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NR 10-12/2007
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Monoclonal anti-TNFα
antibody (infliximab) in the treatment of patient with thyroid
associated ophthalmopathy
Zastosowanie przeciwciał
anti-TNFα (infliximab) w leczeniu chorej z oftalmopatią
tarczycową
Jan Komorowski1, Joanna
Jankiewicz-Wika1, Agnieszka Siejka1, Hanna
Ławnicka2, Anna Kłysik3, Roman Goś3,
Agata Majos4, Ludomir Stefańczyk4, Henryk
Stępień2
1 Department of Clinical Endocrinology , Medical
University of Łódź, Poland. Head: Professor Jan Komorowski, MD,
PhD
2 Department of Clinical Immunoendocrinology ,
Medical University of Łódź, Poland. Head: Professor Henryk
Stępień, MD, PhD
3 Department of Clinical Ophthalmology , Medical
University of Łódź, Poland. Head: Professor Roman Goś, MD, PhD
4 Department of Radiology, Medical University of
Łódź, Poland. Head: Professor Ludomir Stefańczyk, MD, PhD |
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| Summary: |
TNFα (tumor necrosis
factor alpha) plays a central role in the development of
thyroid associated ophthalmopathy (TAO). We describe and
document by ophthalmic (CAS and NO SPECS scales) and
radiological (MRI) evaluation a positive effect of
anti-TNFα antibody (infliximab) administration on active
TAO in a 58 years old woman with Graves’ disease. The
single dose of infliximab administration resulted in a
dramatic reduction of inflammation studies and
improvement of visual function as measured by MRI and
CAS and NO SPECS scales, without noticeable short-term
side effects. A randomized prospective study is needed
to determine whether infliximab proves to be
sufficiently effective in reducing the inflammatory
symptoms of TAO, and whether it can be administered
safely for a prolonged period without side effects. |
| Słowa kluczowe: |
TNFα, anty-TNFα,
oftalmopatia Graves’a. |
| Key words: |
TNFα, anti-TNFα, Graves’
ophthalmopathy. |
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Introduction
Graves’ ophthalmopathy or thyroid associated ophthalmopathy
(TAO) is an autoimmune disease of the orbit involving both the
retroorbital connective tissue and the extraocular muscles, but
the exact mechanism of the pathogenesis is still unknown (1).
TAO is the most common cause of proptosis in adults and occurs
in about 45% of patients with Graves’ disease (2). Examination
of retroorbital tissues in the initial inflammatory phase of TAO
reveals an accumulation of hydrophilic glycosaminoglycans,
increased fat volume, marked T and B lymphocytic infiltration,
and presence of many pro-inflammatory cytokines and growth
factors. Serum levels of pro-inflammatory cytokines released
from T and B lymphocytes (IFNγ, IL-1β, IL-2, sIL-2R TNFα, IL-6)
and antibodies of TSH receptor (TRAb) secreted from B
lymphocytes are markers of the immune system activity (3,4).
TRAb antibodies are thought to stimulate orbital fibroblasts to
produce hydrophilic glycosaminoglycans and cause proliferation
of adipocytes (4). Several studies suggest a fundamental role
for TNFα in the acute phase of TAO with elevated levels of TNFα
in orbital tissues and serum (2,3,4).
In the acute phase of TAO, oral (prednisone, dexamethasone) or
intravenous corticosteroids (methylprednisolone) are the
mainstay of immunomodulatory treatment but side effects limit
their long-term use, and up to 35% of patients fail to respond
(5, 6). The antioxidants, somatostatin analogs, orbital
radiotherapy, orbital decompression are also used in the
treatment of TAO in selected patients with severe disease, but
results obtained with these treatment are often unsatisfactory.
Recently it has been focused on the rationale for B lymphocyte
depletion therapy in TAO using monoclonal anti-CD20 antibody
therapy with rituximab (7,8). Therefore, the anticytokine
therapy may also offer novel method of TAO treatment that
targets the molecules involved in establishing and propagating
orbital inflammation (2,9).
Aim
The aim of this pilot study was to present a patient with the
acute phase of thyroid associated ophthalmopathy treated by
infliximab (an anti-tumor necrosis factor alpha antibody).
This study was approved by the Local Ethical Committee of the
Medical University of Lódź and accepted by a patient.
Material, methods and results
CASE REPORT
A 58-year-old female was referred to the Department of Clinical
Endocrinology at the Medical University of Lodz with active TAO
and mild hypertension (150/80 mm Hg) on April 15, 2006.
Previously (October 15, 2005), she had been diagnosed as having
hyperthyroid Graves’ disease (without active TAO) and treated in
another hospital with 18 mCi 131I followed by
30 mg of prednisone daily for six weeks.
At the time of the admission to the Department of Clinical
Endocrinology she was euthyroid with signs of active TAO (with
increased blood concentrations of anti-TSH and anti-TPO
antibodies) and, being on 50 μg of L-thyroxine daily
substitution.
Medication: The patient received infliximab (Remicade,
Schering-Plough – a chimeric human-mouse anti-TNFα – monoclonal
antibody IgG1) as i.v. infusion in a one single dose of 300 mg
(3.7 mg per kg body weight, administered during 2 hrs) after
premedication with paracetamol 1g p.o. (60 min. before infusion
of infliximab). Before (I), 5 days (II), 5 weeks (III), as well
as 10 weeks (IV) after the treatment the biochemical, ophthalmic
(with NO SPECS and CAS scale) and radiological (MRI)
examinations were performed.
Ophthalmic examination
Full ophthalmic evaluation was performed before the beginning of
the treatment with infliximab, and also 5 days, 5 weeks and 10
weeks following the treatment (Table I). Additional
investigations included visual evoked responses and visual field
analysis.
The patient presented with 3-month history of progressively
increasing ophthalmic symptoms. She complained of pain and
burning sensation around the eyes as well as constant double
vision. The examination revealed signs of inflammatory thyroid
associated ophthalmopathy. There was a marked lid lag and lid
retraction, as well as lid and conjunctival oedema and redness.
Visual acuities were reduced by two Snellen lines, and pupillary
reactions including Relative Afferent Pupillary Defect (RAPD)
were normal. Exophthalmometry readings were 25 and 26 mm,
respectively. NO SPECS scale (5) was 12c3b4b for both eyes.
Clinical Activity Score (CAS) (5) was 6 points for the right and
7 points for the left eye. Ocular motility function was severely
compromised in all directions of gaze, but in particular for
abduction and elevation for both vergences and ductions in both
eyes. The patient complained of severe constant vertical double
vision. There were 16 prism dioptres right over left hypertrophy.
Visual fields were normal. Fundoscopy revealed no papilloedema.
We performed visual evoked potentials analysis to exclude optic
nerve involvement. We obtained normal pattern and flash
responses. Slight reduction of best corrected visual acuity to
the level of 0.8 was attributed to corneal tear film disturbance
and irregular astigmatism caused by marked proptosis.
Ophthalmic evaluation was repeated 5 days after infliximab
infusion. The patient’s inflammatory symptoms increased slightly
with CAS scores 6 and 8 points. There were no significant
changes in any other symptoms. There was still pain, ocular
discomfort, and burning sensation around the eyes. Double vision
persisted accompanied by increased comparable restriction of
ocular motility.
Five weeks following infliximab infusion there was a significant
reduction in inflammatory signs and CAS score decreased to 3
points for both eyes. Subjectively, there was an improvement in
pain and burning sensation. Redness and swelling of the eyelids
and conjunctiva were no more noticeable. Visual acuities
improved although reduction of eye movements, double vision and
exophthalmos (23 and 25 mm) persisted. Vertical double vision
was accompanied by 16 prism dioptries right over left
hypertropia. NO SPECS score also improved, exept for increased
restriction of ocular movements and was 12a3a4c for the right
eye and 12a3b4c for the left. Ocular motility was decreased
compared to initial examination, in spite of the marked
reduction of all the inflammatory symptoms and exophthalmos. The
above finding was attributed to increased fibrotic process of
the extraocular muscles.
Ten weeks following infliximab infusion the patient was free
from ocular pain and discomfort. She had moderate eyelid oedema
but no lid or conjunctival redness. She was free from excessive
lacrimation, photophobia and grittiness of the eyes.
Exophthalmometry readings were 23 and 24 mm, respectively.
Restriction of eye movements remained very stable compared to
the examination performed 5 weeks earlier, with severe
restriction in all directions of gaze, but in particular,
restriction of elevation more marked on the right side and
abduction restricted symmetrically on both sides. There was 20
prism dioptries vertical disparation right over left. Her double
vision persisted but was well controlled with Fresnel prisms.
The MRI study
The patient underwent MR examination in 1, 5 T scanner Siemens,
Vision+. The head coil was positioned according to the nasion
point. Transversal sections were positioned parallelly to medial
and lateral muscles, coronal ones perpendicularly to a course of
the optic nerve what was tantamount to the long axis of the
orbit.
The patient underwent both spin echo (SE) and STIR imaging with
T1 parameters: TR – 450 ms, TE – 14 ms, FA – 90o, FOV – 250 mm,
number of layers – 15, thickness of layers – 3, dis. Factor – 0,
1, matrix – 192x512, number of acquisitions – 3, time 4 min 22
s, STIR: TR – 5300 ms, TE – 30 ms, TI – 150 ms, FA – 180o, FOV–
250 mm, number of layers – 15, thickness of layers – 3, dis.
Factor – 0,1, matrix – 140x256, number of acquisitions – 2, time
3 min 38s as well as multiecho T2 sequences: TR – 450 ms, TE –
15 ms, 75 ms, 135 ms, FA – 180o, FOV – 250 mm, number of layers
– 11, thickness of layers – 4, dis. Factor – 0,1, matrix –
186x256, number of acquisitions – 2, time 4 min 10 s.
STIR images were quantified by measuring the signal intensity
(10,11), and the multiecho sequence by calculation of T2 time
(12,13,14).
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Eyeball muscles’ volume estimation
The coronal T1 images were used for the eyeball muscles` volume
estimation.
For the purpose of image processing the open source ITK library
[The Insight Software Consortium. The Insight Toolkit (ITK).
http://www.itk.org/] was used. The algorithms employed were
cubic spline re‑sampling and Level Set segmentation. For the
description of above-mentioned algorithms we refer to the ITK
library reference manual [Ibanez, Schroeder, Ng, Cates Internet:
http://www.itk.org/ItkSoftwareGuide.pdf].
In the first step of our workflow the radiologist roughly marked
the position of the muscle on an MRI image. This operation
created a mask image that was further on used as an initial
condition for the Level Set segmentation algorithm. In the
second step both the MRI and the mask images were re‑sampled
into 1x1x1mm isotropic voxel size by means of cubic spline re‑sampling
algorithm.
All further processing was done on the re‑sampled MRI and mask
images. In the third step both re‑sampled MRI and mask images
were input into Level Set segmentation algorithm in order to
obtain a segmented image, that is in fact a refined and more
accurate position of the muscle. This step essentially
classifies every voxel of an image into two classes – either
containing the muscle or not. At the final fourth step of our
workflow the volume of the muscle was estimated by multiplying
the number of voxels in the area of the muscle by the volume of
one voxel.
The first MRI examination carried out before the treatment
revealed the enlargement of medial, inferior muscles of the
right eye and superior, medial and inferior muscles of the left
eye (Table II A). The increase in signal intensity (Table II B)
as well as T2 time (Table II C) of these muscles was also
observed. The next, after 5 days, examination did not reveal any
significant changes both in the size and indexes of disease
activity. Five weeks later there were still no differences in
the size of the muscles, however T2 time values of affected
muscles decreased evidently. That decrease was found to be
continued in 10 weeks following infusion examination. Then
reduction of the muscle volume was also found. Signal intensity
of the muscles did not change at all throughout 10 weeks what
proves the low value of this parameter in estimating the
activity of pathological process in Graves’s ophthalmopathy.
Discussion
Many clinical trials have shown a beneficial effect of
anti-TNFα treatment in Leśniowski-Crohn disease, rheumatoid
arthritis, psoriasis, ankylosis spondylitis and, recently, acute
uveitis (15).
Moreover, several studies suggest a key role of TNFα in the
acute phase of TAO with elevated levels of TNFα in orbital
tissues and serum (4,6)
The results of our study have clearly shown that the single dose
of infliximab administration resulted in a dramatic reduction of
inflammation and improvement of visual function as measured by
MRI and CAS and NO SPECS scales without noticeable short-term
side effects. Especially improvement was observed on the CAS
scale which refers directly to the active inflammatory process.
The good results of a single infusion of infliximab have also
been noted in a patient with active TAO (2). In etanercept study
of ten patients with Graves’ ophthalmopathy (another anti – TNF
drug administered twice weekly during 12 weeks) TAO signs also
improved significantly (9). Therefore, we hope that TNFα
antagonist may be a novel therapeutic option in selected
patients with active TAO.
A randomized prospective study is needed to determine whether
infliximab proves sufficiently effective in reducing the
inflammatory symptoms of TAO, and whether it can be administered
safely for a prolonged period without side effects.
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Praca wpłynęła do Redakcji 20.10.2006 r. (947)
Zakwalifikowano do druku 11.09.2007 r.Adres do
korespondencji (Reprint request to):
Professor Jan Komorowski, MD, PhD,
Department of Clinical Endocrinology,
Medical University of Łódź,
Sterlinga 3,
91-425 Łódź, Poland |
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