35.5) | ||
| Stricturing (B2, N %) | 50 (32.9) | ||
| Penetrating (B3, N %) | 48 (31.6) | ||
| Perianal (p, N %) | 30 (19.7) | ||
| Ileum (L1, N %) | 40 (26.3) | ||
| Colon (L2, N %) | 31 (20.4) | ||
| Ileocolon (L3, N %) | 74 (48.7) | ||
| Upper GI (L4, N %) | 7 (4.6) | ||
| Use of immunomodulators (N, %) | 140 (43.2) | 57 (53.8) | 197 (45.8) |
| History of surgery for IBD (N, %) | 183 (56.5) | 20 (18.9) | 195 (47.2) |
CD, Crohn’s disease; IBD, inflammatory bowel disease; IQR, Interquartile range; UC, ulcerative colitis
Changes in disease activity and biomarkers
Table 2 shows the comparison of laboratory data, activity indices and quality of life scores in these 352 IBD patients treated with anti-TNF agents at year 0 and year 1. The median clinical activity scores in both diseases (HBI and UCAI) were significantly decreased in year 1 compared to year 0 (p=0.03 and p=0.02 respectively). In parallel the median SIBDQ scores were significantly increased at year 1 compared to year 0 (p=0.002). Regarding biochemical markers of inflammation no significant difference in the median levels of CRP and ESR between year 1 and year 0 was found. Median Hb levels (minimum and median) of IBD patients treated with anti-TNF were also not significant different between year 1 and year 0 (Table 2).
Table 2.
Hemoglobin levels, disease activity indices and quality of life scores in inflammatory bowel disease patients (whole cohort N=352, with anemia N=134) treated with anti-TNF agents at year 0 and year 1
| Parameter | Year 0 (IQR) | Year 1 (IQR) | P |
|---|---|---|---|
| Minimum Hb (g/dL, IQR) | |||
| IBD cohort | 12.8 (11.2–13.8) | 12.9 (11.6–14.1) | 0.17 |
| Patients with anemia | 10.8 (9.8–11.6) | 11.6 (10.0–13.1) | 0.0001 |
| Median Hb (g/dL, IQR) | |||
| IBD cohort | 13.2 (12.4–14.4) | 13.4 (12.3–14.4) | 0.39 |
| Patients with anemia | 11.4 (10.4–12.0) | 11.8 (10.8–13.3) | 0.0009 |
| Median CRP (mg/L, IQR) | |||
| IBD cohort | 0.31 (0.12–1.1) | 0.25 (0.09–1.1) | 0.19 |
| Patients with anemia | 1.10 (0.23–3.13) | 0.65 (0.11–1.72) | 0.01 |
| Median ESR (mm/h, IQR) | |||
| IBD cohort | 16.0 (10.0–27.0) | 15.0 (8.3–28) | 0.26 |
| Patients with anemia | 28.7 (14.9–47.0) | 21.0 (11.7–34.0) | 0.01 |
| Median HBI (IQR) | |||
| IBD cohort | 3.9 (1.5–7.3) | 3.0 (1.0–6.0) | 0.03 |
| Patients with anemia | 6.0 (3.0–9.6) | 3.7 (1.5–6.2) | 0.002 |
| Median UCAI (IQR) | |||
| IBD cohort | 4.0 (1.0–9.2) | 2.0 (0.0–4.9) | 0.02 |
| Patients with anemia | 6.7 (4.5–13.7) | 4.0 (1.0–8.0) | 0.0001 |
| Median SIBDQ (IQR) | |||
| IBD cohort | 50.5 (40.0–59.0) | 54.0 (43.3–62.0) | 0.002 |
| Patients with anemia | 48.7 (37.0–56.2) | 55.0 (41.8–57.0) | 0.004 |
Hb, hemoglobin; IQR, Interquartile range; CRP, C-reactive protein; HBI, Harvey-Bradshaw index; SIBDQ, short IBD questionnaire; UCAI, ulcerative colitis activity index
Prevalence of anemia
The prevalence of anemia in IBD patients treated with anti-TNF was 38.1% at year 0 and 36.6% at year 1 and the prevalence of severe anemia (Hb<10g/dL) was 10.0% during year 0 and 9.9% at year 1 (Figure 1). No significant differences in the prevalence of anemia in CD or UC were also found (37.1% vs 38.9%, p=0.77). The screening for other causes of anemia showed 4 cases with positive anti-endomysial antibodies, two of them with histologic evidence of celiac disease. No other causes of anemia in these IBD patients were found. The prevalence of anemia in patients with a history of IBD surgery was 34.6% and 33.9% in CD and 25% and 20% in UC (with a history of proctocolectomy) at year 0 and year 1 respectively. No significant differences were found (P>0.05).
Figure 1.
The prevalence of anemia in inflammatory bowel disease patients (N=352) and subgroups of them treated with anti-TNF agents at year 0 and year 1. In all comparisons P>0.05
IBD, inflammatory bowel disease; IBDA, inflammatory bowel disease (whole cohort) with anemia; IBDSA, inflammatory bowel disease with severe anemia (Hb<10g/dL), CDA, Crohn’s disease (all patients) with anemia; CDSA Crohn’s disease with severe anemia; UCA, ulcerative colitis (all patients) with anemia; UCSA, ulcerative colitis with severe anemia
Effect of anti-TNF treatment in patients with anemia
Subgroup analysis of IBD patients with anemia (N = 134) at year 0 showed that they had significant increase of minimum and median Hb levels at year 1 compared to year 0 (p=0.0001 and p=0.0009 respectively) (Table 2). Median CRP and ESR levels as well as median HBI or UCAI were significantly lower in anemic IBD patients during year 1 compared to year 0. Moreover, median SIBDQ was significantly higher in year 1 compared to year 0 (p=0.004) (Table 2). The median change (positive or negative) of the minimum Hb levels between year 0 and year 1 in IBD patients with or without anemia is presented in Figure 2. This change was more profound in patients with severe anemia (Hb<10g/dL, median Hb change 2.5g/dL [IQR −0.6–6.5]).
Figure 2.
Box and Whisker plots of median changes in minimum hemoglobin levels in groups of inflammatory bowel disease patients treated with anti-TNF agents
IBD, inflammatory bowel disease; IBDA, inflammatory bowel disease with anemia; IBDSA, inflammatory bowel disease with severe anemia (Hb<10g/dL); IBDNA, inflammatory bowel disease with non-anemia
Hematopoietic response (increase of Hb ≥2 g/dL) was observed in only 45 anemic IBD patients (33.6%) including 14 patients with severe anemia (40%). This happened despite iron replacement being administered in 126 anemic patients (oral 77 %). Thirty nine anemic patients (29.1%) improved to non-anemic range. Among 218 patients who did not have anemia at baseline 45 (20.6%) had anemia at year 1 and 173 (79.4 %) remained without anemia. Among the 45 new anemic patients, 19 (42.2%) demonstrated a significant drop of Hb (≥2g/dL). Analysis of the 45 new anemic patients showed that 29 (64.4%) were non responders to anti-TNF treatment according to established criteria for anti-TNF treatment response (decrease of HBI or UCAI ≥3 at year 1). Moreover, they had significantly higher median CRP levels [1.17 mg/L (0.02–3.21)] compared to patients who didn’t develop anemia [0.20 mg/L (0.06–0.81)].
Treatment of anemia
One hundred twenty six IBD patients with anemia (94.0 %) received iron replacement treatment [oral iron in 97 patients (77 %), IV iron in 29 patients (23 %)]. The median Hb change was higher in patients who received IV iron [1.6 g/dL(IQR −0.2–2.9)] compared with patients who received oral iron [0.5 g/dL (IQR −0.3–2.3)] but the difference was not statistically significant (p=0.25). Among patients who developed anemia at year 1 (N 45), 38 (84.4 %) received iron treatment [oral iron 30 (78.9%), IV iron 8 (21.1%)]. Intolerance of oral iron was reported in 9 out of the 127 treated patients (7.1%), whereas no adverse events were reported after IV iron.
Correlation analysis demonstrated that the change (positive or negative) of hemoglobin levels (year 1 – year 0) was significantly negatively correlated with median ESR or CRP levels at year 1 (p=0.0001 and p=0.004 respectively) and significantly positively correlated with the change (positive or negative) of median CRP (year 0 – year 1; p=0.0001), median SIBDQ at year 1 (p=0.01) and the use of immunosuppresants (p=0.002) (Table 3). In the logistic regression analysis the improvement of Hb levels between year 0 and year 1 was significantly associated with the change of CRP levels (p=0.04) and use of immunomodulators (p=0.03) (Table 4).
Table 3.
Spearman correlation between change (positive or negative) of hemoglobin levels (year 1 – year 0) and selected characteristics of the inflammatory bowel disease patients
| Characteristic | r | p |
|---|---|---|
| Diagnosis | −0.007 | 0.90 |
| Age (years) | 0.031 | 0.61 |
| Female gender | −0.05 | <0.0001 |
| Disease duration (years) | 0.014 | 0.85 |
| Colonic disease | 0.091 | 0.21 |
| Median CRP year 0 (mg/L) | 0.071 | 0.29 |
| Median CRP year 1 (mg/L) | −0.194 | 0.004 |
| Change of median CRP (mg/L, year 0 -year 1) | 0.234 | 0.0001 |
| Median ESR year 0 (mm/h) | −0.002 | 0.97 |
| Median ESR year 1 (mm/h) | −0.265 | 0.0001 |
| Median HBI year 0 (for CD) | 0.104 | 0.16 |
| Median HBI year 1 (for CD) | −0.054 | 0.48 |
| Median UCAI year 0 (for UC) | −0.176 | 0.19 |
| Median UCAI year 1 (for UC) | −0.259 | 0.06 |
| Median SIBDQ year 0 | 0.004 | 0.96 |
| Median SIBDQ year 1 | 0.172 | 0.01 |
| Use of immunomodulators | 0.220 | 0.002 |
| Use of oral iron | 0.034 | 0.58 |
| Use of IV iron | 0.087 | 0.15 |
| Surgery for IBD | 0.015 | 0.80 |
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HBI, Harvey-Bradshaw index; IBD, inflammatory bowel disease; IV, intravenous; SIBDQ, short IBD questionnaire; UCAI, ulcerative colitis activity index
Table 4.
Determinants of the improvement (any improvement) of median hemoglobin levels in inflammatory bowel disease patients under anti-TNF treatment in the multivariate logistic regression analysis
| Independent variables | OR (95% CI) | p |
|---|---|---|
| Median CRP year 1 (mg/L) | 0.88 (0.56–1.36) | 0.56 |
| Median ESR year 1 (mm/h) | 0.99 (0.96–1.02) | 0.43 |
| Change of median CRP (mg/L, year 0 – year 1) | 1.36 (1.01–1.83) | 0.04 |
| Median SIBDQ year 1 | 0.93 (0.98–1.04) | 0.45 |
| Use of immunomodulators | 2.56 (1.09–6.00) | 0.03 |
OD, odds ratio; CI, confidence intervals; CRP, C-reactive protein, ESR, erythrocyte sedimentation rate; SIBDQ, short inflammatory bowel disease questionnaire
Discussion
We have demonstrated that anemia remains a significant extra-intestinal manifestation of IBD one year after initiation of treatment with anti-TNF agents. We found no significant change in Hb levels or the prevalence of anemia in a large number of IBD patients between the year of initiating anti-TNF treatment (year 0) and the following year (year 1). There was a partial therapeutic effect of anti-TNF treatment on hemoglobin levels in IBD patients with anemia. Anemic patients with IBD treated with anti-TNF, (and iron supplementation in the majority of the cases), showed significant increase in Hb levels in year 1 compared to year 0 of treatment, which was particularly true for patients with severe anemia. This Hb increase can be attributed to both treatments (anti-TNF and iron). Hematopoietic response was observed only in one third of the IBD patients with anemia despite iron replacement being administered in the vast majority of them. One fifth of the patients without anemia at the time of anti-TNF initiation (year 0) developed anemia after one year of therapy. Two thirds of these patients with new anemia were not responders to anti-TNF treatment.
The published literature regarding the therapeutic effect of anti-TNF treatment on hemoglobin levels and anemia in IBD patients is limited. In a small series from Italy, treatment with infliximab in 27 CD patients (18 with anemia) showed improvement of Hb levels in 12 patients (18). A study from Sweden of CD patients initiating infliximab (initially enrolled 103 patients continuous treatment in 53) showed increased Hb levels in responders during the first year of treatment (from 12.9±0.3 to 13.1±03 g/dL, p<0.01) (19). A recent study from Israel on pediatric IBD in 120 patients receiving anti-TNF treatment (infliximab or adalimumab) showed no significant differences in Hb levels between responders and non-responders to treatment (20). Our study is in agreement with the recent pediatric report and extends these findings to a large number of adult IBD patients. We confirmed that despite significant beneficial effects on disease activity and clinical outcomes, anti-TNF therapy had only a modest effect on patients’ Hb levels. We found that the prevalence of anemia in IBD patients who start anti-TNF treatment was 38.1% which is similar to other reports on the prevalence of anemia in IBD (21–23). It is especially important to note that one year after the initiation of anti-TNF therapy, the prevalence of anemia remained unchanged at 36.6% despite the initiation of potent anti-inflammatory treatment and the iron supplementation.
Anemia is the most common extra-intestinal manifestation of IBD but this clinical complication remains underappreciated. In contrast to other chronic inflammatory diseases where anemia is felt to result from the action of the inflammatory cascade, specifically the effect of interleukin-6 (IL-6) and hepcidin, anemia in IBD is more challenging as it includes the impact of mucosal blood loss, impaired iron absorption contributing to IDA as well as the anemia of chronic disease. Anti-TNF treatment has been found to significantly improve the hemoglobin levels in rheumatoid arthritis especially in patients with elevated levels of CRP at baseline indicating ACD (10). Our study failed to show similar results in IBD although there was a significant association between Hb change and change in CRP levels. These results indicate a more prominent role of iron deficiency in IBD compared to the role of chronic inflammation on hemopoiesis. Persistent anemia is common in IBD according to previous reports (22,23) but our results indicate that persistent anemia is common even after anti-TNF treatment.
Anemia in IBD correlates with the extent of intestinal disease and activity. The treatment of the underlying disease is considered an essential component for both treatment of anemia and prevention of anemia recurrence in IBD (24). The use of combination treatment with anti-TNF and immunomodulators (thiopurines or methotrexate) has been proven to be more efficacious in both CD and UC compared to monotherapy approaches with either agent (25,26). Our study showed a significant and independent association between the improvement in Hb levels and the use of immunosuppresants in IBD patients under anti-TNF treatment. This finding could be attributed to the higher rates of mucosal healing which is known to be achieved by the use of combination therapy compared to anti-TNF monotherapy (25,26). Future studies should evaluate the possible association between mucosal healing and improvement of anemia in IBD.
Treatment of anemia is associated with significant improvement of the health-related quality of life in IBD patients (4). Two recent systematic reviews and meta-analyses showed that IV iron treatment is better tolerated and more effective than oral iron treatment for anemia in IBD (27,28). According to the European Crohn’s and Colitis Organization (ECCO) guidelines the indications for IV iron are clinically active IBD, previous intolerance to oral iron and Hb levels below 10 g/dL (6). More than three quarters of the IBD patients with anemia and severe disease, as defined by the need for anti-TNF therapy, were treated with oral iron in the present study providing a possible explanation for the observed low rate of hematopoietic response. There is evidence that the response to iron treatment is associated with the severity of chronic inflammation. Especially patients with high CRP at baseline have shown lower hematopoietic response with oral iron therapy compared to patients with low CRP at baseline (29). On the other hand response to IV iron has been found to be independent of inflammation (29). We found better improvement of Hb levels in IBD patients who received IV iron compared to those under oral iron but the difference was not statistically significant probably due to the small number of patients treated with IV iron. These findings suggest that the current practice for the management of anemia in IBD is suboptimal and recently developed strategies for use of IV iron as first line treatment (6) should be considered.
Anemia has been found to recur in IBD patients at high rates even after systemic iron treatment (30,31). Therefore, after initial resolution of anemia and repletion of iron stores, maintenance iron treatment has been suggested. In the present study 20.6% of the initially non-anemic IBD patients presented with anemia after one year of anti-TNF treatment supporting the relapsing characteristic of anemia in IBD.
This study has several strengths but it also has some important limitations. First the study was conducted in a tertiary center and biases related to the referral population and selection of more severe IBD patients could be involved. Second the absence of comprehensive data regarding the iron status of IBD patients did not permit investigation of possible changes during the study period in the type of anemia. Finally an important limitation was the absence of information in the database regarding the exact week of the initiation of anti-TNF treatment (i.e. insurance authorization resulted in delays regarding initiation of subcutaneous anti-TNF treatment which began as an outpatient). This limitation prevented the use of baseline laboratory data from the start of therapy. For this reason we chose to compare the minimum and median measurements of two consecutive years of treatment (year 0 and year 1). The use of median values of CRP and ESR for year 0 may be not representative of the values at the time of the anti-TNF initiation and could be an explanation for the lack of differences between year 0 and year 1 in the entire cohort.
In conclusion, we show that anemia persists and remains a significant manifestation of IBD even after one year of anti-TNF treatment. Our findings support an emerging literature suggesting that anemia in IBD patients is an important extraintestinal manifestation, which should be more aggressively diagnosed, investigated, and treated. This therapeutic strategy targeting the correction of anemia in IBD could help to improve patients quality of life. Effective management of anemia in IBD includes the use of more aggressive treatment for the underlying disease with combination treatment of biologics and immunosuppresants as well as the preferential use of parenteral iron in order to normalize hemoglobin levels.
Acknowledgments
Sources of support: Ioannis Koutroubakis was supported by a sabbatical salary of Medical Faculty University of Crete Greece. Benjamin Click was supported by NIDDK Grant 5T32DK063922-10 (PI: David C. Whitcomb MD PhD) Michael Dunn and David G. Binion were supported by a Grant W81XWH-11-2-0133 from the US Army Medical Research and Materiel Command.
Disclosure of funding received for this work: None
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