Journal of Crohn's and Colitis (2008) 2, 304–309
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
Occurrence of demyelinating diseases after
anti-TNFα treatment of inflammatory bowel disease:
A Danish Crohn Colitis Database study☆
Nynne Nyboe Andersena , Sarah Caspersena , Tine Jessb , Pia Munkholma,⁎
a
b
Department of Medical Gastroenterology C, Herlev University Hospital, Denmark
Institute of Preventive Medicine, Copenhagen University Hospital, Denmark
Received 10 March 2008; accepted 28 April 2008
KEYWORDS
Inflammatory bowel
disease;
Demyelinating disease;
Anti–TNFα;
treatment
Abstract
Introduction: It remains uncertain whether patients with inflammatory bowel disease (IBD) are
at increased risk of developing demyelinating diseases, primarily multiple sclerosis (MS) and
whether the introduction of biologic drugs in the treatment of IBD has altered this risk.
Aim and methods: The aim was to conduct a systematic review of literature on occurrence of
demyelinating diseases in IBD patients, to assess a national Danish anti-TNFα treated IBD cohort
in order to search for and describe the IBD cases with coexisting demyelinating diseases, and
finally to compare the occurrence of MS in the anti-TNFα cohort to the occurrence in the general
Danish population.
A systematic MEDLINE literature search was conducted, medical files were scrutinized for
identification and description of cohort patients with demyelinating disease, and risk of MS was
calculated as a standardized morbidity ratio (SMR) using general population data for comparison.
Results: Four studies on the risk of demyelinating diseases in IBD were identified. One study
revealed an observed prevalence of MS at onset of IBD at 3.7 times the expected (95% CI, 0.8–
10.8). In the Danish anti-TNFα IBD cohort, 4 out of 651 patients developed demyelinating
disorders after anti-TNFα treatment. The SMR for developing MS among Danish IBD patients
treated with anti-TNFα was 4.2 (95% CI, 0.1–23.0).
Conclusion: The literature review revealed an up to four-fold increased risk of demyelinating
diseases, in particular MS, in IBD patients in general. The risk of developing MS in the anti-TNFα
treated Danish cohort did apparently not exceed this risk.
© 2008 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
Abbreviations: IBD, inflammatory bowel disease; CD, Crohn's disease; UC, ulcerative colitis; MS, multiple sclerosis; SMR, standardized
morbidity ratio; PML, progressive multifocal leukoencephalopathy; RA, rheumatoid arthritis; ON, optic neuritis.
☆
This paper was presented at UEGW 2006, Gut 2006 abstract number A109.
⁎ Corresponding author. Department of Medical Gastroenterology C, Herlev University Hospital, 75 Herlev Ringvej, DK-2730 Herlev, Denmark.
Tel.: +45 44 88 37 92.
E-mail address: [email protected] (P. Munkholm).
1873-9946/$ - see front matter © 2008 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.crohns.2008.04.001
Occurrence of demyelinating diseases after anti-TNFα treatment of inflammatory bowel disease
1. Introduction
2. Materials and methods
The inflammatory bowel diseases (IBD), ulcerative colitis (UC)
and Crohn's disease (CD) are chronic intestinal diseases of
unknown origin, often categorized as autoimmune diseases.
The aetiology of IBD remains unknown and consequently
treatment is based on empirical features with the primary
purpose of inducing and maintaining remission. New biological therapies such as the tumor necrosis factor α (TNFα)
blocker infliximab (REMICADE) have shown efficacy in severe
and fistulizing CD1,2 as well as in UC.3 TNFα is a cytokine
released by activated monocytes, macrophages, and Tlymphocytes. It is involved in several processes, but plays
an important role particularly in inflammation. Several
direct side effects of infliximab treatment including an
increased risk of infections, lymphomas and demyelinating
diseases have been suggested,4–10 but still a profound
experience of the long-term outcome of infliximab treatment remains unknown. In addition to infliximab, the
biological drug adalimumab (HUMIRA) has been approved
for CD by the American Food and Drug Administration (FDA)
in February 200711 and subsequently by EMEA (European
Agency for the Evaluation of Medicinal Products) in May
whereas the approval of certolizumab (CIMZIA) is still
awaited. Another biological drug, natalizumab (ANTEGREN)
was originally approved for CD but in 2005 the drug was
suspended by the Adverse Event Reporting System (AERS) due
to three side events reports of progressive multifocal
leukoencephalopathy (PML), a usually fatal demyelinating
disease caused by the JC virus.12 A follow-up study with more
than 3000 patients treated with natalizumab found no
additional cases of PML13 but The EMEA has finally not
approved natalizumab for CD in Europe whereas the decision
from FDA is still awaited. Infliximab is currently by far the
most utilized biological drug in the treatment of Danish IBD
patients and when referring to anti-TNFα in the present
study, it primarily refers to infliximab.
Demyelinating diseases are characterized by inflammation and focal destruction of the myelin sheets in the white
matter of the central nervous system (CNS), which ultimately
can lead to complete block of the nerve signal. The most
common demyelinating disease is multiple sclerosis (MS) and
others to be mentioned are optic neuritis, which can be a
pre-state to MS, progressive multifocal leukoencephalopathy
(PML) and Guillain–Barré syndrome.14
It has been suggested that patients with IBD have a higher
risk of demyelinating diseases than the general population
and that treatment with infliximab and other new biological
therapies may add further to this potentially increased risk.
In a recent study of a population-based national cohort of 651
consecutive Danish IBD patients receiving anti-TNFα treatment during 1999–2005, four cases of possible or certain
multiple sclerosis were observed.15
The aim of the present study was 1) to conduct a systematic review of literature on occurrence of demyelinating
diseases, in particular MS, developed spontaneously or as a
consequence of treatment with biological therapies in
patients with IBD 2) to assess the national Danish anti-TNFα
IBD cohort in order to further describe the four IBD demyelinating diseases cases and 3) to compare the specific
occurrence of MS in the anti-TNFα cohort to the occurrence
in the general Danish population.
2.1. Literature search
305
In order to identify all papers – in English or other European
languages – regarding occurrence of demyelinating disease
in patients with IBD treated or not treated with anti-TNFα
drugs, we conducted a systematic MEDLINE search (1966–
2006) using the terms ‘inflammatory bowel disease AND
demyelinating diseases’ and ‘demyelinating diseases AND
TNFα therapy’ with the following limitations: only items with
abstracts and studies of humans. Lastly, reference lists of all
included papers were scrutinized to disclose additional
literature on the topic.
2.2. Cases from the Danish anti-TNFα IBD cohort
Medical records of patients with a possible or certain
diagnosis of demyelinating disease from the national Danish
anti-TNFα database (1999–2005) were scrutinized for additional clinical information.
2.3. Statistics
The standardized morbidity ratio (SMR) for occurrence of MS
was calculated as the observed number of cases in the Danish
IBD-anti-TNFα cohort divided by the expected number in the
general Danish population. The expected number was
estimated by use of age- and sex-specific incidence rates
of MS in the general population (the Danish Multiple Scleroses
Register16) and age- and gender specific person-years at risk
in the IBD-anti-TNFα cohort (Danish Crohn Colitis Database14). Under the assumption of a Poisson distribution of
observed cases, a 95% confidence interval (CI) for the SMR
was calculated.
3. Results
3.1. Systematic review of demyelinating diseases in
IBD
A total of nine papers concerning the association between
IBD and demyelinating diseases were identified, two population-based studies,17,18 two referral-centers studies,19,20
and five case-reports.4–9 Of these, four studies concerning
the risk of demyelinating disease in IBD patients not treated
with infliximab or other biological therapies were identified
(Table 1). The oldest study from 1982 by Rang et al., reported
10 cases of MS among 2261 female UC patients from the
register of the Ileostomy Association in England, followed
from 1944 until 1979. The incidence was three times that of
the normal population.19
Another population-based study, from Olmsted County,
Minnesota, found four cases of MS in a population of 474 IBD
patients from The Rochester Epidemiology Project Database,
diagnosed between 1950 and 1995.17 The observed prevalence of MS at onset of IBD was 3.7 times the expected
(95% confidence interval, 0.8–10.8). The four patients had
been treated with either sulfasalazine or prednisone and
mercaptopurine.
306
N.N. Andersen et al.
Table 1 Identified international literature on occurrence of demyelinating diseases in patients with inflammatory bowel disease,
not treated with infliximab or other biological therapies
First author,
publication year
Patient
population
IBD
No of
No of cases with
Risk estimates
subtype patients (CD/UC) demyelinating disorders
Rang EH.
The Lancet 198219
Kimura K. Mayo
Clinical Proc 200017
Bernstein CN
Gastroenterology
200518
Gupta G.
Gastroenterology
200520
Ileostomy
register
Populationbased cohort
Populationbased cohort
UC
2261
10 (all MS)
Incidence: 3-fold increased
UC/CD
474 a
4 (MS)
UC/CD
4193/3879
38 (MS)
7988/12.185
60 (MS, ON, D)
Prevalence risk: 3.7
(95% CI, 0.8–10.8)
Prevalence risk: UC: 1.90
(95% CI, 1.19–3.03) CD: 1.11
(95% CI: 0.67–1.84)
Odds ratio: UC: 1.75
(95% CI, 1.28–2.39) CD: 1.54
(95% CI, 1.03–2.32)
General practitioner UC/CD
database
Abbreviations: CD, Crohn's disease; UC, Ulcerative colitis; MS, Multiple sclerosis; ON, Optic neuritis; D, Demyelinating.
a
The fraction of CD and UC patients was not informed.
The third study was a population-based study from Canada
by Bernstein et al. running from 1984 to 2003 who reported a
significantly increased risk of developing MS among 3879
patients with UC compared to controls, but not among 4193
patients with CD, unless less strict diagnostic criteria were
used.18 The Prevalence Risk (PR) for UC patients compared to
the control group was 1.81 (95% CI: 1.3–2.42), for CD patients
this risk was 1.69 (95% CI: 1.31–2.19). Using stricter
diagnostically criteria the PR for UC patients was 1.90 (95%
CI: 1.19–3.03) compared to a non-statistical significant PR of
1.11 (95% CI: 0.67–1.84) for CD patients.
The fourth and largest trial was published in 2005 by
Gupta et al. and concerned 20,000 British IBD patients
matched with 80,000 healthy controls from the General
Practice Research Database (GPRD).20 The relative odds of
being diagnosed with MS, optic neuritis or other demyelinating diseases in patients with CD and UC as compared with
matched controls were 1.54 (95% CI, 1.03–2.32) and 1.75
(95% CI, 1.28–2.39), respectively.
The systematic literature search also identified five case
reports in which CD patients treated with infliximab were
diagnosed with either MS4,7,8 or optic neuritis.5,10 Table 2
summarizes these case reports.
3.2. Demyelinating diseases in the Danish antiTNFα treated IBD cohort
3.2.2. The 2nd patient
A 42-year old male was diagnosed with Crohn's disease in
2003 after a history of tendency to anal abscesses and fistulas
during the past 2 years. In September 2004, infliximab
treatment was initiated based on clinical and endoscopically
findings, frequent relapsing fistulas and intolerability to
conventional therapy. In April 2005 the 5th infliximab
infusion was given and in May 2005 the patient developed
paraesthesis on the left forefoot. Infliximab therapy was
stopped and complete neurological restitution was obtained.
No further neurological examination was made.
3.2.3. The 3rd patient
A 46-year old male was diagnosed with Crohn's disease in
1999 and infliximab therapy was initiated in December 2002.
After the 4th infusion in May 2003, weakness developed in
both lower limbs combined with muscle pain. A neurological
examination and muscle biopsy verified a minor atrophy
caused by neurogenic factors and infliximab therapy
was stopped. After 3 months, neurological restitution slowly
began.
3.2.4. The 4th patient
A 38-year old female was diagnosed with Crohn's disease in
2001. After treatment with conventional therapy infliximab
treatment was initiated in January 2004. Infliximab was
given every 8 weeks with promising efficacy. In 2005, the
patient developed paraesthesis in both hands starting after
each infliximab infusion and persisting for a couple of days.
However, a following MRI, EMG and neurological examination showed no abnormalities.
As described initially, four patients were suspected for
having developed a demyelinating disorder secondary to
treatment with anti-TNFα drugs in a population-based
national Danish cohort of 651 adults and children with IBD
treated and followed during 1999–2005.15 The four cases are
described in detail in the following.
3.3. Risk of multiple sclerosis in the Danish cohort
3.2.1. The 1st patient
A 29-year old female was diagnosed with Crohn's disease in
2001. The patient had 3 infliximab infusions during year 2002
and adalimumab 80 + 40 mg in March 2004. One week after
the first adalimumab injection the patient developed
sensibilities disturbances and weakness in the left leg. Four
weeks after treatment with adalimumab, multiple sclerosis
was diagnosed verified by MRI, EMG and lumbar puncture.
As it appears from above, a diagnosis of MS was only
confirmed in one of the 651 patients receiving anti-TNFα
treatment (0.15%) who were followed for a total of 2009
person-years post-treatment. Correlated for age and sex,
the expected number of MS cases during the period of
observation was 0.11 for men and 0.13 for women or a total
of 0.24. In consequence, the SMR for developing MS among
Danish IBD patients treated with anti-TNFα medications was
Occurrence of demyelinating diseases after anti-TNFα treatment of inflammatory bowel disease
Table 2
Case reports on demyelinating events in Crohn’s disease patients treated with infliximab
Author
Disease/
age/sex
Treatment
Thomas
et al.4
CD/19/
female
Mejico
et al.5
CD/50/
female
Cortocosteroids Right arm and leg
azathioprine
numbness and right
infliximab
hand weakness/MS
like syndrome
Infliximab
Optic neuritis
Dubcenco CD/46/male
et al.7
Freeman
et al.8
CD and AS/
18/female
Strong
CD, NIDDM,
et al.10 bell palsy,
non-granulo
matous
uveitis/46/
female
Cortocosteroids
azathioprine
methotrexate
infliximab
Infliximab
Cortocosteroids
mesalasine
azathioprine
infliximab
Neurological
symptoms/
diagnosis
Numbness and
weakness in his right
hand and foot/
inflammatory
demyelinating
polyneuropathy
Neurological
symptoms
Examinations
Temporal
relationship
Neurological
examination and
MRI
307
History of
Out-come
neurological
disorders
Neurological
symptoms
after one
infusion
MRI
Neurological
symptoms
three weeks
after her last
infusion
Neurological
Neurological
examination, MRI, symptoms
electromyography after nine
and nerve
infusions
conduction
None
None
Complete
recovery
Neurological
examination and
MRI
None
Neurological
symptoms
and MRI
changes
persisted
Three
months later
she regained
her normal
vision
Pain and blurred
Ophthalmoscopic
vision in the left eye/ examination and
retrobulbar optic
MRI
neuritis
Neurological
symptoms
after
multiple
infusions
Neurological
symptoms
one weeks
after her
seventh
infusion
Not
informed
Bells palsy
Follow-up
revealed
symptomatic
improvement
Complete
recovery
Abbreviations: CD, Crohn's disease; AS, ankylosing spondylitis; NIDDM, non-insulin dependent diabetes mellitus; MRI, Magnetic resonance
imaging.
four-fold increased, but the result did not reach statistical
significance (SMR, 4.2; 95% CI, 0.1–23.0).
4. Discussion
The present literature review and cohort study revealed an
up to four-fold increased risk of demyelinating diseases in
patients with IBD independent of medical treatment. Only
case-reports on demyelinating diseases occurring in IBD
patients second to anti-TNFα treatment were available.
Assessment of the population-based national Danish IBD
cohort treated with anti-TNFα also showed a four-fold, but
not significantly increased risk of MS when compared to the
general Danish population.
The main strength of this study was the use of data from
the Danish Crohn Colitis Database (DCCD). Due to free access
to health care in Denmark and thorough registration of
citizens, all patients treated with biological drugs can be
identified. Detailed clinical information was available on
97,2% of IBD patients treated with infliximab in Denmark in
the period 1999–2005.15 Likewise, national data on occurrence of MS were available. A limitation of the present study
was that the size of the Danish anti-TNFα cohort limited the
accuracy of the risk estimate. Also, it would have been of
interest to compare occurrence of MS in the anti-TNFα group
with occurrence in an age-, gender- and disease severity
matched group of IBD patients not receiving biological
agents, but such data were not available.
Due to common genetic susceptibility for various autoimmune disorders like IBD and MS, it has been suggested that
these diseases share common cause21 and in spite of the
different clinical manifestations, IBD and MS share many
common features. Both diseases predominantly affect young
people, occur more often in western and northern latitudes
and are significantly affected by environmental susceptibility factors.22,23 It is therefore reasonably to consider a
pathologically, common underlying mechanism for both
diseases. If the risk of demyelinating disease in IBD patients
is increased it could suggest a common genetic predisposition, common causative triggers, or possibly the triggering of
one inflammatory condition secondary to the treatment of a
primary inflammatory condition.
The results of the four available international studies on
demyelinating diseases in IBD not treated with anti-TNFα
drugs all suggested a more or less pronounced increased risk
of developing demyelinating diseases among patients with
IBD.17–20 The largest risk was observed in Olmsted County
with a 3.7-fold increased risk of MS among patients with IBD
as compared with the background population. The studies
also revealed a higher risk of demyelinating disorders in UC
patients than in CD patients.
Biological drugs have changed and revolutionized the
approach towards treating IBD, particular infliximab which is
308
now the preferred biological treatment of patients with
severe IBD. The temporal relationship between anti-TNFα
treatment and a demyelinating event with complete resolution following discontinuation of the drug suggested a causal
link between treatment and development of neurological
complication in the four Danish cases and the five international case reports.
The single confirmed case of MS in the Danish anti-TNFα
Database, 1999–2005, should be compared to an expected
number of 0.24 MS according to the Danish MS registry 1948–
2000,16 yielding a four-fold increased risk of developing MS
among Danish IBD patients post-treatment with anti-TNFα
drugs, but confidence intervals were wide (SMR, 4.2; 95% CI,
0.1–23.0). Three additional cases had neurological symptoms after treatment with infliximab but all regained their
neurological function following discontinuation of the drug.
This could indicate that infliximab could cause transient and
reversible neurological disturbances. We do not know
whether the neurological symptoms is due to the treatment
or the possibility that the majority of the infliximab-associated demyelinating processes represent exacerbation of
a preexisting state of early or established MS, especially in
light of the fact, that the risk of MS is already known to
be increased in patients with IBD independent of treatment
and that the incidence of MS is generally increasing in the
western countries.23
Since CD patients treated with biologics assumingly have a
more aggressive disease cause than patients not requiring
such treatment, one could speculate, that the first group of
patients also have a greater risk of developing demyelinating
disorders or other immune dysfunctions disorders compared
to the latter group. Along with this, one could hypothesize
that the incidence of demyelinating diseases in the group of
CD patients receiving anti-TNFα treatment would have
been the same if they had not received such treatment.
Anti-TNFα drugs may then tend to unmask a latent demyelinating disease.
On the other hand, if demyelinating diseases are truly
caused by anti-TNFα treatment, then the underlying
mechanism needs to be identified. Given the anti-inflammatory effect of anti-TNFα it has been tested as possible
treatment for MS and interestingly there is evidence that
anti-TNFα in fact causes exacerbation of MS and do not have
the expected positive influence.24 This point towards the
fact that TNFα has a different role in the pathogenesis of MS
compared to other autoimmune disorders. Several theories
have been proposed to explain a potential biologic relationship between TNFα neutralization and demyelinating
processes:25
1) The lack of entry hypothesis: a speculative mechanism
where the anti-TNFα increases the disease activity by
increasing the amount and the activity of the peripheral
auto reactive T cells.
2) The TNFα gradient hypothesis: it is possible that the antiTNFα binds the TNFα in the systemic circuit, thus decreasing the unbound amount of TNFα in the blood. This
could result in a withdrawal of TNFα in the restricted
tissue and thereby have an influence in the pathogenesis
of CD and RA. The exacerbation observed in MS could then
be explained by the transformed gradient of TNFα on each
side of the blood-brain barrier. The gradient transforma-
N.N. Andersen et al.
tion could, by unknown mechanisms result in an up rating
of TNFα whereby the inflammation and thus demyelisation would intensify.
3) The TNFα brain function hypothesis: The effects of TNFα
are not proper clarified and it is a possibility that TNFα
has another or a broader function in the brain compared
to the rest of the body.
4) The infection hypothesis: It is likely that treatment with
anti-TNFα could provoke an infection that normally would
have been in a latent state, as in latent TB. This infection
could afterwards aggravate the inflammatory process.
Any of these theories could explain a biological relationship between infliximab and demyelinating processes and
further research on this topic is required.
In our international literature search on development of
demyelinating disease after treatment with biological drugs
among patients with IBD, no cohort studies were identified.
A number of case reports, on the other hand, reported
occurrence of neurological disorders second to treatment
with infliximab but not with other biological drugs such as
adalimumab or certolizumab. We did, however, identify two
cases of demyelinating disease in patients with rheumatoid
arthritis treated with adalimumab.26,27 It is interesting that
not only infliximab but also other biological drugs as
adalimumab and natalizumab seems to be able to generate
demyelinating disease in patients receiving these drugs, and
accordingly, the Danish CD patient who was diagnosed with
MS had received both infliximab and adalimumab.
Demyelinating events have also been recognized in patients
with rheumatoid arthritis treated with infliximab and etanercept, a TNFα blocker not approved for CD, and the Adverse
Events Reporting System FDA database reported 19 cases of
demyelinating events in RA patients treated with infliximab2
and etanercept.17,28 In these cases all the neurological events
where temporally related to the anti-TNFα therapy and partial
or complete resolution occurred on drug discontinuation. One
patient revealed a positive rechallenge phenomenon, i.e. the
patient developed neurological problems with therapy, symptoms resolved when therapy was stopped and returned when
therapy was restarted.28
Additionally, 68 patients with either CD, rheumatoid
arthritis, psoriatic arthritis or ankylosing spondylitis were
registered in FDA as having developed demyelinating
disorders following treatment with infliximab.11 Because of
the considerable expand in the use of biological drugs, the
increasing focus on patients safety, and the relatively
inadequately knowledge of the long-term outcome after
such treatment, it is of great importance to continue the
constant control and search for potential treatment related
adverse events including demyelinating diseases. It is
important to keep in mind that anti-TNFα drugs and other
new biological therapies have revolutionized the ability to
treat CD patients with a severe and aggressive disease course
and that these benefits have to be held against the risk of
adverse events. Also to be taken into consideration, our
literature review suggests, that demyelinating disorders,
especially MS, occur with increased frequency in IBD patients
independent of treatment and further studies addressing this
question are warranted.
Overall, anti-TNFα treatment should be used with
precaution or simply avoided in patients with a history of
Occurrence of demyelinating diseases after anti-TNFα treatment of inflammatory bowel disease
demyelinating disease and should be withdrawn in patients
who develops neurological symptoms during treatment.
Acknowledgements
The authors would like to thank the Danish Crohn Colitis
Database (DCCD) group. A special thank to Magarita Elkjær
(Herlev Hospital), Natalia Pedersen (Herlev Hospital), Tine
Priø (Bispebjerg hospital), Else Philipsen (Bispebjerg Hospital), Jørgen Agnholt (Aarhus Hospital) and Jens Dahlerup
(Aarhus Hospital) for helping in the collection of data.
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