Accepted Manuscript

Tumefactive multiple sclerosis lesions associated with fingolimod

treatment: report of 5 cases

Pedro Sánchez , Virginia Meca-Lallana , José Vivancos

PII: S2211-0348(18)30199-8
DOI: 10.1016/j.msard.2018.07.001
Reference: MSARD 876

To appear in: Multiple Sclerosis and Related Disorders

Received date: 17 April 2018

Revised date: 17 May 2018
Accepted date: 1 July 2018

Please cite this article as: Pedro Sánchez , Virginia Meca-Lallana , José Vivancos , Tumefactive
multiple sclerosis lesions associated with fingolimod treatment: report of 5 cases, Multiple Sclerosis
and Related Disorders (2018), doi: 10.1016/j.msard.2018.07.001

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 ACCEPTED MANUSCRIPT

Highlights
 Fingolimod can be associated with tumefactive lesions in
predisposed patients.
 Fingolimod withdrawal may be associated with rebound
and development of tumefactive lesions.
 Close monitoring of these patients after stopping
fingolimod is advisable.

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 ACCEPTED MANUSCRIPT

Tumefactive multiple sclerosis lesions associated with

fingolimod treatment: report of 5 cases.
Authors: Pedro Sáncheza, Virginia Meca-Lallanaa, José Vivancosa.

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Demyelinating Disorders Unit, Neurology Department. Hospital Universitario de La Princesa
In o In n n n

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ABSTRACT

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Background and objective: Fingolimod is a sphingosine 1-phosphate receptor

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modulator, which sequesters lymphocytes in lymph nodes and prevents them from
entering the central nervous system. There have been increasing reports of severe
rebounds with tumefactive demyelinatinglesions (TDLs) in patients with Multiple
Sclerosis under fingolimod treatment, as well as following therapy discontinuation. Our

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objective is to review the clinico-radiological characteristics of patients with TDLs
associated with fingolimod.
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Methods: Retrospective review of medical records of MS patients from our center, who
were treated with fingolimod and developed TDLs. We review the literature.

Results: We found 5 cases: 4 developed TDLs as rebounds after treatment cessation

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and 1 under treatment. The 4 rebound cases were women, with a mean age of 34.7 years
(SD=3.6) and a mean disease duration of 10.2 years (SD=4.1). The mean duration of
fingolimod treatment before discontinuation was 36.2 months (SD=22.4) and the mean
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time lapse between treatment withdrawal and rebound was 9.75 weeks (SD=7.4). The
total pre-rebound lymphocyte count (cells/mm3) was 482.5 (SD=325.7) and1017.5
(SD=364.8) during rebound. The TDL patient under fingolimod was a 36-year-old man
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who had been on fingolimod for 32 months after switching from glatiramer acetate.
TDLs were multiple in 2 cases and solitary in 3. Acute treatment for rebound included
high dose steroids (5/5), plasma exchange (3/5) and rituximab (2/5). Treatment after
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fingolimod included rituximab (2/5), alemtuzumab (2/5) and glatiramer acetate (1/5).

Conclusions: Our study, along with similar reports in literature, highlights the need for
close monitoring in patients who plan to switch from fingolimod to other treatments
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because of the risk of severe rebound. The etiopathogenic association between

fingolimod and TDLs is not clear, but given the increasing reports of cases it should be
taken into account for treatment selection in patients with this type of lesions.

Keywords: tumefactive, rebound, fingolimod

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MANUSCRIPT

Fingolimod (FTY) was the first oral drug for treating relapsing-remitting multiple
sclerosis (RRMS). It acts as a sphingosine 1-phosphate (S1P) receptor modulator, which
sequesters lymphocytes in lymph nodes and prevents them from entering the central
nervous system. It is an effective drug, with relapse reduction rates of around 50% (1).
Among the possible side effects are changes in cardiac conduction, macular oedema and
severe lymphopenia, which can lead to opportunistic infections and even progressive
multifocal leucoencephalopathy (PML) (2). Another important aspect to consider is the
possibility of exaggerated reactivation of the disease after stopping the drug. This risk

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was already known with natalizumab (NTZ) (3,4), but an increase numbers of cases
have been reported following discontinuation of FTY (5–9). Sometimes the

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inflammation that comes back is so intense that patients can develop tumefactive
demyelinating lesions (TDLs). These lesions are defined as large lesions (> 2cm), that

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associate mass or oedema effect. They usually exhibit an open-ring enhancement but
other uptake patterns are possible (10,11).

We present 5 cases of TDLs associated with FTY treatment in patients with RRMS: 4 in

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relation to its suspension and 1 under treatment with the drug.
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2. We have retrospectively reviewed the medical records of MS patients from our
centre, who were treated with FTY and developed TDLs. We reviewed the literature.
The study met the requirements of our center's ethics committee.
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3. Patients report:
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Patient 1 is a 34-year-old woman with a 15-year history of RRMS. She had been treated
with interferon (INF) beta-1a, which was replaced by FTY due to persistent relapses.
She remained attack-free for more than two years although her Magnetic Resonance
Imaging (MRI) persistently showed mild activity (few new T2 lesions). Although a
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therapy change to a high-efficacy drug was recommended, treatment was finally

stopped due to pregnancy planning. 14 weeks after the suspension of FTY she presented
a new relapse and her new MRI showed more than 30 new lesions, including two TDLs
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with an open-ring appearance (Figure 1, A). Treatment with two cycles of intravenous
steroids was initiated, with good response. The patient was put on glatiramer acetate
(GA).
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Patient 2 is 40-year-old female with a 5-year history of RRMS. She had been treated
with GA and then NTZ after a severe relapse, which was then changed for FTY due to
an increase in her JC-antibody Index (3.7). Although she was stable on FTY, it was
discontinued after 6 months due to intense fatigue, that the patient attributed to the
medication. Dimethyl fumarate (DMF) was started but after a month of treatment (18
weeks after the suspension of FTY) the patient developed progressive sensory
symptoms in the lower limbs, highly suggestive of a spinal cord relapse. A few days
later she unilaterally decided to stop DMF due to abdominal pain. The sensory
symptoms progressed and she developed a transverse medullary syndrome with
paraplegia and bladder dysfunction within few days (EDSS 8). An MRI showed a
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tumefactive enhancing spinal cord lesion spreading over more than 8 vertebral segments
(Figure 1, B). Anti-AQP4 antibody test was negative and no other features were
compatible with seronegative Neuromyelitis Optica Spectrum Disorder (NMOSD), so a
diagnosis of a catastrophic spinal cord relapse was made. She was treated with steroids
and two consecutive cycles of plasma exchange (PLEX). Rituximab was finally added
as an acute treatment and then maintained as chronic treatment, with a good outcome
(EDSS 6)

Patient 3 is a 32-year-old female (JC antibody positive) with an 11-year history of

RRMS. She had been treated with INF beta 1b, which was replaced by GA due to
intolerance. She presented several disabling relapses while on GA, so therapy was

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escalated to FTY. In the following 5 years FTY was temporarily suspended due to
urinary sepsis in the context of lymphopenia (< 200 cel/mm3) and she continued having

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clinical and radiological activity as well, so a switch to alemtuzumab was planned. 4
weeks after FTY withdrawal the patient developed a plurisymptomatic relapse with

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severe disability (EDSS 8). Her MRI showed multiple new lesions, some of them with a
tumefactive appearance (Figure 1, C). She was first treated with two steroid cycles
followed by PLEX, with an improvement from an EDSS 8 to EDSS 6. Alemtuzumab
was then initiated.

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Patient 4 is a 33-year-old female (JC antibody positive) with a 10-year history of
RRMS. She was on INF beta-1a and a change to FTY was done based on new relapses.
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After 3.7 years of FTY treatment it was discontinued due to persistent severe
lymphopenia (cell count 170 cel/mm3) and a switch to alemtuzumab was proposed. 3
weeks after FTY withdrawal, she presented with dysarthria, dizziness and severe
instability (EDSS 6 during the relapse, previously EDSS 1.5). A new MRI showed
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intense inflammatory activity with more than 30 new lesions, including a large
(>20mm) symptomatic lesion in the middle cerebellar peduncle (Figure 1, D). She was
treated with steroids and subsequently with PLEX. She continued deteriorating and
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rituximab was added as a rescue therapy and then maintained.

Patient 5 is 36-year-old male (JC antibody positive) with an 11-year history of RRMS.
Previously to FTY he had received INF beta 1b and GA, which were stopped due to
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inefficacy. After 2.6 stable years under FTY he developed a brainstem attack and new
activity on MRI, so a change to alemtuzumab was decided. However, before FTY was
stopped the patient presented two epileptic seizures. An MRI showed a large left frontal
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TDL with megacystic morphology (Figure 1, E). NMOSD, PML and other infectious
diseases were ruled out and he was treated with intravenous steroid. Alemtuzumab was
started with good clinical response.
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4. Discussion

In recent years several cases of TDLs have been reported in the context of withdrawal
of FTY (12,13). One of the possible explanations is that after suspension of the drug, a
mass exit of autoreactive lymphocytes from the lymphatic ganglia to the peripheral
blood takes place, penetrating the central nervous system (CNS) and generating an
exaggerated inflammatory response, similar to an Immune reconstitution inflammatory
syndrome (IRIS) (8). In this regard, animal models of experimental autoimmune
encephalomyelitis have shown that after the suspension of FTY an overexpression of
S1P1 receptors in the T lymphocytes takes place, which confers them capacity to escape
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the lymphatic ganglia. A reduction in regulatory T cells and enhancement of effector T

cells in the periphery also occur, boosting the inflammatory response (14). In our study,
patients rapidly increased lymphocyte count after drug discontinuation, with a mean of
482.5 cell/mm3 (SD=325.7), before suspension and 1017.5 cell/mm3 during the relapse
(SD=364.8), which indicates a rapid increase in autoreactive lymphocytes in the blood.
The risk factors for the reactivation of the disease after suspending the drug have not
been clearly identified. Although some reports indicate that a good response to FTY in
patients with an active disease could be a predisposing factor (13), in other cases the
patients who developed these lesions showed persistent disease activity despite the
treatment (15). In our series, among the 4 cases that presented TDLs after withdrawal,
in two of them the reason for discontinuation was therapeutic failure due to a highly

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active disease, while the others were well controlled and withdrawal was due to
intolerance (n=1) or side effects (n=1). The mean treatment duration prior to

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suspension was 35.6 months (SD=23.08), while the mean time from suspension until
rebound relapse was 10.7 weeks (SD=8.97). Patient number 2 started developing

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symptoms of a relapse while on treatment with DMF, however the discontinuation of
this drug might have contributed to the rapid progression of the relapse. Some
neurologists propose the administration of steroids as a bridge therapy after FTY
discontinuation to reduces the risk of rebound, as it has been done with NTZ, although

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no evidence supports this practice (16,17).
The authors have started administering steroid pulses (methylprednisolone 1g iv for 3
days) 10 days after stopping FTY and so far we have not documented any new
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rebounds.

Tumefactive lesions have also been described in patients under active treatment with
FTY, both in naïve and in those previously treated with other disease modifying drugs
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(INF-beta, GA, NTZ) (18–20). It must be stressed that while the majority of reports in
the literature with TDLs after the introduction of FTY did so in the first weeks or
months, our patient had been stable on treatment for 31 months before developing the
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TDL, which is atypical. Cases of large demyelinating lesions associated with NTZ have
also been described, some of them in relation with the development of NTZ neutralizing
antibodies (21,22). A case of a patient who developed a TDL 4 months after the first
alemtuzumab infusion has also been reported (23). Cases of lesions of this type have
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also been reported in NMOSD patients erroneously diagnosed with MS and who have
been treated with FTY, so testing of anti-AQP4 antibodies in these patients is
recommended (24,25).
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Hypotheses on the underlying mechanism of fingolimod-induced TDLs are diverse. A

redistribution of the immune cells after FTY initiation in susceptible MS patients has
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been proposed, particularly affecting effector CD8+ T cells, a subset of cytotoxic cells
capable of releasing perforin and cause direct tissue damage (26). This is supported by
the observation of an increased concentration of this lymphocyte subtype in the CSF
compared to the peripheral blood in a FTY patient who developed recurrent TDLs (27).
Another theory points towards a compensatory over-activation of the innate immune
system in patients with a drug-induced impaired adaptive cell-immunity. The vasogenic
edema and macrophage activation found in these lesions would rather be due to a
cytokine effect than a direct T- or B-cell immunocytotoxicity, which would explain the
development of TDLs in lymphopenic patients (26,28). Although not proven, a
paradoxical exacerbation of B cell-mediated disease activity after FTY initiation has
also been suggested based on the worsening of NMOSD patients under this treatment
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(24,27). This last hypothesis could partially share a mechanism with the reported
alemtuzumab-associated TDL, where an early and exaggerated B-cell repopulation in
the absence of a T-cell recovery might explain the pathogenesis (23)

The fact that TDLs can develop both in patients on FTY as well as in those coming off
treatment poses a challenge in terms of their immunopathogenesis. Although
radiologically indistinguishable, the mechanisms involved in the lesion formation might
be different. Whether TDLs in the context of a rebound represent true TDLs or can be
considered more and IRIS-related phenomenon is not clear, so further studies
addressing this question would be of interest. No etiopathogenic relationship can be
established between FTY and TDLs, but it cannot be ignored that there is an increasing

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n mb of po n h o n’ o w hoh mo fy n
with the same frequency. Our report, together with the literature reviewed, highlights

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the need for close monitoring in patients in whom FTY discontinuation is planned,
considering also therapeutic alternatives in those who present these lesions during the

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course of the disease.

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Figure 1: Axial T2-weighted (T2W) MRI shows two right tumefactive ring-like lesions
(A, patient 1). Sagittal T2W-MRI of the spinal cord shows a longitudinal extensive
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myelitis involving almost all thoracic and lumbar regions (B, patient 2). Axial T2- fluid-
attenuated inversion recovery (FLAIR) MRI shows a left rounded tumefactive lesion
(C, patient 3). Axial T2-FLAIR MRI shows a large lesion on the right cerebellar
peduncle (D, patient 4). Axial T2-FLAIR MRI shows a megacystic lesion on the left
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frontal lobe (E, patient 5)

Acknowledgements: None
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Conflict of interest:
Pedro Sánchez: Reports no conflict of interest.
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Virginia Meca-Lallana: Reports no conflict of interest relevant to the manuscript.

José Vivancos: Reports no conflict of interest relevant to the manuscript.

Study funding: No targeted funding reported.

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Table 1. Comparative table of patients with TDLs after fingolimod discontinuation.

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Time to Lymphocyt Lymphocyt
Disease EDSS EDSS Duration rebound e e
Patient Age, duration Previous pre- during of after count count Acute DMT post- Reason for
sex (years) DMT rebound rebound FTY FTY before during treatmen rebound discontinuatio
treatmen withdrawa FTY rebound t n

1 34, 15
Interferon
beta- 2 3 35
t
(months)
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14
l
(weeks)
withdrawal
(cel/mm3)

550
(cel/mm3)

1090 Steroids Glatiramer

Pregnancy
planning
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F 1a acetate

Glatiramer Steroids,
2 40, 5 acetate, 2 8 6 18 910 1500 PLEX, Rituximab Intolerance
F natalizuma rituximab
b
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Interferon
beta- Treatment
3 32, 11 1b, 6.5 8 59 4 300 800 Steroids, Alemtuzuma failure and
F glatiramer PLEX b adverse effects
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acetate

Steroids, Rituximab Persistent

4 33, 10 Interferon 1.5 6 45 3 170 680 PLEX, severe
F beta- rituximab lymphopenia
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*DMT=Disease modifying therapy; FTY=Fingolimod; F=female, PLEX=Plasma exchange

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