An Elevated Body Mass Index is Associated with
Lower Serum Adalimumab Levels without
Matthew Rolfsen1*, Cameron Wilhoit1, Jen Seminerio-Diehl2 and Nilesh Lodhia3
1 Department of Internal Medicine, Medical University of South Carolina, USA
2Department of Gastroenterology, Medical University of South Carolina, USA
3 CHS Digestive Health, University of North Carolina, USA
Submission: October 17, 2018;Published: November 02, 2018
*Corresponding author: Nilesh Lodhia, Associate Professor, CHS Digestive Health, University of North Carolina, 1025 Morehead Medical Drive, Suite 300, Charlotte, NC 28204, USA.
How to cite this article: Matthew R, Cameron W, Nilesh L, Jen S-D. An Elevated Body Mass Index is Associated with Lower Serum Adalimumab Levels
without Clinical Significance. Adv Res Gastroentero Hepatol. 2018; 11(4): 555818. DOI: 10.19080/ARGH.2018.11.555818.
Background: Biologics, specifically anti-TNF agents, have been an integral part of our treatment paradigm for IBD for several years. However, therapeutic drug monitoring (TDM) enhances our ability to optimize dosing regimens. Studies have shown that trough levels<4.9ug/mL are associated with loss of response to adalimumab (ADA). An increased body weight may change the pharmacokinetics of adalimumab in IBD. The primary aim of this study was to evaluate the impact of body mass index (BMI) on adalimumab drug levels in IBD patients, as well as its potential clinical implications.
Methods:A database was compiled via retrospective chart review of 507 IBD patients seen at our Digestive Disease Center (DDC) between July 2013 and March 2016. Variables in the database include patient’s weight, medications, serum adalimumab levels, dates of medication administration, endoscopic findings, fecal calprotectin, erythrocyte sedimentation rate, and C-reactive protein.
Results: Using ANOVA to compare the two groups, there was a significant association with lower ADA levels in patient with BMI >30kg/m2 when compared to those with BMI <30kg/m2 (p = 0.009). Average adalimumab levels in these two groups were 11.8ug/mL and 8.8ug/mL, respectively. Within these groups, there was no statistically significant difference in severity of endoscopic findings. Furthermore, there was no statistically significant difference in serum inflammatory markers between groups.
Conclusion: In a cohort of patients with inflammatory bowel disease, despite a downward trend in serum adalimumab levels as weight increased, there did not seem to be any apparent clinical significance to these findings. They neither correlated to severity of endoscopic findings, or to elevations in serum inflammatory markers. 57% of the total sample size was either overweight or obese, which we feel accurately reflects the phenotypic breakdown of the overall IBD population, as well as that of the general population. More studies are needed to follow the long-term progression of these lower adalimumab levels to determine if this leads to increased antidrug antibody formation and/or loss of response over time.
Inflammatory Bowel Disease (IBD), comprised of Crohn’s disease and ulcerative colitis, are chronic inflammatory conditions that affect the GI tract. The prevalence of IBD is increasing throughout the world, becoming a substantial global public health concern . Obesity, also considered to be a chronic inflammatory condition contributing to millions of deaths annually, has also seen an increase in prevalence over the past few decades. In 2008, the World Health Organization estimated 35% of adults worldwide to be overweight. This represented a 60% increase from prevalence in 1980 . North and South America have a
particularly high prevalence of overweight and obese population, with 36.5% of their respective populations falling under one of these two categories for the year 2018. Furthermore, this increased prevalence is also seen in youth .
Biologics have been an integral part of our treatment paradigm for IBD for several years, and advances in therapeutic drug monitoring (TDM) enhance our ability to optimize treatment . TDM allows for serum trough levels and antidrug antibody concentrations of biologic agents to be measured. Serum concentration can be correlated clinically by physicians, and used to adjust dosing, or switch to different treatment modalities, but
an absolute cutoff for recommended trough levels has not been
set by guidelines . A median adalimumab trough level of 4.8ug/
mL to correlate with loss of response has been suggested in the
past  and additionally, the formation of antibodies against
adalimumab has been shown to correlate with a loss of response,
with low adalimumab trough levels as a possible predisposing
factor to antidrug antibody formation .
Tumor necrosis factor-alpha (TNF-alpha) agents block
interaction with the p55 and p75 cell surface TNF receptors .
Traditionally, after an initial loading dose, the dose of adalimumab
is 40mg every 14 days, regardless of body mass index (BMI).
However, elevated BMI has been shown to be associated with a
shorter time to dose escalation . Although adalimumab is not
lipophilic , increased (BMI) may result in increased volumes of
distribution, which may correlate with a trend towards lower serum
values of adalimumab . The significance of lower adalimumab
trough levels within the obese population is unknown, but
decreased drug efficacy as well as a higher propensity to develop
antidrug antibodies were concerns we sought to explore within
our IBD population. The primary aim of this study is to assess
the correlation between BMI and adalimumab drug levels in IBD
patients, and to determine any potential clinical implications in
this patient population.
An IRB approved database consisting of all inflammatory
bowel disease patients at the Medical University of South Carolina
(MUSC) was created through the EPIC system and updated in
real time. Within this database, 507 patients were identified
retrospectively with a history of adalimumab use. All patients
had been seen at our Digestive Disease Center (DDC) between
July 2013 and March 2016 and had an ICD-9 diagnosis of either
Crohn’s disease or ulcerative colitis. Of these patients, 296 were
female and 211 were male. 395 had a diagnosis of CD and 112 had
a diagnosis of UC.
Variables in the database include patient’s weight, height,
medication dosing, serum adalimumab levels, dates of medication
administration, and endoscopic findings. Patients were then
broken down by three separate BMI subcategories: BMI <25
(underweight or normal weight), BMI 25-30 (overweight),
and BMI >30 (obese) . Additionally, a separate comparison
between non-obese (BMI< 30) and obese (BMI>30) was made. All
Class A tables compare the BMI classes with the BMI <25, BMI 25-
30, and BMI >30 groups; Class B tables compare the BMI <30 and
>30 groups (Tables 1a&b).
Given this was a retrospective analysis on an IRB approved
database, there was no additional information or data required
from individual patients. All data was obtained through the EPIC
electronic health records system used at MUSC. Within the EPIC
system, data included baseline characteristics such as gender, age,
diagnosis (i.e. Crohn’s disease or ulcerative colitis), weight, and
BMI. Results were based both on lab findings, as well as endoscopic
findings reported on each segment of the bowel visualized during
a prior colonoscopy. In the instance of a report lacking sufficient
detail, images in the electronic medical record were reviewed and
reassessed to determine severity of disease.
Once a correlation between BMI and serum trough levels
was established, patient charts were reopened to assess whether
lower trough levels correlated to a worse clinical outcome with
regards to disease severity. Given the subjective nature of using
patient scoring systems for symptoms, such as the Crohn’s Disease
Activity Index (CDAI), investigators aimed to use an objective
measurement of disease severity. Thus, a classification system
was developed distinguishing normal, mild, moderate, or severe
disease for both Crohn’s disease and ulcerative colitis. These
criteria were created using the Simplified Endoscopy Score for
Crohn’s disease (SES-CD) , and the Mayo Clinic classification
system for ulcerative colitis .
For patients with ulcerative colitis
For patients with ulcerative colitis, the Mayo scoring system
was used, with a score of 0-3; 0 for no disease, 1 for mild disease,
2 for moderate disease, or 3 for severe disease.
For patients with Crohn’s disease, the simple endoscopy score
for Crohn’s disease (SES-CD) was used, with the score based on
4 variables (size of ulcers, percent of surface ulcerated, percent
of colon segment affected and presence of narrowing), while
evaluating 5 bowel segments (rectum, sigmoid colon, descending
colon, transverse colon, ascending colon and ileum) . Each
variable of each segment of the colon was graded from 0-3, making
the scoring system 0-56 .
In terms of lab values, we used the most recent entries in
patients with adalimumab use in their history, and included fecal
calprotectin, erythrocyte sedimentation rate (ESR), and C-reactive
protein (CRP). Adalimumab trough levels were collected through
EPIC and compared to the above variables. The trough levels were
collected, and run through different sources, including Prometheus
and LabCorp, two private diagnostic laboratory companies.
Statistical analyses were run using the R open source
programming language , including a multivariate analysis
using Pearson’s chi-squared test, summary statistics, counts,
and means/averages. Data from the IBD database was analyzed
by a private statistician. ANOVA was first used to compare the
two groups of BMI <30 and BMI >30, and then subsequently, a
multivariate analysis was done breaking down BMI into <25kg/
m2, 25-30kg/m2, and >30 kg/m2 Means and medians were used to describe quantitative variables, while proportions were reported
in percentages. A p-value of 0.05 was used to determine statistical
A total of 507 patients were included in the study and
consisted of individuals with a diagnosis of either ulcerative colitis
or Crohn’s disease, combined with a history of adalimumab use.
296 were female and 211 were male, and the average age was
40.8. 395 had a diagnosis of CD, while 112 had a diagnosis of UC.
The BMI counts are outlined in Table 1. There were 11
patients who did not have a documented BMI and therefore were
not included. Based on results, 281 patients in the study (56.6%)
were overweight or obese.
42 out of 135 patients (31.1%) with BMI > 30 kg/m2 had
serum adalimumab levels drawn, while 44 out of 136 patients
(30.1%) with BMI 25-30 30kg/m2 had adalimumab levels drawn;
54 out of 215 patients (25.1%) with BMI <25 had adalimumab
levels drawn. 385 of 507 patients (75.9%) were currently on
adalimumab at the conclusion of the study.
Two separate analyses were done within different BMI
distributions, and compared with disease severity endoscopically.
Tables 2a&b illustrates the number of patients in each BMI
subgroup who were found to have one of the four designated
endoscopic classifications, and although Tables 2a&b show a trend
towards statistical significance for an association with a lower
BMI with more severe disease, neither demonstrate statistical
Tables 3a&b controls endoscopic disease severity by BMI for
gender and does not show any statistically significant difference in
endoscopic disease severity between males and females.
Tables 4a&b compared differences in the severity of endoscopic
findings across BMI ranges in both Crohn’s disease and Ulcerative
colitis. Table 4a illustrates that the severity of endoscopic findings
may be inversely related to BMI in Crohn’s disease (p=0.027), but
not in ulcerative colitis (p=0.45). Table 4b shows a possible trend
towards statistical significance in Crohn’s disease (p=0.059), but
not in ulcerative colitis (p=0.53).
Fecal calprotectin, C-reactive protein (CRP), and erythrocyte
sedimentation rate (ESR) were compared with BMI populations
in order to investigate possible correlation between lower serum
adalimumab level and abnormal lab values. Fecal calprotectin
was checked in 137 of the 507 patients (27%) included in the
study. Analyses compared Crohn’s disease to ulcerative colitis
populations, as well as males to females.
Tables 5a&b reveals the total number of patients, as well as
the number with Crohn’s disease and ulcerative colitis in Groups
A and B. Tables 6a&b outlines the level of fecal calprotectin, again
outlined based on disease state, and subsequently separated into
BMI Groups A and B.
After this analysis was conducted, a second analysis looking
only at patients who were actively on adalimumab was performed,
and within this calculation, only 93 of the original 137 patients
(68%) with fecal calprotectin levels remained. Tables 7a&b
outlines the number of patients with fecal calprotectin and
currently on adalimumab, stratified by disease specificity. Tables
8a&b outlines the level of fecal calprotectin within this same group
of patients and shows that fecal calprotectin levels were notably
higher (70.0% increase in combined groups) in patients with both
Crohn’s disease and ulcerative colitis with BMI <25.
CRP was performed in 430 of the 507 patients (85%) in the
study. Tables 9a&b outlines the total number of patients in each
BMI subgroup classifications compared with total patients and
specific disease. Tables 10a&b shows the same comparison groups
but averages the CRP value per group. Again, CRP levels were
notably higher (62.5% increase in combined groups) in patients
with both Crohn’s disease and ulcerative colitis who also had a
ESR was performed in 431 of the 507 patients (85%) in the
study. Tables 11a&b outlines the total number of patients in
each BMI subgroup classifications compared with total patients
and specific disease. Tables 12a&b shows the same comparison
groups but averages the ESR value per group. Interestingly, unlike
CRP and fecal calprotectin levels which showed large differences
between groups, average ESR levels were very similar with <1%
140 patients of the total 507 (28%) had adalimumab levels
drawn while on receiving the drug. With this information we
were able to calculate the levels within the Crohn’s disease and
ulcerative colitis groups, as well as breaking it down into male and
female, which is shown in Table 13. Table 14 shows adalimumab
levels broken down by BMI subgroup, and illustrates a lower
adalimumab level as BMI increases.
Of the 140 patients who had adalimumab levels and antidrug
antibodies drawn, 39 were found to have developed antidrug
antibodies. Within the Crohn’s disease group, 33 of 117(28%)
were found to have antidrug antibodies, while 6 of 33(18%) of
ulcerative colitis patients were found to have antidrug antibodies.
Table 15 looks at antidrug antibody formation based on BMI
subclass, with a p value of 0.2398 when comparing the different
Previous studies have examined the effect of adalimumab
therapy on disease state with regards to weight, 7,8 however
our goal was to examine the IBD specific population, and directly
compare clinical markers, endoscopic findings, and the role of
therapeutic drug monitoring in different weight classes.
This study illustrates that approximately 27% of our 496
patients fall into the obese category, but if you expand the elevated
BMI group to include the overweight category with the obese
category, the group then includes over half of our patients (57%).
It was previously published that the trend in weight amongst
IBD patients follows that of the general population and therefore
generally speaking, this will have implications on the medical
comorbidities of IBD patients due to the obesity epidemic . It
should be noted as well that the median age in the study is 38,
and population studies show that should weight increase, we
will continue to have a population of rising weight and older age.
Thus, with obesity rates increasing throughout the world, it is
especially important to establish any differences in drug clearance
in patients with varying BMI’s.
Interestingly, our study did not show any significant changes
in endoscopic findings across different BMI categories. We
recognize that retrospective evaluation of endoscopic findings is
difficult but given the fact that the procedures were performed by
one of two total IBD providers at MUSC, we hope this minimizes
potential bias. The Mayo Clinic score is a well validated tool to
assess endoscopic activity in ulcerative colitis, and there was no
significant difference between mild, moderate, severe, and normal
endoscopic findings when divided into the three separately
examined weight classes.
We also looked at BMI compared with CRP, ESR and fecal
calprotectin, but found that no clinically significant data was seen,
which is of particular interest given that obesity is thought to be a
state of systemic inflammation [18,19]. Fecal calprotectin is a gut
specific inflammatory marker, and therefore should eliminate the
role of obesity. It is postulated that this again confirms that weight
had no bearing on disease status in this study.
When evaluating adalimumab levels, we can clearly follow a
downtrend in the level of drug based on increasing BMI in both
ulcerative colitis and Crohn’s disease. Previous data within the
adalimumab population showed that weight did not play a role in
efficacy, and therefore weight based dosing is not recommended.
8 Despite the lack of endoscopic and laboratory evidence of
clinical significance, we still feel that long-term, this difference
could account for loss of response, as well as antidrug antibody
formation, and that longer-term data may be necessary to shed
light on the significance of these drug levels. There is a fair
possibility that over an increased time period, lower levels may
lead to worsened clinical outcomes and an increased propensity
for antibody formation.
This study has multiple strengths. It was conducted at
an academic center with a well-established department of
gastroenterology and specialists in IBD, the sample size was
larger than previous studies, 8 and furthermore, endoscopic
exams were available to be reviewed, which made grading disease
severity possible. Data was collected in real time and updated
This study does have some limitations that need to be noted.
It was undertaken in a single center in a retrospective fashion, and
not all patients seen at this center who were on adalimumab had
serum trough levels drawn. The scoring system endoscopically
for Crohn’s disease is also limited to a retrospective analysis and
categorization into mild, moderate, and severe for study purposes.
Finally, this study aimed to determine if there was a relationship
between elevated BMI and serum adalimumab levels/endoscopic
findings but did not look directly at the relationship between
various serum adalimumab levels and endoscopic findings.
Multivariate analysis using lower cutoffs of adalimumab levels in
relation to SES-CD may have yielded more statistically significant
results. The analysis was also done on multiple groups in contrast
to a direct comparison of one group to another, although this
could be done if necessary. Finally, not every patient within the
study had the lab data collected, and certain BMI categories were
underrepresented and underpowered.
In conclusion, in patients with IBD on adalimumab, a higher
BMI is associated with a lower serum adalimumab level. The
lower level of adalimumab seen in this study did not reflect any
significant change in endoscopic or laboratory findings, however,
longer follow up may be necessary to establish clinical correlation.