1. No category

Alimentary Pharmacology and Therapeutics
Systematic review: thalidomide and thalidomide analogues for
treatment of inflammatory bowel disease
C. Yang*, P. Singh*, H. Singh†, M.-L. Le* & W. El-Matary*
*Department of Pediatrics, Faculty of
Health Sciences, College of Medicine,
University of Manitoba, Winnipeg,
MB, Canada.
†
Department of Internal Medicine,
Faculty of Health Sciences, College of
Medicine, University of Manitoba,
Winnipeg, MB, Canada.
Correspondence to:
Dr W. El-Matary, Section of Pediatric
Gastroenterology, Department of
Pediatrics, College of Medicine,
Faculty of Health Sciences, University
of Manitoba, Winnipeg, MB, Canada
E-mail welmatary@hsc.mb.ca
Publication data
Submitted 27 December 2014
First decision 13 January 2015
Resubmitted 17 February 2015
Resubmitted 9 March 2015
Accepted 10 March 2015
This uncommissioned review article was
subject to full peer-review.
SUMMARY
Background
It has been reported that thalidomide may be effective in treating inflammatory bowel disease (IBD).
Aim
To review the evidence examining the efficacy and safety of thalidomide for
inducing and maintaining remission in Crohn’s disease (CD) and ulcerative
colitis (UC).
Methods
The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE,
PubMed (1950–August 2014), EMBASE (1984–August 2014), Scopus, and
Web of knowledge were searched for randomised controlled trials (RCTs),
observational studies and case series. The primary outcomes were induction
of remission or response for active IBD or relapse rate for patients in remission and subsequently on thalidomide/analogues for at least 3 months.
Results
Twelve studies (2 RCTs and 10 case series) met the inclusion criteria for
inducing remission and included 248 patients (10 with UC, 238 with CD).
Only one RCT of paediatric CD achieved high quality scores (remission
rate thalidomide: 46%, placebo: 12%; p=0.01). The crude pooled remission
rate for thalidomide was 49% and 25% in luminal and perianal CD respectively. For UC, 50% achieved remission and 10% had partial response. One
case series reported 21 patients (17 CD, four UC) who maintained remission for 6 months. Many adverse events were reported including sedation
(32%) and peripheral neuropathy (20%).
Conclusions
One high quality RCT showed that thalidomide is effective for inducing
remission in paediatric CD. The current evidence is insufficient to support
using thalidomide to induce remission in UC or adult CD, or to maintain
remission in IBD. Significant adverse events may occur, necessitating discontinuation of thalidomide.
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
doi:10.1111/apt.13181
1
C. Yang et al.
INTRODUCTION
Inflammatory bowel disease (IBD) is a group of disorders characterised by chronic inflammation of the gastrointestinal tract with intermittent clinical remissions and
relapses.1 The two most common subtypes are Crohn’s
disease (CD) and ulcerative colitis (UC).1 The aetiology
of IBD is unknown; however, it is currently believed that
environmental and/or microbial triggers may induce IBD
among the genetically predisposed.2–6 The prevalence of
IBD is increasing worldwide both in children and
adults,7 with 2.6 million people in Europe and 1.2 million in North America estimated to be affected.8–12
As there is no cure for IBD, the main goals of therapy
are induction and maintenance of remission.1, 2 Commonly used medications include corticosteroids that have
shown to be effective in inducing remission, but not
maintenance of remission in IBD.13, 14 Corticosteroids
induce remission in up to 80% of patients with CD.15,
16
Other commonly used agents include immunomodulators such as azathioprine (AZA), mercaptopurine, and
methotrexate and biological agents such as anti-tumour
necrosis factor (anti-TNF) therapies including infliximab
and adalimumab.17 Maintenance of remission is achieved
in 51–71% of CD patients receiving AZA/mercaptopurine.18 Remission rates with anti-TNF therapies may
reach up to 60%.16, 19, 20 Corticosteroids induce remission in up to 46% of UC patients.13 A total of 56% of
UC patients have been reported to be disease free after
1-year treatment with AZA.21 Infliximab induces remission in up to 57% of patients with UC.22
Despite the array of drugs that are currently available,
achieving and maintaining remission remains a challenge
for many IBD patients. Hence, there remains a great
need for new therapies that are both effective and safe.
Cytokines play a crucial role in controlling intestinal
inflammation and pathogenesis of IBD.23, 24 Uncontrolled activation of the mucosal immune system and
subsequent production of cytokines promote chronic
inflammation of the gastrointestinal tract.23 With the
success of infliximab, an antibody specific for TNF, it
became clear that TNF is a key target of therapy for
IBD.25–28 Production of TNF by macrophages, adipocytes, fibroblasts and T cells is significantly elevated in
patients with IBD.23 TNF exerts many pro-inflammatory
effects that are involved in mucosal inflammation in
IBD.23, 29 TNF promotes angiogenesis, increases T-helper
cell 1 (Th1) cytokine production, induces death of intestinal epithelial cells (IECs), and drives T-cell resistance
to apoptosis.30–33 Therefore, therapies that target TNF
can simultaneously suppress many pro-inflammatory
2
pathways implicated in IBD.23 Studies in animal models
and CD patients have shown that elevated mucosal TNF,
excessive Th1 response and upregulation of angiogenesis
may all be involved in the pathogenesis of CD.31, 34–38
Increased production of interleukin-12 (IL-12) and interferon-c (IFN-c) were also seen in intestinal mucosa of
CD patients, consistent with a Th1 type response.39–43
Both TNF and IFN-c have been shown to cause tight
junction disruption and apoptosis of IECs, contributing
to the epithelial barrier dysfunction associated with
IBD.44–46
Originally used as an antiemetic agent in pregnancy,
thalidomide was withdrawn from the market due to its
teratogenic effects.47 It has been re-introduced to treat a
number of conditions, including erythema nodosum leprosum, discoid lupus erythematosus, aphthous stomatitis,
Behcet’s syndrome, graft-versus-host disease and IBD.48
However, it is limited by many side effects including
peripheral neuropathy, sedation, constipation, mood disturbances, skin rash, pedal oedema, neutropenia and
deep vein thrombosis.2, 49
Thalidomide has many immunomodulatory properties
(Figure 1). It is an inhibitor of TNF, IFN-c and IL-12.50–53
It also stimulates production of IL-4 and IL-5.52 This shifts
the pattern of lymphocyte cytokine from a Th1 (IFN-c,
IL-12) to Th2 (IL-4, IL-5) type.52–54 Thalidomide also
interferes with integrin expression, decreases circulating
helper T cells and inhibits angiogenesis.49, 55–57
In their attempt to understand the mechanism of
action of thalidomide as a treatment of multiple myeloma, Segarra et al.,58 demonstrated that thalidomide, on
therapeutic doses, disrupted integrin mediated signalling
pathway, resulting in less production of several mediators that promote invasiveness of malignant B lymphoid
cell lines.
Thalidomide may block NF-kB activation through a
mechanism that involves the inhibition of activity of the
IkB kinase. Thalidomide may also be able to block the
cytokine-induced expression of NF-kB-regulated genes
such as those encoding interleukin-8, TRAF1 and c-IAP2.
Consequently, the therapeutic potential for thalidomide
may be based on its ability to block NF-kB activation
through suppression of IkB kinase activity.59 Moreover,
thalidomide may block cell adhesion molecule expression
in human intestinal microvascular endothelial cells (HIMEC), the relevant endothelial cell population in inflammatory bowel disease.60 Rafiee et al.,60 investigated the
effect of thalidomide on primary cultures of human HIMEC. Expression of cell adhesion molecules (E-selectin,
intercellular adhesion molecule-1 (ICAM1), vascular cell
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
Systematic review: thalidomide in IBD
adhesion molecule-1 (VCAM1)) was examined using
radioimmunoassay. Although thalidomide did not alter
the expression of E-selectin, ICAM-1 or VCAM-1 on
resting HIMEC, it was associated with inhibition of the
upregulation of all three molecules. Thalidomide blocked
vascular endothelial growth factor (VEGF) with subsequent decrease in HIMEC growth and activation.60
Enhanced expression of VEGF may play an important
pathological mechanism in chronic inflammation in
IBD.61
The effect of thalidomide on leucocyte-endothelial
interaction in rats with experimental colitis was investigated by Lienenl€
uke and colleagues.62 The investigators
demonstrated a reduction in VCAM-1 expression with
subsequent decrease in leucocyte adhesion to endothelial
cells.62
The aim of this study was to systematically review the
evidence examining the efficacy and safety of thalidomide and/or thalidomide analogues for induction and
maintenance of remission in patients with IBD.
http://www.crd.york.ac.uk/PROSPERO/display_record.asp?
ID=CRD42014010361
Search strategy and study selection
A literature search was performed in the following databases: Cochrane Central Register of Controlled Trials
(CENTRAL), Cochrane IBD/FBD Specialised Trial Register, MEDLINE (1966–August 2014), PubMed (1950–
August 2014), EMBASE (1984–August 2014), SCOPUS,
Web of Knowledge. An example of search terms used is
provided in Table S1.
Inclusion criteria
(i) Randomised controlled trials (RCT), cohort studies,
case series (involving five or more patients) examining the efficacy of thalidomide/thalidomide analogue in either induction of remission/response or
maintaining remission in
METHODS
The current systematic review was registered in
PROSPERO. Registration number: CRD42014010361.
•
•
•
•
Luminal CD
Perianal CD
UC
IBD
(ii) Participants: Patients with IBD of all age groups
TRAF1
c-IAP2
Th2 (T helper)
IL-8
Th2
cytokines
(IL-4,
IL-5)
NF-kB
Thalidomide
Monocytes
Cell adhesion of HIMEC
Tumour necrosis factor
Vascular endothelial
cells
Th1 cytokines
(IFN-γ, IL -12)
Angiogenesis
T-cell resistance
to apoptosis
Figure 1 | Thalidomide proposed mechanism of action in inflammatory bowel disease. TNF- tumour necrosis factor; TH - T
helper; IL - interleukin; IFN-c - interferon-c; NF - nuclear factor; HIMEC - human intestinal microvascular endothelial cells.
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
3
C. Yang et al.
(iii) Intervention: Thalidomide and thalidomide analogues (any route, dose, duration)
(iv) Human trials
(v) Full papers
(vi) Published in English
Exclusion criteria
(i) Individual case reports (<5 CD patients)
(ii) Review articles
(iii) Abstracts
(iv) Studies not published in English
PICOS criteria
P (Participants: Patients of all ages with IBD including
Crohn’s [both luminal and perianal] and Ulcerative colitis). I (Interventions: Thalidomide and thalidomide analogues [any route]). C (Comparisons: Any comparator
including placebo or no placebo). O (Outcome: Induction or maintenance of remission). S (Study design: Case
series [five or more patients], cohort studies and RCTs).
Data extraction and quality assessment
Articles retrieved from the literature search were independently screened based on the title and abstract by
two authors (PS and CY) and categorised as either
‘include’, ‘exclude’ or ‘unsure’. The full-text articles of all
‘include’ and ‘unsure’ categories were reviewed independently by two authors (PS and CY) and eventually categorised as ‘included’ or ‘excluded’. Any disagreements
were resolved by mutual discussion or by consulting with
the senior author (WE). Data extraction was then carried
out independently by two authors (PS and CY). Data
extracted from each article included: study methods
(study design, method of randomization if RCT, withdrawals and loss to follow-up), study participants (sample size, age and gender), method used for assessing
disease activity, intervention type, dose, route, compliance, comparator if available, co-medications, route,
duration of treatment, adverse events and outcomes
(types of outcome measures, timing of measurements,
reported outcomes). For quality assessment, the Cochrane Risk of Bias tool was utilised for RCTs,63 the Newcastle Ottawa Score (NOS) for observational trials,64 and
the National Institute and Clinical Excellence (NICE)
defined criteria for case series.65
Data extraction methodology
The primary outcome measure was remission or
response based on any activity index including: CD
4
activity index (CDAI) or Pediatric CD activity index
(PCDAI) for paediatric patients; Modified clinical activity
index (MCAI); Perianal disease activity index (PDAI);
physician global assessment (PGA), or endoscopic and
Magnetic Resonance Imaging (MRI) findings. Relapse
rate was used for assessing maintenance of remission.
Secondary outcome was the reported adverse events
related to thalidomide and/or thalidomide analogues.
RESULTS
The literature search is summarised in Figure 2. Additional information regarding excluded studies can be
found in Table S2. Many articles were excluded as they
did not fulfil the inclusion criteria. These articles were
individual case reports, or series <5 patients, review articles, editorials, animal studies, articles not in English,
abstracts or articles that addressed colitis/IBD, but did
not investigate the effect of thalidomide on IBD.
The characteristics of each study included in this
review are summarised in Table S3.
Twelve studies met the inclusion criteria for the
review.66–77 Two of these studies were RCTs while the
remaining 10 were case series. These studies included 248
patients in total (including 92 paediatric patients) with
192 patients receiving thalidomide and 56 patients receiving lenalidomide. Of the patients receiving thalidomide, 10
patients had a diagnosis of UC, and 182 patients had CD
(luminal, perianal, or unspecified). All 56 adult patients in
the single RCT examining lenalidomide had CD.72 Only
one study that met the inclusion criteria examined the
maintenance of remission in IBD (mixed group of patients
with UC and CD) with thalidomide.70
The quality of the 10 case series studies ranged from
2/8 to 7/8 on the National Institute for Health and Clinical Excellence scale for case series. Using the Cochrane
Risk of Bias tool, the RCT by Lazzerini et al.,71 was
assessed to have a low risk of bias, whereas the RCT by
Mansfield et al.,72 had an unclear risk of bias.
RCT: Induction of remission in unspecified Crohn’s
disease by thalidomide
There was only one RCT by Lazzerini et al.,71 that studied the effect of thalidomide in IBD (Table 1). Specifically, it examined the use of thalidomide for induction
of remission in paediatric CD.71 However, they did not
differentiate between luminal and perianal CD.71 Remission was defined as PCDAI <10. Results showed significant differences in remission rate between thalidomide
group and placebo (46% vs. 12%; P = 0.01).71 In the
open-label extension of their study, 21 non responders
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
Identification
Systematic review: thalidomide in IBD
Records identified through
database searching
(n = 1068)
Additional records identified
through other sources
(n = 0)
Screening
Records after duplicates removed
(n = 1001)
Records screened
(n = 1001)
Records excluded
(n = 837)
319 Not IBD
288 Review articles
140 Thalidomide not investigated
29 Not human studies
16 Molecular studies
12 Insufficient IBD patients (<5)
8 Editorials
7 Conference reports
6 Pharmacology studies
4 Correspondences
3 Commentaries
2 Practice guidelines
1 Not English
1 News article
1 Book chapter
Eligibility
Full-text articles excluded
(n = 145)
Full-text articles assessed
for eligibility
(n = 164)
38 Insufficient IBD patients (< 5)
27 Review articles
18 Abstract only
14 Not IBD
9 Correspondences
8 Insufficient sample size receiving
Thalidomide (< 5)
8 Editorials
6 Thalidomide not investigated
5 Abstracts of another article
4 Commentaries
4 Full-text not available
3 Molecular studies
1 Not English
Marked as “unsure” but
excluded after further
review
(n = 7)
2 Did not report/define
remission
2 Thalidomide not
investigated
1 Insufficient IBD patients
(<5)
1 Results of IBD patients
not distinguished
1 Did not study IBD
Included
Studies included in
qualitative synthesis
(n = 12)
Studies included in
quantitative synthesis
(meta-analysis)
(n = 0)
Figure 2 | Flow algorithm of different phases of the systematic review.
to placebo began receiving thalidomide and 11 of these
patients (52% vs. 12%; P = 0.01) subsequently achieved
remission.71
RCT: Induction of remission in Crohn’s disease by
lenalidomide
One RCT by Mansfield et al.,72 examined lenalidomide
for the induction of remission in adult CD (Table 2).
Remission and response were defined using CDAI.
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
Twenty-three patients received lenalidomide at 25 mg
per day; 33 patients received 5 mg per day and 28
patients were given placebo. Rates of remission were 9%
(P = 0.15), 30% (P = 1.00) and 25% for the three groups
respectively. Therefore, lenalidomide was not effective
for induction of remission in adult CD when compared
to placebo. A total of 27 patients (48%) on Lenalidomide
and 13 patients (46%) on placebo withdrew from the
study due to adverse events.
5
C. Yang et al.
Table 1 | RCTs assessing efficacy of thalidomide for induction of remission in CD
Study (year)
No. of
patients
Lazzerini
et al.
201371 –
RCT
28
Lazzerini
et al.
201371 –
openlabel
extension
21
26
Rx
route
Duration
of
therapy
50–150
mg/day
Placebo
PO
8 weeks
PO
8 weeks
50–150
mg/day
PO
8 weeks
Dose
Evaluation
of response
Remission,
n (%)
Partial
response,
n (%)
No response,
n (%)
Withdrawals*,
n (%)
Remission:
PCDAI ≤10.
Response:
Reduction
in PCDAI
of ≥25%.
Remission:
PCDAI ≤10.
Response:
Reduction
in PCDAI
of ≥25%.
13 (46)
[P = 0.01]
3 (12)
5 (18)
[P = Not provided]
5 (19)
10 (36)
[P = Not provided]
18 (69)
0
11 (52%)
4 (19)
6 (29%)
Conclusion
‘In children and adolescents
with refractory Crohn
disease, thalidomide
compared with placebo
resulted in improved
clinical remission at 8
weeks of treatment and
long-term maintenance of
remission in an open-label
follow-up. These findings
require replication to
definitively determine
clinical utility of this
treatment.’
0
0
CD, Crohn’s disease; PO, per oral; PCDAI, paediatric Crohn’s disease activity index.
* Withdrawals here refer to number of patients who did not have their responses evaluated due to early suspension of therapy,
and does not include patients who discontinued thalidomide after achieving remission or response. Same applies for subsequent
tables. Refer to Safety Profile of Thalidomide and Lenalidomide for information regarding total number of discontinuations.
Table 2 | RCTs assessing efficacy of lenalidomide for induction of remission in CD
Study
(year)
No. of
patients
Mansfield
et al.
200772
23
33
28
Dose
25
mg/day
5
mg/day
Placebo
Rx
route
Duration
of
therapy
Evaluation
of
response
PO
12 weeks
PO
12 weeks
PO
12 weeks
Remission:
CDAI <150
and reduction
in CDAI by
≥100 point.
Response:
Reduction in
CDAI by ≥70
point.
Total no. of patients receiving lenalidomide = 56
Total %
Remission,
n (%)
Partial
response,
n (%)
No
response,
n (%)
Withdrawals,
n (%)
2 (9)
[P = 0.15]
10 (30)
[P = 1.0]
7 (25)
4 (17)
[P = not provided]
6 (18)
[P = not provided]
4 (14)
2 (9)
15 (65)
5 (15)
12 (36)
4 (14)
13 (46)
12
21.4
10
17.9
7
12.5
27
48.2
Conclusion
‘Lenalidomide, an oral
agent with
anti-tumour
necrosis factor-a
properties, was not
effective in active
Crohn’s disease in
contrast to reports
of benefit from
thalidomide. The
reasons for this lack
of efficacy are
speculative, other
physiological
activities may offset
its action on
inflammatory
cytokines, or its
anti-tumour necrosis
factor-a action
without apoptosis
may be insufficient
for activity in
Crohn’s disease.’
CD, Crohn’s disease; CDAI, Crohn’s disease activity index; PO, per oral.
Case series: Induction of remission in luminal
Crohn’s disease
There were no RCTs or comparative cohort studies
specifically examining the use of thalidomide in luminal CD, but six case series were found to fulfil inclusion criteria (Table 3).67–69, 74–76 Two of these studies
6
used CD activity index (CDAI) alone as the primary
measure for determining remission.67, 75 The remaining studies used either: CDAI and clinical improvement, CDAI and steroid withdrawal, HarveyBradshaw Index (HBI) or endoscopic evaluation for
this purpose.
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
Systematic review: thalidomide in IBD
Table 3 | Case series assessing efficacy of thalidomide for induction of remission in luminal CD
Study (year)
No.
of
patients
Dose
Rx
route
Duration
of
therapy
Evaluation
of
response
Remission: CDAI <150.
Response: Reduction in
CDAI by >150.
Remission: Confirmed with
endoscopy.
Response: Assessed by
using PCDAI, modified
Harvey-Bradshaw scores
and reduction in steroid
therapy; exact criteria
not defined.
Remission:
Resolution of symptoms
and a HBI <5.
Response: Reduction in
symptoms at 2–6
months on thalidomide
and a HBI of 5–7.
Remission:
Symptom resolution and
an ‘estimated’ CDAI
<150.
Response: Symptom
improvement and a
reduction in ‘estimated’
CDAI by >100.
Remission: CDAI <150.
Response:
Reduction in CDAI
by >70.
Remission:
Reduction in CDAI
by ≥100, CDAI <150 and
complete withdrawal of
steroids.
Response: Reduction in
CDAI by ≥100 and reduction
in steroid dosage by ≥50%.
Ehrenpreis
et al.
199967
Facchini
et al.
200168
9
50–300
mg/day
PO
12 weeks
5
1.5–2
mg/kg/
day
PO
Variable
(19–24
months)
Felipez
et al.
201269
12
0.7–3.0
mg/kg/
day
PO
Mean 39.5
months
(range
1–96
months)
Plamondon
et al.
200774
12
50–200
mg/day
PO
Median 14
weeks
(range
2–236
weeks)
Sabate
et al.
200275
6
100
mg/day
PO
Variable
Vasiliauskas
et al.
199976
12
50–100
mg/day
PO
12 weeks
Total no. of patients = 56
Total %
Remission,
n (%)
Partial
response,
n (%)
No
response,
n (%)
Withdrawals,
n (%)
3 (33)
2 (22)
0
4 (44)
4 (80)
0
0
1 (20)
10 (83)
0
2 (17)
0
5 (42)
4 (33)
2 (17)
1 (8)
3 (50)
1 (17)
2 (33)
0
2 (17)
5 (42)
3 (25)
2 (17)
27
48.2
12
21.4
9
16.1
8
14.3
CD, Crohn’s disease; CDAI, Crohn’s disease activity index; PCDAI, paediatric Crohn’s disease activity index; HBI, Harvey-Bradshaw
Index; PO, per oral.
A total of 56 patients with luminal CD received thalidomide for inducing remission. Twenty-seven patients
(48.2%) achieved remission as defined in the respective
studies. Twelve patients (21.4%) had a partial response
to thalidomide. Nine patients (16.1%) had no response.
Eight patients (14.3%) withdrew from the studies due to
adverse events from thalidomide.
Case series: Induction of remission in perianal
Crohn’s disease
Similar to luminal CD, there were no RCTs or comparative cohort studies that specifically examined
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
induction of remission in perianal CD by thalidomide.
There were a total of four case series that examined
the use of thalidomide for perianal disease
(Table 4).67, 73, 74, 76 Remission was defined as complete closure of fistulas in three of these studies.73, 74, 76 One study defined remission as a score of
greater than 2+ in all clinical parameters of treatment
goal interval score (GIS).67
Based on these studies, 40 perianal CD patients
received thalidomide for induction of remission. Ten of
these patients (25%) achieved remission as defined by
each study. Eleven patients (27.5%) had a partial
7
C. Yang et al.
Table 4 | Case series assessing efficacy of thalidomide for induction of remission in perianal CD
Study (year)
No.
of
patients
Dose
Rx
route
Duration
of
therapy
Evaluation
of
response
Remission: Scores of
≥2+ in all clinical parameters
of treatment goal interval
score (GIS); if not receiving
steroids at start, need 2 scores
of ≥2+ in all clinical parameters.
Response: 2 scores of ≥1+
in two of the three clinical
parameters of ;the GIS.
Remission: Cessation of fistula
drainage on history, absence of
perianal drainage to gentle finger
compression of external opening,
and absence of spontaneous
drainage between two
consecutive visits.
Response: Closure of ≥50%
of externally draining fistulas or
marked reduction in drainage
of all fistula together with less
pain and induration as reported
by the patient for at least two
consecutive visits.
Remission:
Fistulizing Disease: Complete
fistula closure (absence of
active drainage from all fistula
based on history and clinical exam).
Perianal ulcerating disease:
Complete ulcer healing.
Response:
Fistulizing Disease: Improvement
by ≥50% in the number of
draining fistulas.
Perianal ulcerating disease: Global
improvement as assessed by
attending doctor and reduction in
discomfort.
Remission:
Complete fistula closure.
Response: Decreased drainage,
induration, pain and/or reduction
in pain medication requirement.
Ehrenpreis
et al.
199967
12
50–300
mg/day
PO
12
weeks
Ng
et al.
200973
8
50–300
mg/day
PO
Variable
(2–52
weeks)
Plamondon
et al.
200774
14
50–200
mg/day
PO
Median
14 weeks
(range
2–236
weeks)
Vasiliauskas
et al.
199976
6
50–100
mg/day
PO
12 weeks
Total no. of patients = 40
Total %
Remission,
n (%)
Partial
response,
n (%)
No
response,
n (%)
Withdrawals,
n (%)
6 (50)
2 (17)
0
4 (33)
0
0
0
8 (100)
3 (21)
8 (57)
3 (21)
0
1 (17)
1 (17)
2 (33)
2 (33)
10
25.0
11
27.5
5
12.5
14
35.0
CD, Crohn’s disease; PO, per oral.
response to thalidomide and five patients (12.5%) had
no response. The remaining 14 patients (35%) withdrew
from the study due to adverse events. This included one
study where all eight patients involved withdrew before
the completion of the study due to adverse effects from
prolonged exposure to thalidomide.73
Case series: Induction of remission in unspecified
Crohn’s disease
Three case series examining thalidomide use in CD did
not specify whether patients had perianal or luminal CD,
8
or did not stratify the results by disease location
(Table 5).66, 70, 77 One of these studies defined remission
as paediatric CD activity index (PCDAI) <7.5.77 Another
study defined remission using CDAI.66 Finally, one of
the three studies used a combination of CDAI and
PCDAI depending on the age of the patient.70 The criteria used to define partial response were not clear in the
three case series.66, 70, 77
Based on the three studies that met the inclusion criteria, a total of 34 patients received thalidomide.
Twenty-eight patients (82.3%) achieved remission. Two
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
Systematic review: thalidomide in IBD
Table 5 | Case series assessing efficacy of thalidomide for induction of remission in unspecified CD
Study (year)
Bauditz
et al.
200266
Lazzerini
et al.
200770
Zheng
et al.
201177
Rx
route
Duration
of
therapy
300
mg/day
PO
12 weeks
Remission: CDAI <150.
Response: Not defined.
19
1.5–2.5
mg/kg/day
PO
Variable
6
0.5–3.0
mg/kg/day
PO
Mean 10
months
(range
7–14
months)
Remission: If <18 years old:
PCDAI <7.5; if >18 years old:
CDAI <150, with decrease of
at least 70 points from baseline.
Response: Not defined.
Remission: PCDAI <7.5.
Response: Not defined.
No.
of
patients
9
Dose
Remission,
n (%)
Evaluation of response
4 (44)
Total no. of patients on thalidomide = 34
Total %
18 (95)
6 (100)
28
82.4
Partial
response,
n (%)
No
response,
n (%)
2 (22)
0
3 (33)
0
0
1 (5)
0
0
0
2
5.9
0
0
Withdrawals,
n (%)
4
11.8%
CD, Crohn’s disease; CDAI, Crohn’s disease activity index; PCDAI, paediatric Crohn’s disease activity index; PO, per oral.
Table 6 | Case series assessing efficacy of thalidomide for induction of remission in UC
Study (year)
Bauditz
et al.
200266
Lazzerini
et al.
200770
No.
of
patients
Dose
Rx
route
Duration
of
Therapy
Evaluation of response
Remission,
n (%)
Partial
response,
n (%)
No
response,
n (%)
Withdrawals,
n (%)
1
300
mg/day
PO
12 weeks
Remission: CAI <5.
Response: Not defined.
0
1 (100)
0
0
9
1.5–2.5
mg/kg/day
PO
Variable
Remission: Complete
resolution of clinical
symptoms (all clinical
UCSS subscores equal
to 0) with a
proctosigmoidoscopy
score of 0 or 1.
Response: Not defined.
5 (56)
0
1 (11)
3 (33)
5
50.0
1
10.0
1
10.0
3
30.0
Total no. of patients = 10
Total %
UC, ulcerative colitis; CAI, colitis activity index; UCSS, ulcerative colitis scoring system; PO, per oral.
patients (5.9%) experienced partial response and zero
patients (0%) had no response. Four patients (11.8%)
withdrew prior to the completion of the study.
Case series: Induction of remission in ulcerative
colitis
There were only two case series that examined the use of
thalidomide for induction of remission in UC
(Table 6).66, 70 Remission was defined by one study as
Colitis Activity Index (CAI) <5 and by the other study
as complete resolution of clinical symptoms with a proctosigmoidoscopy score of 0 or 1.
A total of 10 patients with UC received thalidomide
for induction of remission. Five patients (50.0%)
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
achieved remission. One patient achieved partial
response and one patient did not achieve any response.
Three patients (30%) withdrew from the studies due to
adverse events.
Case series: Maintenance of remission in IBD
Only one case series examined the efficacy of thalidomide for maintenance of remission in IBD (both CD
and UC) (Table 7).70 Remission and relapse were defined
by PCDAI and CDAI depending on the age of the
patient. A total of 21 patients (17 CD, 4 UC) achieved
remission with thalidomide and continued the drug for
maintenance of remission. All 21 patients were in
remission at 6 month follow-up. Twenty patients (95%)
9
C. Yang et al.
Table 7 | Case series assessing efficacy of thalidomide for maintenance of remission in IBD (CD & UC)
Study (year)
No.
of
patients
Lazzerini
et al.
200770
21
(17 CD,
4 UC)
Dose
0.5–1.5
mg/kg/day
Rx
route
Duration
of
therapy
PO
Variable
Duration
of Follow-up
Median
32 months
Evaluation of response
Relapse rate (%)
Remission: If <18 years old:
PCDAI <7.5; if >18 years old:
CDAI <150, with decrease
of at least 70 points
from baseline.
Relapse: PCDAI >15
or CDAI >200.
6 months: 0/21 pts
12 months: 0/20 pts
18 months: 0/18 pts
24 months: 0/15 pts
IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; CDAI, Crohn’s disease activity index; PCDAI, paediatric Crohn’s disease activity index; PO, per oral.
completed twelve-month follow-up and all were in
remission. By 24 months, 15 patients (71%) were still
taking thalidomide and were in remission. The others
had to discontinue because of neuropathy.
Safety profile of thalidomide and lenalidomide
Many adverse events with thalidomide use have been
reported in the 12 included studies (Table 8). A total of
192 patients on thalidomide and 56 patients on lenalidomide were included in the analysis of safety profile. The
most commonly reported adverse events were sedation
(32.3%), peripheral neuropathy (19.8%) and dermatitis
(12%). Peripheral neuropathy was the most common reason for discontinuation with thalidomide therapy, with
14.6% of all patients having to discontinue the drug due
to neuropathy. In total, 29% of all patients had to discontinue thalidomide therapy at some point due to adverse
events. Seven of the case series reported that peripheral
neuropathy was reversible by discontinuation of thalidomide in the majority of patients. The other case series did
not comment on reversibility of adverse effects. However,
Lazzerini et al.,71 reported only half of patients recovered
from peripheral neuropathy following dose tapering.
In the only study that examined lenalidomide, leucopenia, rash, worsening IBD and abdominal pain were the
main adverse events associated with its use (Table 9).72
Worsening IBD and abdominal pain were the most common reason for discontinuation of lenalidomide. In total,
32% of all patients discontinued lenalidomide therapy
due to adverse events.
DISCUSSION
Inflammatory bowel disease is a major cause of morbidity. Many agents have been examined and have shown
success in inducing or maintaining remission, including
10
corticosteroids, immunomodulators (AZA, mercaptopurine, methotrexate) and biological agents such as antiTNF therapies.
Based on one high quality RCT, thalidomide may be
an effective therapeutic agent for the induction of remission in paediatric CD. However, there is no good evidence to support its efficacy in the induction of
remission in adult CD, induction of remission in UC or
maintenance of remission in IBD. There is no evidence
of lenalidomide’s efficacy in IBD.
There were many adverse effects associated with thalidomide. The most common adverse effect was sedation,
which was reported in 32.3% of all patients, followed by
peripheral neuropathy, which was reported in 19.8% of
patients. Peripheral neuropathy was the most common
cause of discontinuation. A total of 14.6% of patients discontinued thalidomide due to peripheral neuropathy, and
5.7% of patients discontinued due to sedation. Thalidomide-induced peripheral neuropathy (TiPN) is generally
reversible with dose reduction or cessation of therapy,
though there have been cases of irreversible injury after
therapy is discontinued.78, 79 Several mechanisms of TiPN
has been proposed, including capillary damage, secondary
anoxemia in nerve fibres and acceleration of neuronal cell
death secondary to downregulation of TNF-a.78, 80
Patients on thalidomide should be closely monitored for
symptoms and signs of peripheral neuropathy.
The strength of the available evidence is limited by
the poor quality of many of the studies. Results from the
two RCTs were not combined in meta-analyses because
they examined different medications (thalidomide vs. lenalidomide) and included patients in different age
groups (paediatric vs. adult).
Historically, remission rates achieved by placebo for
patients with CD have been reported to be about 18%.81
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
Systematic review: thalidomide in IBD
Table 8 | Adverse events with use of thalidomide
Adverse events of
thalidomide
No. of cases
reported
% of total
patients
% of total patients discontinued
as a result of the adverse event
Sedation
Peripheral neuropathy
Dermatitis
EMG alterations with no neuropathy
Constipation
Fatigue
Headache
Worsening IBD
Dizziness/vertigo
Asymptomatic bradycardia
Vision changes
Rash
Abdominal pain
Oedema
Seizures
Difficulty concentrating
Strength deficit
Leucopenia
Hypertension
Chest pain
Allergic reaction
Gynaecomastia
Scotoma
Hemeralopia
Atrioventricular block
62
38
23
16
11
10
7
5
5
4
3
3
2
2
2
2
2
2
2
1
1
1
1
1
1
32.3
19.8
12.0
8.3
5.7
5.2
3.6
2.6
2.6
2.1
1.6
1.6
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
5.7
14.6
0
0
0
0
0.5
2.6
1.6
0
0.5
0.5
1.0
0
0.5
0
0
0.5
0
0
0.5
0
0
0
0.5
Table 9 | Adverse events with use of lenalidomide
Adverse events of
lenalidomide
No. of cases
reported
% of total
patients
% of total patients discontinued as
a result of the adverse event
Leucopenia
Rash
Worsening IBD
Abdominal pain
Headache
Nausea/vomiting
Diarrhoea
Deep vein thrombosis
11
7
6
6
3
3
3
1
19.6
12.5
10.7
10.7
5.4
5.4
5.4
1.8
0
0
10.7
10.7
0
5.4
5.4
0
One should take into account the placebo effect of therapy for CD patients when interpreting remission rates
reported by case series that lack controls. Overall, the
majority of studies conducted thus far on the use thalidomide and thalidomide analogues in IBD has been case
series with small sample size and were found to be of
poor quality. There were no case–control or comparative
cohort studies and there are only two RCTs in this area.
Only one RCT examined the use of thalidomide in paediatric CD,71 and another RCT on the use of lenalidomide in adult CD.72 Lazzerini et al.,71 demonstrated
efficacy of thalidomide over placebo for the induction of
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
remission in paediatric CD (46% vs. 12%; P = 0.01). The
majority of children in the study had luminal disease
and few had perianal disease. However, based on the
information given, we could not extrapolate the rate of
remission specific to the type of CD. There have been
very limited studies examining the efficacy of thalidomide in UC and maintenance of remission in IBD.
To our knowledge, this is the most complete systematic review looking at the role of thalidomide and thalidomide analogues in IBD. This is also the first review that
included studies on the efficacy of thalidomide in UC
and stratified the efficacy for luminal and perianal CD.
11
C. Yang et al.
Although there have been systematic reviews in the past
for CD, their primary focus was on RCTs and did not
include other available evidence such as cohort studies
or case series.82, 83
There were some limitations to our study. First,
abstracts were excluded in our literature search, because
they are not available in full text and often represent
preliminary data. Several attempts were made to contact
the authors, but we were unsuccessful in retrieving the
full data of these studies. Second, several studies did
not stratify between luminal and perianal CD. For
example, Bauditz et al.,66 Lazzerini et al.,70 and Lazzerini et al.,71 did not stratify patients into luminal and
perianal CD. Consequently, we could not include their
data in our stratified analysis for the induction of
remission in luminal and perianal CD. These results
were reported separately as unspecified CD. Another
limitation was the wide variation in the definition of
the outcome measures used in the studies. For instance,
Ehrenpreis et al.,67 defined remission as CDAI <150,
Facchini et al.,68 based remission on endoscopy findings
and Felipez et al.,69 defined remission as symptom resolution and a Harvey-Bradshaw Index (HBI) <5. Furthermore, some studies reported results on disease
outcomes that were not the main focus of the respective study. For example, the main focus of Vasiliauskas
et al.,76 was to assess induction of remission in luminal
CD, but they also reported results for perianal CD as
well. Therefore, the results for perianal CD from this
study should be considered of lower quality as the
study was not initially designed for that purpose. Last,
variable treatment regimens with regard to duration
and dose were used in the different studies. This
resulted in not only heterogeneity among different studies but also variability within the same study as well.
For example, Facchini et al.,68 used thalidomide at a
dose of 1.5–2.0 mg/kg/day for 19–24 months, compared
to Felipez et al.,69 who used a dose of 0.7–3.0 mg/kg/
day for 1–96 months. Some studies reported dose as
mg/kg/day while others only reported it as mg/day,
making it difficult for comparison. Some studies, such
as the one by Sabate et al.,75 did not report the duration of the treatment.
There was a limited number of studies for maintenance of remission. The maintenance of remission data
from the study by Sabate et al.,75 had to be excluded
because it was not clear how many patients with luminal
or perianal disease were in remission prior to thalidomide treatment, and how many of those relapsed.
12
CONCLUSIONS
Despite the poor quality of the available evidence, this
systematic review demonstrated that thalidomide may
be an effective therapeutic agent for the induction of
remission in paediatric CD, based on one RCT that
compared thalidomide to placebo for induction of
remission in children with active CD. Using a placebo
as a sole treatment for active CD in children was unusual and initiated some discussions.84 The results of this
study need to be reproduced in future studies before a
solid conclusion can be established. Currently, there is
not enough high quality evidence to support use of thalidomide or its analogue for the induction of remission
in adult CD or patients of any age with UC. There is
also a lack of evidence for the use of thalidomide or
thalidomide analogue in maintenance of remission in
CD and UC. Many adverse events may occur with the
use of thalidomide or lenalidomide, some of which
cause discontinuation of therapy. This highlights major
safety concern on the use of these medications. For lenalidomide, there is probably sufficient evidence of no
benefit in adult patients with CD and further trials in
CD would be difficult to support. Further controlled trials with larger sample size are needed to verify the role
of thalidomide in IBD.
AUTHORSHIP
Guarantor of the article: W El-Matary.
Author contributions: CY and PS performed screening of
papers, data extraction, quality assessment, collected and
analysed the data and wrote the manuscript. HS critical
appraisal and edited the manuscript. ML performed the
literature search. WE developed the study concept and
protocol, leading role of coordinating the project, senior
authorship to resolve disagreements on inclusion, exclusion and quality assessment of papers and critiquing and
editing the manuscript.
All authors approved the final version of the article,
including the authorship list.
ACKNOWLEDGEMENTS
Declaration of personal interests: Dr El-Matary’s has
served as a member in the Pediatric Advisory Boards of
both Janssen, Canada and Abbvie, Canada. Dr Singh has
consulted to Medial Cancer Screening Ltd., Israel.
Declaration of funding interests: Dr El-Matary’s research
programme is supported by a grant from the Manitoba
Institute of Child Health and Winnipeg Children’s Hospital Foundation.
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
Systematic review: thalidomide in IBD
SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Table S1. Example of search strategy: MEDLINE
(OVID).
Table S2. Table of excluded studies.
Table S3. Characteristics of included studies.
REFERENCES
1. Walsh A, Mabee J, Trivedi K.
Inflammatory bowel disease. Prim Care
2011; 38: 415–32.
2. Fakhoury M, Negrulj R, Mooranian A,
Al-Salami H. Inflammatory bowel
disease: clinical aspects and treatments.
J Inflamm Res 2014; 7: 113–20.
3. Szigethy E, McLafferty L, Goyal A.
Inflammatory bowel disease. Pediatr
Clin North Am 2011; 58: 903–20.
4. Kleessen B, Kroesen AJ, Buhr HJ, Blaut
M. Mucosal and Invading Bacteria in
Patients with Inflammatory Bowel
Disease Compared with Controls. Scand
J Gastroenterol 2002; 37: 1034–41.
5. Ott SJ. Reduction in diversity of the
colonic mucosa associated bacterial
microflora in patients with active
inflammatory bowel disease. Gut 2004;
53: 685–93.
6. Frank DN, St Amand AL, Feldman RA,
Boedeker EC, Harpaz N, Pace NR.
Molecular-phylogenetic characterization
of microbial community imbalances in
human inflammatory bowel diseases.
Proc Natl Acad Sci USA 2007; 104:
13780–5.
7. El-Matary W, Moroz SP, Bernstein CN.
Inflammatory bowel disease in children
of manitoba: 30 years’ experience of a
tertiary center. J Pediatr Gastroenterol
Nutr 2014; 59: 763–6.
8. Burisch J, Jess T, Martinato M, Lakatos
PL. The burden of inflammatory bowel
disease in Europe. J Crohns Colitis
2013; 7: 322–37.
9. Burisch J, Munkholm P. Inflammatory
bowel disease epidemiology. Curr Opin
Gastroenterol 2013; 29: 357–62.
10. Molodecky NA, Soon IS, Rabi DM, et al.
Increasing incidence and prevalence of
the inflammatory bowel diseases with
time, based on systematic review.
Gastroenterology 2012; 142: 46–54.
11. Benchimol EI, Fortinsky KJ, Gozdyra P,
Van den Heuvel M, Van Limbergen J,
Griffiths AM. Epidemiology of pediatric
inflammatory bowel disease: a
systematic review of international
trends. Inflamm Bowel Dis 2011; 17:
423–39.
12. Kappelman MD, Moore KR, Allen JK,
Cook SF. Recent trends in the
prevalence of Crohn’s disease and
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
ulcerative colitis in a commercially
insured US population. Dig Dis Sci
2013; 58: 519–25.
Ford AC, Bernstein CN, Khan KJ, et al.
Glucocorticosteroid therapy in
inflammatory bowel disease: systematic
review and meta-analysis. Am J
Gastroenterol 2011; 106: 590–9.
Steinhart AH, Ewe K, Griffiths AM,
Modigliani R, Thomsen OO.
Corticosteroids for maintenance of
remission in Crohn’s disease. Cochrane
Database Syst Rev 2003; (4): CD000301.
Benchimol EI, Seow CH, Steinhart AH,
Griffiths AM. Traditional
corticosteroids for induction of
remission in Crohn’s disease. Cochrane
Database Syst Rev 2008; (2): CD006792.
Peyrin-Biroulet L, Lemann M. Review
article: remission rates achievable by
current therapies for inflammatory
bowel disease. Aliment Pharmacol Ther
2011; 33: 870–9.
Lichtenstein GR, Hanauer SB, Sandborn
WJ. Management of Crohn’s disease in
adults. Am J Gastroenterol 2009; 104:
465–83.
Prefontaine E, Sutherland LR,
Macdonald JK, Cepoiu M. Azathioprine
or 6-mercaptopurine for maintenance
of remission in Crohn’s disease.
Cochrane Database Syst Rev 2009; (1):
CD000067.
Hyams J, Crandall W, Kugathasan S,
et al. Induction and maintenance
infliximab therapy for the treatment of
moderate-to-severe Crohn’s disease in
children. Gastroenterology 2007; 132:
863–73.
Peyrin-Biroulet L, Deltenre P, de Suray
N, Branche J, Sandborn WJ, Colombel
JF. Efficacy and safety of tumor
necrosis factor antagonists in Crohn’s
disease: meta-analysis of placebocontrolled trials. Clin Gastroenterol
Hepatol 2008; 6: 644–53.
Timmer A, McDonald JWD,
Macdonald JK. Azathioprine and 6mercaptopurine for maintenance of
remission in ulcerative colitis.
Cochrane Database Syst Rev 2007; (1):
CD000478.
Ford AC, Sandborn WJ, Khan KJ,
Hanauer SB, Talley NJ, Moayyedi P.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Efficacy of biological therapies in
inflammatory bowel disease: systematic
review and meta-analysis. Am J
Gastroenterol 2011; 106: 644–59.
Neurath MF. Cytokines in
inflammatory bowel disease. Nat Rev
Immunol 2014; 14: 329–42.
Strober W, Fuss IJ. Proinflammatory
cytokines in the pathogenesis of
inflammatory bowel diseases.
Gastroenterology 2011; 140: 1756–67.
Present DH, Rutgeerts P, Targan S,
et al. Infliximab for the treatment of
fistulas in patients with Crohn’s disease.
N Engl J Med 1999; 340: 1398–405.
Hanauer SB, Feagan BG, Lichtenstein
GR, et al. Maintenance infliximab for
Crohn’s disease: the ACCENT I
randomised trial. Lancet 2002; 359:
1541–9.
Van Dullemen HM, van Deventer SJH,
Hommes DW, et al. Treatment of
Crohn’s disease with anti-tumor
necrosis factor chimeric monoclonal
antibody (cA2). Gastroenterology 1995;
109: 129–35.
Targan SR, Hanauer SB, van Deventer
SJ, et al. A short-term study of
chimeric monoclonal antibody cA2 to
tumor necrosis factor alpha for Crohn’s
disease. Crohn’s Disease cA2 Study
Group. N Engl J Med 1997; 337: 1029–
35.
Kollias G, Douni E, Kassiotis G,
Kontoyiannis D. On the role of tumor
necrosis factor and receptors in models
of multiorgan failure, rheumatoid
arthritis, multiple sclerosis and
inflammatory bowel disease. Immunol
Rev 1999; 169: 175–94.
Frater-Schroder M, Risau W, Hallmann
R, Gautschi P, Bohlen P. Tumor
necrosis factor type alpha, a potent
inhibitor of endothelial cell growth
in vitro, is angiogenic in vivo. Proc Natl
Acad Sci 1987; 84: 5277–81.
Plevy SE, Landers CJ, Prehn J, et al. A
role for TNF-alpha and mucosal T
helper-1 cytokines in the pathogenesis
of Crohn’s disease. J Immunol 1997;
159: 6276–82.
G€
unther C, Martini E, Wittkopf N,
et al. Caspase-8 regulates TNF-ainduced epithelial necroptosis and
13
C. Yang et al.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
14
terminal ileitis. Nature 2011; 477: 335–
9.
Atreya R, Zimmer M, Bartsch B, et al.
Antibodies against tumor necrosis
factor (TNF) induce T-cell apoptosis in
patients with inflammatory bowel
diseases via TNF receptor 2 and
intestinal CD14+ macrophages.
Gastroenterology 2011; 141: 2026–38.
Reinecker HC, Steffen M, Witthoeft T,
et al. Enhanced secretion of tumour
necrosis factor-alpha, IL-6, and IL-1
beta by isolated lamina propria
mononuclear cells from patients with
ulcerative colitis and Crohn’s disease.
Clin Exp Immunol 1993; 94: 174–81.
Breese EJ, Michie CA, Nicholls SW,
et al. Tumor necrosis factor alphaproducing cells in the intestinal mucosa
of children with inflammatory bowel
disease. Gastroenterology 1994; 106:
1455–66.
MacDonald TT, Hutchings P, Choy
MY, Murch S, Cooke A. Tumour
necrosis factor-alpha and interferongamma production measured at the
single cell level in normal and inflamed
human intestine. Clin Exp Immunol
1990; 81: 301–5.
Monteleone G, MacDonald TT.
Manipulation of cytokines in the
management of patients with
inflammatory bowel disease. Ann Med
2000; 32: 552–60.
Koutroubakis IE, Tsiolakidou G,
Karmiris K, Kouroumalis EA. Role of
angiogenesis in inflammatory bowel
disease. Inflamm Bowel Dis 2006; 12:
515–23.
Parronchi P, Romagnani P, Annunziato
F, et al. Type 1 T-helper cell
predominance and interleukin-12
expression in the gut of patients with
Crohn’s disease. Am J Pathol 1997; 150:
823–32.
Breese E, Braegger CP, Corrigan CJ,
Walker-Smith JA, MacDonald TT.
Interleukin-2- and interferon-gammasecreting T cells in normal and diseased
human intestinal mucosa. Immunology
1993; 78: 127–31.
Fuss IJ, Neurath M, Boirivant M, et al.
Disparate CD4+ lamina propria (LP)
lymphokine secretion profiles in
inflammatory bowel disease. Crohn’s
disease LP cells manifest increased
secretion of IFN-gamma, whereas
ulcerative colitis LP cells manifest
increased secretion of IL-5. J Immunol
1996; 157: 1261–70.
Powrie F, Leach MW, Mauze S, Menon
S, Barcomb Caddle L, Coffman RL.
Inhibition of Thl responses prevents
inflammatory bowel disease in scid mice
reconstituted with CD45RBhi CD4+ T
cells. Immunity 1994; 1: 553–62.
43. Mosmann TR, Coffman RL. TH1 and
TH2 cells: different patterns of
lymphokine secretion lead to different
functional properties. Annu Rev
Immunol 1989; 7: 145–73.
44. Su L, Nalle SC, Shen L, et al. TNFR2
activates MLCK-dependent tight
junction dysregulation to cause
apoptosis-mediated barrier loss and
experimental colitis. Gastroenterology
2013; 145: 407–15.
45. Nava P, Koch S, Laukoetter MG, et al.
Interferon-gamma regulates intestinal
epithelial homeostasis through
converging beta-catenin signaling
pathways. Immunity 2010; 32: 392–402.
46. Wang F, Schwarz BT, Graham WV,
et al. IFN-gamma-induced TNFR2
expression is required for TNFdependent intestinal epithelial barrier
dysfunction. Gastroenterology 2006;
131: 1153–63.
47. Moffatt D, Bernstein CN. Chapter 7:
State-of-the-art medical therapy of the
adult patient with IBD: the
immunomodulators. In: Cohen RD, ed.
Inflammatory bowel disease: diagnosis
and therapeutics. 2nd ed. New York:
Humana Press, 2011; 93–110.
48. Tseng S, Pak G, Washenik K, Keltz
Pomeranz M, Shupack JL.
Rediscovering thalidomide: a review of
its mechanism of action, side effects,
and potential uses. J Am Acad
Dermatol 1996; 35: 969–79.
49. Shanbhag PS, Viswanath V, Torsekar
RG. Thalidomide: current status. Indian
J Dermatol Venereol Leprol 2006; 72:
75–80.
50. Moreira AL. Thalidomide exerts its
inhibitory action on tumor necrosis
factor alpha by enhancing mRNA
degradation. J Exp Med 1993; 177:
1675–80.
51. Sampaio EP. Thalidomide selectively
inhibits tumor necrosis factor alpha
production by stimulated human
monocytes. J Exp Med 1991; 173: 699–
703.
52. McHugh SM, Rifkin IR, Deighton J,
et al. The immunosuppressive drug
thalidomide induces T helper cell type
2 (Th2) and concomitantly inhibits Th1
cytokine production in mitogen- and
antigen-stimulated human peripheral
blood mononuclear cell cultures. Clin
Exp Immunol 1995; 99: 160–7.
53. Moller DR, Wysocka M, Greenlee BM,
et al. Inhibition of IL-12 production by
thalidomide. J Immunol 1997; 159:
5157–61.
54. Bousvaros A, Mueller B. Thalidomide
in gastrointestinal disorders. Drugs
2001; 61: 777–87.
55. Bujanover Y, Weiss B. Anti-tumor
necrosis factor therapy for pediatric
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
inflammatory bowel diseases. Isr Med
Assoc J 2008; 10: 634–9.
D’Amato RJ, Loughnan MS, Flynn E,
Folkman J. Thalidomide is an inhibitor
of angiogenesis. Proc Natl Acad Sci
USA 1994; 91: 4082–5.
Ginsburg PM, Dassopoulos T,
Ehrenpreis ED. Thalidomide treatment
for refractory Crohn’s disease: a review
of the history, pharmacological
mechanisms and clinical literature. Ann
Med 2001; 33: 516–25.
Segarra M, Lozano E, Corbera-Bellalta
M, et al. Thalidomide decreases
gelatinase production by malignant B
lymphoid cell lines through disruption
of multiple integrin-mediated signaling
pathways. Haematologica 2010; 95:
456–63.
Keifer JA, Guttridge DC, Ashburner
BP, Baldwin AS Jr. Inhibition of NF-kB
activity by thalidomide through
suppression of IkB kinase activity. J
Biol Chem 2001; 276: 22382–7.
Rafiee P, Stein DJ, Nelson VM,
Otterson MF, Shaker R, Binion DG.
Thalidomide inhibits inflammatory and
angiogenic activation of human
intestinal microvascular endothelial cells
(HIMEC). Am J Physiol Gastrointest
Liver Physiol 2010; 298: G167–76.
Folkman J. Angiogenesis in cancer,
vascular, rheumatoid and other disease.
Nat Med 1995; 1: 27–31.
Lienenluke B, Stojanovic T, Fiebig T,
et al. Thalidomide impairment of
trinitrobenzene sulphonic acid-induced
colitis in the rat-role of endothelial cellleukocyte interaction. Br J Pharmacol
2001; 133: 1414–23.
Higgins J, Altman D, Sterne J. Chapter
8: Assessing risk of bias in included
studies. In: Higgins JPT, Green S, eds.
Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0
(updated March 2011). The Cochrane
Collaboration, 2011. Available at: http://
www.cochrane-handbook.org
Wells G, Shea B, O’connel D, et al. The
Newcastle-Ottawa Scale (NOS) for
assessing the quality of nonrandomised
studies in meta-analyses. Canada:
Department of Epidemilogy and
Community Medicine, University of
Ottawa, http://www.ohri.ca/programs/
clinical_epidemiology/oxford.asp.
National Institute for Health and
Clinical Excellence (NICE). Quality
assessment for case series. Available at:
http://www.nice.org.uk/guidance/cg3/
resources/appendix-4-quality-of-caseseries-form2 (accessed 20 Septemer
2014).
Bauditz J, Wedel S, Lochs H.
Thalidomide reduces tumour necrosis
factor a and interleukin 12 production
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
Systematic review: thalidomide in IBD
67.
68.
69.
70.
71.
72.
in patients with chronic active Crohn’s
disease. Gut 2002; 50: 196–200.
Ehrenpreis ED, Kane SV, Cohen LB,
Cohen RD, Hanauer SB. Thalidomide
therapy for patients with refractory
Crohn’s disease: an open-label trial.
Gastroenterology 1999; 117: 1271–7.
Facchini S, Candusso M, Martelossi S,
Liubich M, Panfili E, Ventura A.
Efficacy of long-term treatment with
thalidomide in children and young
adults with Crohn disease: preliminary
results. J Pediatr Gastroenterol Nutr
2001; 32: 178–81.
Felipez LM, Gokhale R, Tierney MP,
Kirschner BS. Thalidomide use and
outcomes in pediatric patients with
Crohn disease refractory to infliximab
and adalimumab. J Pediatr
Gastroenterol Nutr 2012; 54: 28–33.
Lazzerini M, Martelossi S, Marchetti F,
et al. Efficacy and safety of thalidomide
in children and young adults with
intractable inflammatory bowel disease:
long-term results. Aliment Pharmacol
Ther 2007; 25: 419–27.
Lazzerini M, Martelossi S, Magazzu G,
et al. Effect of thalidomide on clinical
remission in children and adolescents
with refractory Crohn disease: a
randomized clinical trial. JAMA 2013;
310: 2164–73.
Mansfield JC, Parkes M, Hawthorne
AB, et al. A randomized, double-blind,
Aliment Pharmacol Ther
ª 2015 John Wiley & Sons Ltd
73.
74.
75.
76.
77.
placebo-controlled trial of
lenalidomide in the treatment of
moderately severe active Crohn’s
disease. Aliment Pharmacol Ther 2007;
26: 421–30.
Ng SC, Plamondon S, Gupta A, et al.
Prospective evaluation of anti-tumor
necrosis factor therapy guided by
magnetic resonance imaging for
Crohn’s perineal fistulas. Am J
Gastroenterol 2009; 104: 2973–86.
Plamondon S, Ng SC, Kamm MA.
Thalidomide in luminal and fistulizing
Crohn’s disease resistant to standard
therapies. Aliment Pharmacol Ther
2007; 25: 557–67.
Sabate JM, Villarejo J, Lemann M,
Bonnet J, Allez M, Modigliani R. An
open-label study of thalidomide for
maintenance therapy in responders to
infliximab in chronically active and
fistulizing refractory Crohn’s disease.
Aliment Pharmacol Ther 2002; 16:
1117–24.
Vasiliauskas EA, Kam LY, AbreuMartin MT, et al. An open-label pilot
study of low-dose thalidomide in
chronically active, steroid-dependent
Crohn’s disease. Gastroenterology 1999;
117: 1278–87.
Zheng CF, Xu JH, Huang Y, Leung YK.
Treatment of pediatric refractory
Crohn’s disease with thalidomide. World
J Gastroenterol 2011; 17: 1286–91.
78. Morawska M, Grzasko N, Kostyra M,
Wojciechowicz J, Hus M. Therapyrelated peripheral neuropathy in
multiple myeloma patients. Hematol
Oncol 2014; doi:10.1002/hon.2149
[Epub ahead of print].
79. Ghobrial IM, Rajkumar SV.
Management of thalidomide toxicity. J
Support Oncol 2003; 1: 194–205.
80. Fernyhough P, Smith DR, Schapansky
J, et al. Activation of nuclear factorkappaB via endogenous tumor necrosis
factor alpha regulates survival of
axotomized adult sensory neurons. J
Neurosci 2005; 25: 1682–90.
81. Su C, Lichtenstein GR, Krok K,
Brensinger CM, Lewis JD. A metaanalysis of the placebo rates of
remission and response in clinical trials
of active crohn’s disease.
Gastroenterology 2004; 126: 1257–69.
82. Srinivasan R, Akobeng AK.
Thalidomide and thalidomide analogues
for induction of remission in Crohn’s
disease. Cochrane Database Syst Rev
2009; (2): CD007350.
83. Akobeng AK, Stokkers PC.
Thalidomide and thalidomide analogues
for maintenance of remission in
Crohn’s disease. Cochrane Database
Syst Rev 2009; (2): CD007351.
84. El-Matary W. Use of placebo in a trial
of thalidomide for pediatric Crohn
disease. JAMA 2014; 311: 1251.
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