Clinical Gastroenterology and Hepatology 2019;17:1533–1540

Retrospective Analysis of Safety of Vedolizumab in Patients

With Inflammatory Bowel Diseases
Joseph Meserve,* Satimai Aniwan,‡,§ Jenna L. Koliani-Pace,k Preeti Shashi,¶
Aaron Weiss,# David Faleck,* Adam Winters,** Shreva Chablaney,** Gursimran Kochhar,¶
Brigid S. Boland,* Siddharth Singh,* Robert Hirten,** Eugenia Shmidt,**,‡‡ Justin G. Hartke,§§
Prianka Chilukuri,§§ Matthew Bohm,§§ Sashidhar Varma Sagi,§§ Monika Fischer,§§
Dana Lukin,# David Hudesman,kk Shannon Chang,kk Youran Gao,¶¶ Keith Sultan,¶¶
Arun Swaminath,## Nitin Gupta,*** Sunanda Kane,‡ Edward V. Loftus Jr,‡ Bo Shen,§
Bruce E. Sands,** Jean-Frederic Colombel,** Corey A. Siegel,k William J. Sandborn,* and
Parambir S. Dulai*

*Department of Gastroenterology, University of California, San Diego, La Jolla, California; ‡Department of Gastroenterology,
Mayo Clinic, Rochester, Minnesota; §Department of Gastroenterology, Thai Red Cross Society, King Chulalongkorn Memorial
Hospital, Chulalongkorn University, Bangkok, Thailand; kDepartment of Gastroenterology, Dartmouth-Hitchcock Medical
Center, Lebanon, New Hampshire; ¶Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, Ohio;
#
Department of Gastroenterology, Montefiore Medical Center, New York, New York; **Department of Gastroenterology, Icahn
School of Medicine at Mount Sinai, New York, New York; ‡‡Department of Gastroenterology, University of Minnesota,
Minneapolis, Minnesota; §§Department of Gastroenterology, Indiana University, Indianapolis, Indiana; kkDepartment of
Gastroenterology, New York University, New York, New York; ¶¶Department of Gastroenterology, North Shore University
Hospital, Manhasset, New York; ##Department of Gastroenterology, Lenox Hill Hospital, New York, New York; ***Department of
Gastroenterology, University of Mississippi, Jackson, Mississippi

BACKGROUND & AIMS: There are few real-world data on the safety of vedolizumab for treatment of Crohn’s disease
(CD) or ulcerative colitis (UC). We quantified rates and identified factors significantly associ-
ated with infectious and non-infectious adverse events in clinical practice.

METHODS: We performed a retrospective review of data from a multicenter consortium database (from
May 2014 through June 2017). Infectious and non-infectious adverse events were defined as
those requiring antibiotics, hospitalization, vedolizumab discontinuation, or resulting in death.
Rates were quantified as proportions and events per 100 patient years of exposure (PYE) or
follow up (PYF). We performed multivariable logistic regression analyses to identify factors
significantly associated with events and reported as odds ratios (OR) with 95% CIs.

RESULTS: Our analysis comprised 1087 patients (650 with CD and 437 with UC; 55% female; median age,
37 years) with 861 PYE and 955 PYF. Infections were observed in 68 patients (6.3%; 7.9 per 100
PYE, 7.1 per 100 PYF); gastrointestinal infections (n [ 31, 2.4 per 100 PYE, 2.2 per 100 PYF)
and respiratory infections (n [ 14, 1.6 per 100 PYE, 1.5 per 100 PYF) were the most common.
Arthralgias were the most common non-infectious adverse events (n [ 31, 2.9%; 3.6 per 100
PYE). Two patients developed malignancies (squamous cell skin cancer and colorectal cancer;
0.23 per 100 PYE, 0.21 per 100 PYF). Active smoker status (OR, 3.39) and number of
concomitant immunosuppressive agents (corticosteroids or immunomodulators; OR, 1.72 per
agent) used were independently associated with infections.

CONCLUSION: In a retrospective cohort study of patients with IBD, we found vedolizumab to be well tolerated
with an overall favorable safety profile. Active smoking and concomitant use of immunosup-
pressive agents were independently associated with infections

Keywords: a4b7 Integrin; IBD; Drug; AE.

Abbreviations used in this paper: CD, Crohn’s disease; CI, confidence
interval; IBD, inflammatory bowel disease; IQR, interquartile range; OR,
odds ratio; PYE, patient-years of exposure; PYF, patient-years of follow-
up; TNF, tumor necrosis factor; UC, ulcerative colitis; VDZ, vedolizumab.
Most current article
© 2019 by the AGA Institute. Published by Elsevier, Inc. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
1542-3565
https://doi.org/10.1016/j.cgh.2018.09.035
1534 Meserve et al
rohn’s disease (CD) and ulcerative colitis (UC) are
C inflammatory bowel diseases (IBDs) character-
ized by chronic inflammation of the gastrointestinal
tract. Tumor necrosis factor (TNF) antagonists have
become a mainstay of treatment in patients with
moderately to severely active disease, alone or in
combination with corticosteroids and immunomodula-
tors. While efficacious, these agents are associated with
an increased risk for infectious and noninfectious
adverse events.1,2 Newer classes of medications, which
are more selective, may offer an opportunity to avoid
toxicities seen with traditional systemically active
therapeutic agents.
Vedolizumab (VDZ) is a monoclonal anti-integrin
antibody that inhibits lymphocyte migration by antag-
onizing the a4b7 integrin receptor. The Phase 3, Ran-
domized, Placebo-Controlled, Blinded, Multicenter
Study of the Induction and Maintenance of Clinical
Response and Remission by Vedolizumab (MLN0002)
in Patients with Moderate to Severe Ulcerative Colitis
and Crohn's Disease (GEMINI) randomized controlled
trials have demonstrated significant efficacy for this
agent in both CD and UC, and a recent integrated safety
analysis of 2830 patients with 4811 patient years of
exposure observed no increased risk for serious infec-
tion with VDZ as compared with placebo.3 Real-world
cohort analyses have similarly observed a favorable
safety profile, however, the majority of these data are
from small single-center experiences. A robust real-
world assessment of VDZ safety has yet to be per-
formed. Given the significant differences in patient
populations between clinical trials and clinical practice,
this assessment will help ensure that the favorable
safety profile observed with VDZ in the carefully
selected patient population in clinical trials can be
extrapolated to the more refractory or complicated
patient populations treated in clinical practice, and to
identify potentially modifiable risk factors for adverse
events. Using a large multicenter consortium, we aimed
to quantify rates of serious infection and serious
adverse events, and to identify subgroups at greatest
risk for treatment related adverse events.
Methods
Study Design
This is a retrospective review of a multicenter con-
sortium dataset.4 In brief, this is a collaborative research
group where outcomes are pooled for IBD patients
treated with biologics. Institutional Review Board
approval was obtained from each site for ongoing data
collection and transfer. Data on variables of interest were
collected individually by sites using a standardized data
collection form and transferred (after de-identification)
to the coordinating site (University of California, San
Diego) for data compilation and analysis. The current
Clinical Gastroenterology and Hepatology Vol. 17, No. 8
What You Need to Know
Background
Vedolizumab is an anti-integrin antibody that inhibits
lymphocyte migration to the gut. It has been
observed to have a favorable safety profile in clinical
trials; however, a robust analysis of its safety in
routine practice is lacking. Furthermore, it is unclear
which patients are at greater risk for the develop-
ment of treatment related adverse events.
Findings
In this large retrospective multicenter cohort study
of over 1000 vedolizumab treated IBD patients, we
observed that the rates of serious infections and
serious adverse events were low, despite the re-
fractory nature of the cohort studied. We further
observed that the single greatest driver for the
development of treatment related adverse events
was the use of concomitant immunosuppressive
therapy with an incremental increase in risk associ-
ated with the number of concomitant agents used.
Implications for patient care
Vedolizumab is well tolerated in clinical practice with
an overall favorable safety profile. Thoughtful
consideration should be given to the concomitant use
of immunosuppressive agents with vedolizumab,
particularly dual immunosuppression with steroids
and immunomodulators.
analysis represents data collected between May 2014
and June 2017. The results of this study are reported in
accordance with the STROBE (Strengthening the
Reporting of Observational Studies in Epidemiology)
guidelines for cohort studies (Supplementary Material).5
Participants
Patients were included in the current analysis if they
had: (1) a confirmed diagnosis of UC or CD based on
clinical and endoscopic or histologic data, (2) active
disease (defined as clinical, endoscopic, radiographic
disease, or steroid-dependence) attributed to UC or CD
before VDZ therapy, and (3) at least 1 follow-up after
VDZ initiation (Supplementary Figure 1).
Outcomes
Our primary outcome of interest was the rates of in-
fections defined as those requiring antibiotics, or resulting
in discontinuation of VDZ, hospitalization, or death. Our
secondary outcome of interest was the rates of serious
adverse events defined as having an infectious or nonin-
fectious adverse event requiring discontinuation of VDZ,
hospitalization, or death. All adverse events were reveri-
fied by local site investigators, and a central data coding
July 2019 Safety of Vedolizumab for IBD 1535

quality control was performed where sites were asked to all remaining variables had a P value of <.05. Significant
provide de-identified medical record data to support and associations are reported with odds ratio (OR) and
confirm adverse event severity grading and outcomes. associated 95% confidence interval (CI).

Statistical Analysis Results

Statistical analyses were performed using SPSS
Version 25 (IBM, Armonk, New York, NY). Continuous
variables were presented as mean  SD or median
(interquartile range [IQR]) if the distribution was skewed,
and categorical or binary variables were presented as
proportions or percentages. For the comparison of base-
line continuous variables we used the independent sample
t test (2 group comparisons) or 1-way analysis of variance
with Bonferroni correction (3 or more group compari-
sons), and for the comparison of baseline binary variables
we used Pearson chi-square or Fisher’s exact test.
Infections and serious adverse events were described
quantitatively as the proportion of patients developing
these adverse events, and incidence rates were derived
as number of events occurring over patient-years of
exposure (PYE) and patient-years of follow-up (PYF).
PYF were defined as all follow-up period after receiving
VDZ until the last follow-up, or until the patient transi-
tioned to an alternative therapy in the case of patients
who were not responding and discontinued therapy.
Rates of infections and serious adverse events be-
tween various subgroups were compared using logistic
regression. Multivariable logistic regression analyses
were performed to identify potentially significant asso-
ciations where all variables associated with a P value of
<.20 were included in the model and then a backward
model selection technique was used where the variable
with the highest P value was sequentially removed until
Of the 1112 patients identified between May 2014
and June 2017, 1087 patients (650 CD, 437 UC; 45%
men) with a median age of 37 (IQR, 27–53) years were
included in the current analysis (Table 1). The remaining
25 were excluded because VDZ was started for mainte-
nance of remission in patients who had achieved
remission with a TNF antagonist but subsequently
developed an adverse reaction (n ¼ 11) or postsurgical
maintenance of remission (n ¼ 14). None of these
patients developed adverse events while on VDZ.
Patients included in the current analysis had a
median duration of VDZ exposure of 264 days (IQR,
146–413 days; 861 PYE) and a median duration of
follow-up of 302 days (IQR, 171–434 days; 955 PYF).
Prior TNF antagonist exposure was observed in 884
patients (81% of the cohort), with 534 (49%) patients
exposed to 2 or more TNF antagonists before VDZ.
Concomitant corticosteroids at the time of VDZ initiation
were used in 536 (49%) patients, with 279 (26%) being
on high-dose (>20 mg daily) corticosteroids. Concomi-
tant immunomodulators were used in 417 (38%) pa-
tients, and a total of 214 (20%) patients were on both
concomitant corticosteroids and an immunomodulator.
Table 2. Incidence of Infections on Vedolizumab
Per 100 PYE (861 Per 100 PYF (955
cumulative PYE) cumulative PYF)

Infection (n ¼ 68) 7.90 7.12

Table 1. Baseline Demographics of Cohort Gastrointestinal infections 3.60 3.25
(n ¼ 31)
Variable Patients (N ¼ 1,087) Clostridium difficile 2.44 2.20
(n ¼ 21)
Crohn’s disease 650 (60) Gastroenteritis (n ¼ 6) 0.70 0.63
Age, y 37 (27–53) CMV colitis (n ¼ 4) 0.47 0.42
Disease duration, y 9 (4–16) Respiratory tract 1.63 1.47
Female 597 (55) infections (n ¼ 14)
Current smoker 79 (7) Pneumonia (n ¼ 7) 0.81 0.73
BMI, kg/m2 24 (21–29) Sinusitis (n ¼ 5) 0.58 0.52
Albumin 4 (3.6–4.3) URI (n ¼ 2) 0.23 0.21
CRP 3.2 (0.9–11) Abscess (n ¼ 10) 1.16 1.04
Hospitalized within preceding year 345 (32) Bacterial sepsis (n ¼ 2) 0.23 0.21
Stricturing/penetrating complication history 439/650 (40) Skin infection (n ¼ 3) 0.35 0.31
Fistulizing disease history 237/650 (22) Zoster (n ¼ 2) 0.23 0.21
Severe clinical disease 363 (33) UTI (n ¼ 2) 0.23 0.21
Severe endoscopy 302 (28) Transverse myelitis (n ¼ 1) 0.12 0.11
Prior TNF antagonist exposure 884 (81) Meningitis (n ¼ 1) 0.12 0.11
Concomitant corticosteroids 536 (49) Colonic perforation 0.12 0.11
Concomitant IM 417 (38) (n ¼ 1)a
Concomitant corticosteroids and IM 214 (20) Cholangitis (n ¼ 1) 0.12 0.11

Values are n (%), median (interquartile range), or n/n (%). CMV, cytomegalovirus; PYE, patient-years of exposure; PYF, patient years of
BMI, body mass index; CRP, C-reactive protein; IM, immunomodulator; TNF, follow-up; URI, upper respiratory tract infection; UTI, urinary tract infection.
a
tumor necrosis factor. Microperforation after colonoscopy, treated with antibiotics.
1536 Meserve et al Clinical Gastroenterology and Hepatology Vol. 17, No. 8

Infections Table 3. Factors Significantly Associated With the

Development of Infections and Serious Adverse
Events
There were a total of 68 (6.3%) serious infections,
with 29 of these being treated with outpatient antibiotics Univariable Multivariable
without needing to discontinue VDZ, and the remaining
39 required VDZ discontinuation, hospitalization, or the OR 95% CI OR 95% CI
serious infection resulted in death. One patient died due
Infections
to a postoperative infectious complication that has UC 0.65 0.38–1.10
previously been reported on in detail.4 The incidences of Age at biologic initiation 0.99 0.97–1.00
all reported serious infections are quantified in Table 2. Current smoker 3.02 1.55–5.91 3.30 1.67–6.50
The most common serious infection was gastrointestinal, Severe disease 1.53 0.93–2.51
Severe endoscopic activity 1.52 0.86–2.70
with Clostridium difficile infection being the most
Number of IS agents 1.61 1.14–2.28 1.69 1.18–2.41
commonly observed (n ¼ 21). Patients developing Serious adverse events
C. difficile infection while on VDZ tested negative before UC 0.73 0.44–1.20
VDZ initiation. Hospitalization was required in 7 of these Current smoker 2.67 1.37–5.19 2.89 1.47–5.66
21 patients, and fecal microbial transplantation required Severe endoscopic activity 1.47 0.84–2.57
Number of IS agents 1.59 1.14–2.21 1.64 1.17–2.31
in 2. Cytomegalovirus colitis was reported in 4 patients,
with 1 requiring colectomy. Other infectious gastroen-
teritis reported included Salmonella (n ¼ 1), Campylo- CI, confidence interval; OR, odds ratio; IS, immunosuppressant; UC, ulcerative
bacter (n ¼ 1), adenovirus (n ¼ 1), and Entamoeba colitis.

histolytica (n ¼ 1). Hospitalization was required in 5 of

the 7 patients who developed pneumonia. One patient
developed sinusitis after escalating to Q4 week VDZ. The
single patient developing transverse myelitis was treated
with antibiotics and had resolution of symptoms with
continuation of VDZ and no recurrence. The patient who
developed meningitis has previously been described.6
Noninfectious Adverse Events
A total of 40 (3.7%) patients developed infusion
reactions over 8595 infusions (4.65 per 1000 infusions).
None of these patients required discontinuation of
therapy due to these infusion reactions. A total of 7
noninfectious adverse events required discontinuation of
VDZ therapy. The most common noninfectious adverse
event reported was arthralgias that developed after an
infusion (n ¼ 31/1087, 2.9%; 3.60 per 100 PYE). Almost
all of these patients developed the arthralgias during
VDZ induction therapy with resolution over time, how-
ever, 4 (0.36%) patients required discontinuation of
therapy due to arthralgias (0.47 per 100 PYE) and 1
patient developed arthralgias after escalation to Q4 week
VDZ maintenance. Other noninfectious adverse events
reported included: tinnitus (n ¼ 1), squamous cell cancer
of the hand (n ¼ 1), skin rash (n ¼ 7), severe headaches
(n ¼ 1), rising Epstein-Barr viral load (n ¼ 1), psoriasis
(n ¼ 1), hepatic biochemical abnormalities in trans-
aminases (n ¼ 2), hair loss (n ¼ 1), colon cancer (n ¼ 1),
neurological dysfunction (n ¼ 2) (see the following), and
a seizure (n ¼ 1).
The first patient with neurological dysfunction had
ataxia, altered gait, and difficulty concentrating after VDZ
infusions. A work-up was unremarkable for a stroke or
progressive multifocal leukoencephalopathy and
neurology consultation determined the symptoms were
not related to VDZ. The second patient with neurological
dysfunction developed optic neuritis and has been pre-
viously reported on,4 and the optic neuritis was deter-
mined by the neurological consultative service to be
unrelated to VDZ and the VDZ was restarted without any
further neurological symptoms.
The incidence of de novo malignancy in our cohort
was 0.23 per 100 PYE and 0.21 per 100 PYF. The single
patient who developed squamous cell cancer of the hand
was a 59-year-old female UC patient with pancolitis for
nearly 30 years, with prior exposure to TNF antagonist
therapy and concurrent exposure to azathioprine which
she had been on for more than 2 years. The single patient
who developed colon cancer was a 39-year-old female
UC patient with pancolitis for more than 9 years, who
had prior exposure to azathioprine and TNF antagonist
therapy. There were no reported lymphomas.
Variables Associated With Development of
Adverse Events
On multivariable logistic regression analyses active
smoker status (OR, 3.39; 95% CI, 1.71–6.70) and number
of concomitant immunosuppressive agents used (OR,
1.72 per agent; 95% CI, 1.20–2.46) were independently
associated with developing an infection (Table 3). In-
fections occurred in 15% of active smokers versus 5% of
never smokers and 6% of ex-smokers. The majority
(75%) of infections developing in active smokers were
respiratory in origin or related to worsening CD (ie,
abscesses). The only noninfectious adverse events
observed in active smokers were arthralgias (3.8% of
active smokers vs 4.5% of ex-smokers and 2.2% of never
smokers).
Rates of infections and serious adverse events strat-
ified by number of concomitant immunosuppressive
agents are quantified in Table 4. Rates of adverse events
July 2019 Safety of Vedolizumab for IBD 1537

Table 4. SAE Stratified by Concomitant Immunosuppressive Agents

SAE Incidence Infection Incidence

VDZ monotherapy (n ¼ 348; 272 PYE; 287 PYF) 4.6 (16) 5.9/100 PYE 4.0 (14) 5.2/100 PYE
5.6/100 PYF 4.9/100 PYF
VDZ þ IMMa (n ¼ 203; 174 PYE; 191 PYF) 4.9 (10) 5.8/100 PYE 4.9 (10) 5.8/100 PYE
5.2/100 PYF 5.2/100 PYF
VDZ þ corticosteroids (n ¼ 322; 243 PYE; 274 PYF) 8.1 (26) 10.7/100 PYE 7.1 (23) 9.5/100 PYE
9.5/100 PYF 8.4/100 PYF
VDZ þ IMMa þ corticosteroids (n ¼ 214; 173 PYE; 192 PYF) 10.7 (23) 13.3/100 PYE 9.8 (21) 12/100 PYE
12.0/100 PYF 11/100 PYF

Values are % (n), unless otherwise indicated.

IMM, immunomodulator; PYE, patient-years of exposure; PYF, patient-years of follow-up; SAE, serious adverse event; VDZ, vedolizumab.
a
Azathioprine, 6-mercaptopurine, methotrexate.

were comparable between VDZ monotherapy and VDZ in
combination with an immunomodulator, but the addition
of corticosteroids at VDZ initiation to either group
resulted in incremental increases in risk of infection and
serious adverse events (Figure 1). This trend was
consistent across multiple subgroup analyses (Figure 2,
Supplementary Material).
Discussion
We report on real world safety data for more than
1000 IBD patients treated with VDZ and make several
key observations. First, VDZ is well tolerated in a
heterogenous and refractory patient population
(including 81% with prior TNF antagonist therapy) with
a safety profile comparable to that seen in the GEMINI
clinical trials. Second, the most common infections
observed were gastrointestinal and respiratory in origin
and the most common noninfectious adverse event
observed was arthralgias. A minority of these patients
required hospitalization or discontinuation of therapy for
these adverse events. Third, the risk for infection and
serious adverse events was incremental based on the
number of concomitant immunosuppressive agents
being used, with the majority of this risk being driven by
concomitant corticosteroid use across all subpopulations.
Finally, we observed no cases of progressive multifocal
leukoencephalopathy or lymphoma, and the incidence of

Figure 1. Proportions of
patients on vedolizumab
therapy developing
serious adverse events or
infections when stratified
by concomitant immuno-
suppressive therapy.
1538 Meserve et al
malignancy was very low in our cohort, with both sets of
patients having been exposed to thiopurines.
The integrated safety analysis of the VDZ clinical trial
programs quantified the exposure-adjusted incidence
rate of serious infections to be 2.7 per 100 PYE.3 Inte-
grated safety analyses of pivotal infliximab trials have
quantified the incidence of serious infection to be 6.5 per
100 PYF,7 and for adalimumab and certolizumab in CD it
has been quantified to be 6.7 and 8.5 per 100 PYE,
respectively.8,9 In Productivity Safety and Efficacy: Long
Term Results in Adalimumab Treated Patients with CD
(PYRAMID) registry, an observational noninterventional,
multicenter and multinational registry for adalimumab in
CD, a total of 11.1% of patients experienced at least 1
serious infection, with an overall incidence rate of
serious infection of 4.7 per 100 PYE.10 In our cohort, we
observed an incidence rate of 7.9 per 100 PYE and 7.12
per 100 PYF for infection, but it is important to note that
in our definition we allowed for outpatient antibiotic use
to qualify as an infection. When limiting the more
traditional definition of serious infections, which in-
cludes patients who required hospitalization, discontin-
uation of VDZ, or where the infection resulted in death,
the incidence rate for serious infections with VDZ in our
cohort was 4.5 per 100 PYE and 4.1 per 100 PYF. This is
comparable to that reported in the integrated safety
analysis of VDZ clinical trials and that reported with
infliximab, adalimumab, and certolizumab. Similar to the
integrated VDZ clinical trial safety analyses, the most
common infections observed in our cohort were respi-
ratory or gastrointestinal in origin.
We observed that the addition of immunosuppressive
agents results in an incremental increase in risk for
Clinical Gastroenterology and Hepatology Vol. 17, No. 8
Figure 2. Proportions of
patients on vedolizumab
therapy developing in-
fections when stratified by
concomitant immunosup-
pressive (IS) therapy and
key treatment history.
TNF, tumor necrosis
factor.
infections and serious adverse events. Most notably, it
was the concomitant use of corticosteroids at VDZ
initiation rather than immunomodulators that resulted
in the greatest risk of adverse events. However, the
combination of these 2 agents (corticosteroids and im-
munomodulators) was synergistic in their impact on
adverse events, which is similar to what has been re-
ported with other biologic agents.1 This observation
was consistent when limiting the analysis to patients
who were not corticosteroid dependent or refractory at
the time of VDZ initiation, and the effect of corticoste-
roids on infection risk was actually more pronounced
among those who were immunomodulator and biologic
naïve. VDZ is felt to have a slow onset of action and
therefore providers often use corticosteroid coin-
duction as a strategy to bridge patients through until
maintenance therapy. Our observations highlight the
fact that a better understanding is needed for which
patients will have an early response to VDZ and may
therefore avoid corticosteroid coinduction, or if alter-
native coinduction regimens can be studied to avoid the
significant increase in risk for adverse events.
Smoking has been associated with an increased risk
for disease flares and disease related complications
(hospitalization and surgery) in CD, whereas in UC it is
associated with reductions in disease severity and
corticosteroid utilization.11,12 However, among UC
patients undergoing elective colectomy, smoking has
been associated with an increased risk for surgical site
infections.13 Smoking has also been associated with
the presence or development of extraintestinal manifes-
tations in IBD, with arthralgias being 1 of the most
common.14 In our cohort we observed active smokers to
July 2019
be at a 3-fold increased risk for infections with VDZ, and
the only noninfectious adverse event reported in active
smokers was arthralgia. Given respiratory tract in-
fections and arthralgias were 2 of the most common
adverse events observed, this highlights the importance
of counseling active smokers on smoking cessation when
starting VDZ to optimize the safety profile. Alternatively,
this may highlight the importance to consider VDZ target
expression in the lungs and the incremental risk of res-
piratory tract infections with any second risk factor
(ie, smoking).
Extraintestinal manifestations are an important
component of IBD impact, and arthralgias are among the
most commonly reported. A recent study by the Groupe
d’Etude Thérapeutique des Affections Inflammatoires
Digestives (GETAID) network observed that incident ar-
thralgias or joint pains were observed in 13.8% of pa-
tients treated with VDZ, with the majority of these being
peripheral arthralgias without evidence of arthritis.15 In
our VDZ cohort we observed de novo arthralgias in 2.9%
of patients, with the majority of these occurring during
induction therapy and lower rates being observed in
patients on concomitant immunomodulator therapy. The
discrepancy between our findings and those seen in the
GETAID network study may be due to differences in
assessments for arthralgias, but it is reassuring that in
our cohort of over 1000 patients, only 4 (0.36%) patients
required discontinuation of VDZ due to severe arthral-
gias. An interesting observation in our cohort was that 2
patients developed adverse events after dose escalating
VDZ to Q4 week maintenance, 1 of which was severe
arthralgia. This raises the possibility that these arthral-
gias are potentially previously treated extraintestinal
manifestation that were controlled with off-TNF antag-
onists but worsened when transitioning to a more se-
lective biologic, or they are off-target effects of the drug
as opposed to an extraintestinal manifestation related
to persistent disease activity. It is entirely unknown
what happens to activated T cells when they are acutely
blocked from homing to the gut and if they then have
preferential migration to alternative sites, but changes
in lymphocyte trafficking during VDZ induction need to
be studied and could yield important information on
disease mechanisms, treatment prognostication, and
risks of therapy.
We observed no cases of progressive multifocal
leukoencephalopathy or lymphoma in our cohort, and
the incidence of malignancy was very low (2.1 per 100
PYF). Both patients developing malignancy had exposure
to immunomodulators, and the patient developing a
squamous cell cancer of the skin had extensive exposure
to azathioprine, which is known to be associated with an
increased risk for this malignancy. The selectivity of VDZ
may result in a more favorable safety profile in high-risk
populations, such as those with active or previous
malignancies. Prior IBD studies have observed that the
risk of cancer (new or recurrent) is higher in patients
Safety of Vedolizumab for IBD 1539
with a prior history of cancer, but treatment with an
immunosuppressant or TNF antagonist wasn’t observed
to increase this risk.16,17 Further studies including
comparative studies will need to be done to understand
if the risk of incident cancer with VDZ is comparable to
that seen with immunomodulators and TNF antagonists,
and if this is different among those with or without a
history of cancer.
Although our study is 1 of the largest safety analyses
reported to date for VDZ, and we have made several
important observations, it is not without limitations.
First, the median follow-up is under 1 year for the cohort
and therefore longer-term safety and risks of therapy
cannot be accurately quantified, particularly pertaining
to risk of malignancy. Second, we did not have a detailed
observation period and therefore an accurate assessment
of duration on concomitant corticosteroids cannot be
ascertained, and assessment of timing for greatest risk
(ie, 3, 6, or 12 months) cannot be assessed. Given the
incremental risk for serious adverse events with
concomitant corticosteroids, further studies are needed
to understand the optimal dose, duration, and route for
corticosteroid coinduction with VDZ to optimize efficacy
while minimizing risks. Third, sites participating in this
consortium are tertiary referral centers with expertise
in IBD and therefore a bias may exist toward over es-
timations of risk with more complex disease phenotypes
or practice patterns (ie, use of concomitant immuno-
suppressive therapy). Real-world data sources such as
large claims analyses may yield more accurate expec-
tations for adverse events in routine practice. We also
did not have a detailed assessment of viral infections
that did not require medical care, or de novo joint pains
or arthralgias, and future prospective studies are likely
needed to quantify these rates and understand whether
de novo joint pains or arthralgias are simply uncon-
trolled disease activity or off target effects of blocked
trafficking. Finally, although our rates of infectious
appear similar to those seen with TNF antagonists it
should be noted that TNF antagonist registry studies
had more stringent observation thereby limiting the
comparability.
In summary, we report on safety data for over 1000
VDZ treated IBD patients and observed that VDZ is well
tolerated in clinical practice. Active smokers and patients
on concomitant immunosuppressive therapy, particu-
larly concomitant corticosteroids at the time of VDZ
initiation, were at an increased risk for infections and
noninfectious adverse events. The most common adverse
events reported were respiratory, gastrointestinal, or
rheumatological (joint pain or arthralgias) in origin, but
only a minority required discontinuation of therapy or
resulted in hospitalization. These data will be of value to
clinicians as they look to understand and explain the
relative safety of VDZ and identify opportunities to
further optimize the safety profile of this selective bio-
logic agent in IBD.
1540 Meserve et al
Supplementary Material
Note: To access the supplementary material accom-
panying this article, visit the online version of Clinical
Gastroenterology and Hepatology at www.cghjournal.org,
and at https://doi.org/10.1016/j.cgh.2018.09.035.
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Reprint requests
Address requests for reprints to: Parambir S. Dulai, MD, University of California
at San Diego, Division of Gastroenterology, 9500 Gilman Drive, La Jolla, Cal-
ifornia 92093. e-mail: pdulai@ucsd.edu; fax: (858) 657-5022.
Conflicts of interest
These authors disclose the following: Parambir S. Desai: Research support,
travel support, and honorarium from Takeda, research support from Pfizer.
Brigid S. Boland: Research support from Takeda, and support from CCFA
career development award and UCSD KL2 (1KL2TR001444). Siddharth Singh:
Research support from Pfizer, and support from the American College of
Gastroenterology and the Crohn’s and Colitis Foundation. Jenna L. Koliani-
Pace: Travel support from Takeda. Eugenia Shmidt: Travel support from
Takeda. Sunanda Kane: Consulting Abbvie. Research Support Takeda, Abbvie,
Pfizer, Genentech, Celgene. Dana Lukin: Consulting for Abbive, Salix. David
Hudesman: Consulting for Abbvie, Takeda, Janssen. Bo Shen: Consulting for
Janssen, Salix, Abbvie, Takeda, Theravence, Robarts Clinical Trials. Corey A.
Siegel: Consulting for Abbvie, Amgen, Celgene, Lilly, Janssen, Sandoz, Pfizer,
Prometheus, Takeda; speaker for CME activities for Abbvie, Janssen, Pfizer,
Takeda; grant support from Abbvie, Janssen, Pfizer and Takeda. Edward V.
Loftus Jr: Consulting for Janssen, Takeda, AbbVie, UCB, Amgen, Pfizer, Salix,
Mesoblast, Eli Lilly, Celgene, and CVS Caremark; research support from
Janssen, Takeda, AbbVie, UCB, Amgen, Pfizer, Genentech, Gilead, Receptos,
Celgene, MedImmune, Seres Therapeutics, and Robarts Clinical Trials.
Sunanda Kane: Consultant to AbbVie, Janssen, Merck, Spherix Health, Pfizer,
UCB. Research support from UCB. Board member ABIM Bruce E. Sands:
Consulting and research support from Amgen, Celgene, Janssen, Pfizer,
Prometheus Laboratories, Takeda; consulting for AbbVie, Akros Pharma, Arena
Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb,
Cowen Services Company, Forest Research Institute, Forward Pharma, Im-
mune Pharmaceuticals, Lilly, Receptos, Salix Pharmaceuticals, Shire, Synergy
Pharmaceuticals, Theravance Biopharma R&D, TiGenix, TopVert Pharma, UCB
Vivelix Pharmaceuticals, Target Pharmasolutions, Allergan. Jean-Frederic
Colombel: Consultancy/advisory board membership: AbbVie, Amgen,
Boehringer-Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring,
Genentech, Janssen and Janssen, Medimmune, Merck & Co., Pfizer, Protag-
onist, Second Genome, Seres, Takeda, Theradiag; Speaker: AbbVie, Ferring,
Takeda, Shire; Research support: AbbVie, Janssen and Janssen, Genentech,
Takeda; Stock options: Intestinal Biotech Development, Genfit. William J.
Sandborn: Personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuti-
cals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Cata-
basis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Cosmo
Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts
Pharma, Am Pharma BV, Dr August Wolff, Avaxia Biologics, Zyngenia, Iron-
wood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuti-
cals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare,
Ferring Research Institute, Novo Nordisk, Mesoblast Inc., Shire, Ardelyx Inc.,
Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid
Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries Inc, Teva Pharma-
ceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Phar-
maceuticals, Celgene, Arena Pharmaceuticals, personal fees from Ambrx Inc.,
Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron,
Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen,
University of Western Ontario (owner of Robarts Clinical Trials); grants and
personal fees from Prometheus Laboratories, AbbVie, Gilead Sciences,
Boehringer Ingelheim, Amgen, Takeda, Atlantic Pharmaceuticals, Bristol-Myers
Squibb Genentech, GlaxoSmithKline, Pfizer, Nutrition Science Partners,
Receptos, Amgen; grants, personal fees and nonfinancial support from Jans-
sen; grants from Broad Foundation, American College of Gastroenterology,
Exact Sciences. The remaining authors disclose no conflicts.
Funding
Takeda Pharmaceuticals provided funding for statistical support to analyze the
data. Takeda Pharmaceuticals and associated employees did not have access
to any of the data, and all data analyses were performed at the University of
California, San Diego, by consortium investigators or statisticians.
July 2019
Supplementary Material
Variables
Data on variables of interest were collected,
including patient characteristics (age at diagnosis, age
at vedolizumab [VDZ] initiation, gender, smoking status,
body mass index), disease characteristics (prior hospi-
talizations, prior surgeries, disease-related complica-
tions, and phenotype classified according to Montreal
subclassifications), and treatment history (corticoste-
roids, immunomodulators, and tumor necrosis factor
antagonists; duration of use; indication for discontinu-
ation; and complications). Variables of interest specific
to VDZ use were baseline disease severity (endoscopic,
radiographic, or clinical assessments), concomitant
treatments at VDZ initiation (corticosteroids or immu-
nomodulators), infusions, and follow-up assessments.
Concomitant corticosteroid or immunomodulator use
was defined as active treatment with these therapies or
initiating these therapies at the time of initiating VDZ
therapy.
Adverse Event Sensitivity Analyses
Sensitivity analyses were performed for infection
risk with concomitant therapies in patients who were
not corticosteroid refractory or dependent, those who
Safety of Vedolizumab for IBD 1540.e1
were immunomodulator and biologically naïve, and
those with prior exposure to tumor necrosis factor
antagonist therapy at the time of starting VDZ. Across
all the groups, the concomitant use of corticosteroids
led to an incremental increase in infections (Figure 2).
In patients who were naïve to immunomodulators and
biologics before starting VDZ (n ¼ 110), concomitant
immunomodulators were not used in any of these pa-
tients, and corticosteroid coinduction was used in
56 patients. Rates of infection were more than 4 times
higher in those patients receiving corticosteroid coin-
duction (8.9% vs 1.9%; P ¼ .21). Rates of infection
were numerically lower in patients receiving cortico-
steroid coinduction with budesonide or budesonide
Multi Matrix System in UC (n ¼ 115) as compared with
systemic prednisone (n ¼ 421; 5.2% vs 9.0%; P ¼ .25).
Among those receiving prednisone coinduction, rates of
infection were comparable between high-dose predni-
sone (>20 mg daily) and low-dose prednisone (9.9% vs
8.6%; P ¼ .72).
Among patients receiving VDZ in combination with an
immunomodulator, rates of infection and serious adverse
events were numerically lower in those taking azathio-
prine versus methotrexate (4.5% vs 5.8%; P ¼ .74). The
rates of de novo arthralgias were numerically lower in
patients on concomitant immunomodulators (2.2% vs
3.1%; P ¼ .45), with lower rates being reported in those
on concomitant azathioprine (1.8%) as compared with
concomitant methotrexate (2.9%).
1540.e2 Meserve et al Clinical Gastroenterology and Hepatology Vol. 17, No. 8

Supplementary Figure 1. Flow chart of patient inclusion.