Therapeutic Apheresis and Dialysis 12(2):105108

doi: 10.1111/j.1744-9987.2008.00554.x
2008 International Society for Apheresis

Therapeutic Plasma Exchange Combined With

Immunomodulating Agents in Secondary Progressive
Multiple Sclerosis Patients
Eirini Grapsa,1 Nicolaos Triantafyllou,2 Antonios Rombos,2 Antonios Lagouranis,1
and Meletios-Athanasios Dimopoulos1
1

Department of Clinical Therapeutics, Renal Unit, Alexandra Hospital, and 2Neurology Department, Aeginition
Hospital, University of Athens, Athens, Greece

Abstract: Multiple sclerosis (MS) is the most common

cause of neurological disability. Therapeutic plasma
exchange (TPE) has been used in the management of
patients with MS with equivocal efficacy. With this work we
would like to present our experience with 10 patients
(seven male and three female, mean age 34 years [range
2753 years]) with secondary progressive MS, who were
treated with immunomodulating agents and who also
underwent TPE. The patients expanded disability status
scale (EDSS) score of entry to the study varied from 5.0 to
6.5. One year before study entry all patients showed a
marked deterioration (12 months before starting TPE they
had been rated 4.55.5 on the EDSS). TPE was performed
three times a week for two weeks and thereafter once a
week, or once a month for the stable patients. The machine
used was the Cobe Spectra and albumin 5% was the
replacement fluid. Peripheral veins were used in nine

patients and indwelling vascular access was required in one

patient. Eighteen months later, patients stopped taking the
immunomodulating agent therapy and continued only with
TPE. No side-effects occurred during the TPE session.
After 36 months of TPE therapy, five patients were stabilized in their disability, while two patients showed a minor
progression of the disease (an additional 0.5 degree in disability as determined by the EDSS). No relapses occurred
during TPE. Three patients stopped the therapy: one
patient because of persistent nausea and two patients for
reasons unrelated to TPE. Periodic TPE was associated
with reduced accumulation of neurological deficits (as
documented by EDSS) in patients with secondary progressive MS. Key Words: Autoimmune disorder, Disability,
Immunomodulator, Multiple sclerosis, Plasmapheresis,
Therapeutic plasma exchange.

Autoimmune diseases are significant causes of

morbidity and disability in more than 8.5 million
Americans (1). Neurological disorders represent
about half of the diseases for which there is evidence
of autoimmune pathogenesis, and these diseases fall
into four general categories. Multiple sclerosis (MS)
and stiffperson syndrome represent one of these
categories and are the most important central
nervous system autoimmune disorders. Progressive
MS is a permanently active disease with no effective
treatment. Progress has been made recently in elucidating evidence-based treatment such as interferons,

intravenous immunoglobulin and plasma exchange.

Therapeutic plasma exchange (TPE) has been used
in the past for the management of progressive MS
with little or equivocal efficacy. Despite this equivocal
efficacy, plasma exchange and immunoadsorption
plasmapheresis (IAPP) are still in use worldwide to
treat patents with MS who are resistant to other
established treatments (25). Clinical improvement
with plasma exchange in combination with interferon
has been observed in 54% of 13 patients treated by
Medenica et al. (3). Also, another double-blind controlled study showed that TPE is significantly effective in delaying the progression of the disease in
patients with progressive MS taking immunosuppressive drugs (6). The combination of cyclophosphamide
with TPE proved also to be effective, according to
studies by Weiner et al. (7) and Khatri et al. (6), but

Received February 2007; revised May 2007.

Address correspondence and reprint requests to Dr Grapsa
Eirini, Associate Director, Renal Unit, Alexandra Hospital, 97
Kousidou, 15772 Athens, Greece. Email: egrapsa@teledomenet.gr

105

106

E Grapsa et al.

not according to the Canadian Cooperative Multiple

Sclerosis Study Group (8). The exact role of TPE
in the management of patients with MS remains
unclear.
In this small pilot study we present our experience
with the combination of TPE and immunomodulating agents in 10 patients suffering from secondary
progressive MS.
PATIENTS AND METHODS
Ten patients with secondary progressive MS (seven
male and three female, age range 2753 years, mean
age 34 years), already treated with immunomodulators, underwent TPE on an outpatient basis for a
36-month period. The duration of the disease ranged
from 5 to 16 years. Patients had clinical deterioration
over the 12 months preceding TPE, in spite of
continuous immunomodulation therapy taken for
at least two years. Five of the patients were taking
interferon (IFN) b-1a (6 MIU once a week, IM),
one patient was taking Glatiramer acetate and four
others were taking Azathioprine (2 mg/kg/day).
Plasma exchange was performed for three years.
Patients received immunomodulating agents and
TPE for the first 18 months, and then only TPE for
the remaining 18 months. Patients were clinically
evaluated by two neurologists before they began TPE
(baseline), and then at 6, 12, 18, 24 and 36 months
afterwards.Their disability status was estimated using
the Kurtzke expanded disability status scale (EDSS)
(9). Magnetic resonance imaging (MRI) of the brain
was performed on all patients at the baseline, at 6, 12,
18 and 24 months after starting TPE, and at the end of
the study. The existence of gadolinium-enhancing
lesions and new T2 lesions were evaluated each time.
Therapeutic plasma exchange protocol
Plasma exchange was performed three times a
week for 2 weeks, using the Cobe Specta machine
(TPE Flowpath, Cobe Laboratories, Lakewood, CO,
USA), thereafter once a week for 2.5 months, and
then once a month for patients who showed stabilization or once a week for the others. After 6 months,
TPE was performed once a month until the end of
the study.
Peripheral veins could be used in nine patients and
indwelling vascular access was required in one
patient.
During each TPE procedure, a 50 kg body weight
of the patients plasma volume was treated (e.g.
50 70 kg = 3500 mL plasma volume/TPE procedure). Albumin 5% containing 6.9 mEq Ca2+/L,
1.2 mEq Mg2+/L and 4 mEq K+/L was used as a
Ther Apher Dial, Vol. 12, No. 2, 2008

replacement liquid. The plasma was separated by a

continuous flow centrifugation device (TPE Flowpath) at a rate of 40100 mL/min.
RESULTS
Clinical evaluation
The procedure was safe and had no side-effects
with the exception of nausea, which occurred in one
patient 23 h after each TPE session. This side-effect
caused the discontinuation of the procedure after six
months, despite the stability of the disease. The
patients EDSS scores one year before the study
ranged from 4.0 to 5.5, and at the time TPE was
begun the scores ranged from 5.5 to 6.5. At the end of
the study, after 36 months of TPE, five patients were
stabilized in their disability; while two patients
showed a minor progression of the disease (with
an additional 0.5 degree in disability as determined
by the EDSS) (Table 1). No relapse occurred during
TPE therapy. Two other patients, even they were
also stable, stopped TPE (after 8 and 12 months,
respectively) for reasons unrelated to the therapy
(difficulty to get to the clinic). Spasticity improved in
all patients, and one patient with cerebellar tremor
was free of it after 6 months of therapy.
Neuroimaging study
At baseline, all patients had enhancing lesions and
more T2 lesions than in previous MRIs. Thirty-six
months later, seven patients had no enhancing lesions
in their T1-MRI. Two patients had more T2 lesions in
their MRI (Table 2).
DISCUSSION
As shown in Table 1, our patients deteriorated in
their clinical status one year before starting TPE
despite being on immunomodulating drugs. When we
started the TPE treatment, all patients (100%) were
stable during the first six months when the frequency
of the treatment was once a week or once a month.
One year later 75% of patients were stable and the
deterioration of the other patients was only 0.5
degree according to the EDSS. No patients showed
an improvement according to the EDSS scale, but
all patients had improvement in their spasticity. A
slight trend favoring the plasma exchange has been
reported at 1224 months by the Canadian cooperative trial of cyclophosphamide and plasma exchange,
but the authors report that this was not sustained
at the final assessment (8). As can be seen in the
Medenica et al. study (3), 13 out of 24 patients with
progressive MS on interferon therapy showed clinical
2008 International Society for Apheresis

 2008 International Society for Apheresis

Aza
Aza
Aza
Aza
IFN b-1a
IFN b-1a
IFN b-1a
IFN b-1a
IFN b-1a
Gl Ac

34/M
27/F
29/M
39/F
29/M
28/M
45/M
41/M
49/F
53/M

5.0
5.5
5.0
5.0
5.0
5.5
4.5
4.0
5.0
5.0

EDSS 1 year
before TPE
6.0
6.5
6.5
6.0
6.5
6.5
6.0
5.5
6.5
6.5

EDSS at
baseline
6.0
6.5
6.5
6.0
6.5
6.5
6.0
5.5
6.5
6.5

EDSS 6 months
of TPE
6.5
6.5
6.5
6.5
6.5
6.5
6.0

6.5
6.5

EDSS 12 months
of TPE
6.5
6.5

6.5
6.5
6.0

6.5
6.5

EDSS 18 months
of TPE
6.5
6.5

6.5
6.5
6.0

6.5
6.5

EDSS 24 months
of TPE
6.5
6.5

6.5
6.5
6.0

7.0
6.5

+/+
+/+
+/+
+/+
+/+
+/+
+/+
+/+
+/+
+/+

+
+
+
+
+
+
+
+
+
+

Pts

1
2
3
4
5
6
7
8
9
10

-/-/-/-/+
-/-/-/-/-/-/-

Gd-enhancing/more
T2 lesions,
6 months of TPE
-/+
-/-/+/+
-/-/-/?
-/-/-

Gd-enhancing/more
T2 lesions,
1 year of TPE

Gd, Gadolinium; TPE, therapeutic plasma exchange; +, present; -, not present; ?, unknown.

Gd-enhancing/more
T2 lesions,
at baseline

Gd-enhancing
lesions 1 year
before TPE

-/-/?
?
-/-/-/?
-/-/-

Gd-enhancing/more
T2 lesions,
1.5 years of TPE

-/+
-/?
?
-/-/-/?
-/+
-/-

Gd-enhancing/more
T2 lesions,
2 years of TPE

Worse (0.5)
Stable
Dropped out
Dropped out
Stable
Stable
Stable
Dropped out
Worse (0.5)
Stable

Outcome

-/+
-/?
?
-/-/-/?
-/+
-/-

Gd-enhancing/more
T2 lesions,
3 years of TPE

EDSS 36 months
of TPE

TABLE 2. Patients MRI findings, 1 year before entry into the study, at baseline and at different stages of the TPE treatment

Aza, azathioprine; EDSS, expanded disability status scale; Gl Ac, glatiramer acetate; IFN, interferon; TPE, therapeutic plasma exchange.

Treatment

Patients (Age/sex)

TABLE 1. Patients disability status (according to EDSS) at each assessment

Plasma Exchange and Multiple Sclerosis

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E Grapsa et al.

improvement after plasma exchange, while eight stabilized and three worsened. Removal of interferon
inhibitor factor (IIF) from circulation by plasma
exchange, and increased IFN levels were associated
with the clinical improvement as measured by EDSS.
Two out of five of our patients who were on interferon were stable, but the small number of patients in
the study does not allow us to give an explanation.
The stable patients were either on interferon, azathioprine or glatiramer acetate. How the combination of immunomodulating agents (IFN-, azathioprine, glatiramer acetate) and TPE works in the
course of progressive MS is not clear.
Another double-blind controlled study of plasmapheresis in patients taking immunosuppressive
drugs (6) reported improvement in 11 of 14 TPE
patients with chronic progressive MS and in 5 of 8
sham TPE patients, and improvement was maintained 11 months after entry into the study. Twelve
TPE patients and 18 sham TPE patients were at
the same disability level as on entry, while three
patients in the TPE group and six in the sham TPE
group deteriorated. The overall difference in the
degree of improvement as measured on EDSS at 11
months after entry (between the TPE and sham
TPE groups) was significant at P < 0.017. The author
concludes that since the natural course of CPMS
[chronic progressive MS] is predictable (continuous
worsening by definition) stabilization or improvement with any form of therapy would be a significant outcome.
It is true that the risk benefit and cost benefit
of any kind of therapy raise some very important
questions. Therapeutic plasma exchange is a safe and
well established treatment worldwide, and no significant side-effects were observed in our patients during
the procedures. Iron therapy is the only need of the
patients during the chronic therapy with TPE due to
the small quantity of blood depletion that occurs
during the procedures. The cost benefit remains a
very important issue and we think that it has to be
kept in mind. Therefore, from the article in the
American Academy of Neurology (10), we can see
that TPE is of little or no value in the treatment of
progressive MS (type A recommendation), but it may
be helpful in the treatment of severe acute episodes
of demyelination in previously non-disabled individuals (type C recommendation) (10). Also, according to the latest European guidelines, Sellebjerg et al.
(11) report that: plasma exchange is probably efficacious in a subgroup of patients with severe relapses
not responding to methylprednisolone therapy and
should be considered in this patient subgroup (level
B recommendation).
Ther Apher Dial, Vol. 12, No. 2, 2008

According the above recommendations TPE is

probably efficacious in a subgroup of patients with
severe acute episodes and in previously non-disabled
individuals. Progressive MS is a permanently active
disease. The open character of this study, the small
number of participants and the use of patients as
their own controls do not allow solid conclusions to
be reached. Besides, the lack of objective biological
markers, apart from clinical tools (EDSS), for evaluation of disease progression adds another limitation.
Of course, if we similarly define the stability of the
disease, our patients were all stable after 36 months, a
fact that could not be underestimated.

CONCLUSION
Therapeutic plasma exchange could be beneficial,
without serious acute or chronic complications, in
patients with secondary progressive MS, and this has
to be taken into consideration when we decide to
order TPE, although its cost-benefit remains a serious
problem.

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2008 International Society for Apheresis