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 [email protected]
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
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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
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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.
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