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PO Box 2345, Beijing 100023, China World J Gastroenterol 2006 January 28; 12(4): 520-525
www.wjgnet.com World Journal of Gastroenterology ISSN 1007-9327
wjg@wjgnet.com © 2006 The WJG Press. All rights reserved.
EDITORIAL
Safety and clinical efficacy of granulocyte and monocyte
adsorptive apheresis therapy for ulcerative colitis
Takayuki Yamamoto, Satoru Umegae, Koichi Matsumoto
www.wjgnet.com
Takayuki Yamamoto, Satoru Umegae, Koichi Matsumoto,
Infl ammatory Bowel Disease Center, Yokkaichi Social Insurance
Hospital, 10-8 Hazuyamacho, Yokkaichi, Mie 510-0016, Japan
Correspondence to: Takayuki Yamamoto, MD, Inflammatory
Bowel Disease Center, Yokkaichi Social Insurance Hospital, 10-8
Hazuyamacho, Yokkaichi, Mie 510-0016,
Japan. nao-taka@sannet.ne.jp
Telephone: +81-593-31-2000 Fax: +81-593-31-0354
Received: 2005-07-18 Accepted: 2005-08-03
Abstract
Active ulcerative colitis (UC) is frequently associated with
infi ltration of a large number of leukocytes into the bowel
mucosa. Therefore, removal of activated circulating
leukocytes by apheresis has the potential for improving
UC. In Japan, since April 2000, leukocytapheresis using
Adacolumn has been approved as the treatment for
active UC by the Ministry of Health and Welfare. The
Adacolumn is an extracorporeal leukocyte apheresis
device fi lled with cellulose acetate beads, and selectively
adsorbs granulocytes and monocytes/macrophages. To
assess the safety and clinical efficacy of granulocyte
and monocyte adsorptive apheresis (GMCAP) for UC, we
reviewed 10 open trials of the use of GMCAP to treat
UC. One apheresis session (session time, 60 min) per
week for fi ve consecutive weeks (a total of fi ve apheresis
sessions) has been a standard protocol. Several studies
used modifi ed protocols with two sessions per week, with
90-min session, or with a total of 10 apheresis sessions.
Typical adverse reactions were dizziness, nausea,
headache, fl ushing, and fever. No serious adverse effects
were reported during and after GMCAP therapy, and
almost all the patients could complete the treatment
course. GMCAP is safe and well-tolerated. In the majority
of patients, GMCAP therapy achieved clinical remission
or improvement. GMCAP is a useful alternative therapy
for patients with steroid-refractory or -dependent UC.
GMCAP should have the potential to allow tapering the
dose of steroids, and is useful for shortening the time
to remission and avoiding re-administration of steroids
at the time of relapse. Furthermore, GMCAP may have
effi cacy as the fi rst-line therapy for steroid-naive patients
or patients who have the first attack of UC. However,
most of the previous studies were uncontrolled trials. To
assess a defi nite effi cacy of GMCAP, randomized, double-
blind, sham-controlled trials are necessary. A serious
problem with GMCAP is cost; a single session costs
¥145 000 ($1 300). However, if this treatment prevents
hospital admission, re-administration of steroids and
surgery, and improves a quality of life of the patients,
GMCAP may prove to be cost-effective.
© 2006 The WJG Press. All rights reserved.
Key words: Clinical effi cacy; Granulocyte and monocyte
adsorptive apheresis; Leukocytapheresis; Safety;
Ulcerative colitis
Yamamoto T, Umegae S, Matsumoto K. Safety and clinical
effi cacy of granulocyte and monocyte adsorptive apheresis
therapy for ulcerative colitis.
World J Gastroenterol
2006;
12(4): 520-525
http://www.wjgnet.com/1007-9327/12/520.asp
INTRODUCTION
Ulcerative colitis (UC) is an inflammatory bowel disease
of unknown etiology that involves colon and rectum.
Active UC is frequently associated with infiltration of
large number of leukocytes into the bowel mucosa[1,2].
The infiltrated leukocytes can cause extensive mucosal
tissue injury by releasing a large number of infl ammatory
mediators such as prostaglandins, leukotrienes, platelet
activating factor, thromboxanes, oxygen radicals, proteases,
and cytokines[3]. Therefore, removal of activated circulating
leukocytes by apheresis has the potential for improving
the bowel infl ammation and patient status in UC. Recently,
leukocytapheresis has been tried as a novel approach for
UC[4,5].
Clinical effi cacy and safety of leukocytapheresis for UC
were initially investigated in a multicenter study in Japan,
and the results were published in 1999[5]. In that study,
120 patients were randomly divided into two groups; one
group received leukocytapheresis and the other group
conventional drugs (corticosteroids and/or sulfasalazine/
mesalazine). Clinical efficacy was observed in 58% of
patients in the leukocytapheresis group compared with
44% in the drug group. Adverse effects were noted in 8%
of patients in the leukocytapheresis group compared with
43% in the drug group. From these data, leukocytapheresis
seemed to be superior to conventional drugs, and this
was more striking in patients with severe and intractable
diseases[5]. In Japan, since April 2000, leukocytapheresis
using Adacolumn (Japan Immunoresearch Laboratories,
Takasaki, Japan)[6] has been approved as the treatment of
patients with active UC by the Ministry of Health and
Yamamoto T
et al.
Leukocytapheresis for ulcerative colitis 521
www.wjgnet.com
Welfare. Hence, currently the Adacolumn is available in
the market throughout Japan and is being used for treating
UC. The Adacolumn is an extracorporeal leukocyte
apheresis device filled with cellulose acetate beads,
and selectively adsorbs granulocytes and monocytes/
macrophages; lymphocytes are not signifi cantly adsorbed[7].
Thus, the Adacolumn is for selective granulocyte and
monocyte/macrophage adsorptive apheresis (GMCAP).
As leukocytapheresis therapy, Cellsorba (Asahi Kasei
Medical Co., Ltd, Tokyo, Japan)[8] is also available in Japan.
The Cellsorba is filled with very fine polyester fiber as
adsorptive carriers, and removes lymphocytes in addition
to granulocytes and monocytes.
In this paper, we have discussed safety and effi cacy of
GMCAP using the Adacolumn, which has been used as
leukocytapheresis therapy in our institution. Since 2000,
there have been 10 open trials of the use of GMCAP
to treat UC (Table 1)[9-18]. Eight of the ten trials were
performed in Japan. We mainly reviewed these trials to
assess clinical efficacy and safety of GMCAP for UC.
Finally, we discussed possible future role of GMCAP in
the management of UC.
GMCAP procedures
The Adacolumn[6] is a single use adsorptive type apheresis
column, with a volume of 335 mL, fi lled with 220 g of
cellulose acetate beads of 2 mm diameter as the column
adsorptive carriers. An outline of GMCAP procedures
using the Adacolumn is shown in Figure 1. GMCAP was
Table 1 Summary of trials of GMCAP therapy using Adacolumn for patients with active UC
Authors (yr) Indications for
GMCAP
n
Apheresis
protocol
Adverse effects
(% of patients)
Effi cacy (%)
Shimoyama et al[9]
(2001)
Refractory to
conventional drugs
53 Standard19% Remission: 21%
Improvement: 37%
Tomomasa et al[10]
(2003)
Steroid-refractory
children
12 1 session/wk for 5-10 wk 9% Improvement: 67%
Hanai et al[11]
(2003)
Steroid-refractory
Steroid-naive
31
8
10 or 11 sessions
over 11 wk
18% Remission:
Steroid-refractory 81%
Steroid-naive 88%
Improvement:
Steroid-refractory 6%
Steroid-naive 12%
Suzuki et al[12]
(2004)
Steroid-naive 20 2 sessions/wk
for 3-5 wk
10% Remission: 85%
Naganuma et al[13]
(2004)
Steroid-refractory
Steroid-dependent
44 Standard15% Remission: 55%
Improvement: 20%
Hanai[14]
(2004)2
Steroid-dependent 46 11 sessions over 10 wk 22% Remission: 83%
Yamamoto et al[15]
(2004)
Mild-to-moderate
active distal disease
30 Standard127% Remission: 70%
Improvement: 17%
Domenech et al[16]
(2004)3
Steroid-dependent 14 Standard115% Remission: 62%
Improvement: 14%
Kanke et al[17]
(2004)
Mild-to-severe disease 60 10 sessions over 12 wk418% Remission: 23%
Improvement: 60%
Kim et al[18]
(2005)
Refractory to
conventional drugs
27 Standard111% Improvement: 70%
GMCAP, granulocyte and monocyte/macrophage adsorptive apheresis; UC, ulcerative colitis.
1Five apheresis sessions for fi ve consecutive weeks; session time, 60 min; blood fl ow rate, 30 mL/min.
2This study was a randomized controlled trial comparing effi cacy of GMCAP and prednisolone.
3This study also included 12 patients with Crohn’s disease.
4One or two sessions per week; session time, 60 or 90 min.
Figure 1 An outline of GMCAP procedures using the Adacolumn. Blood is drawn
into the column from the antecubital vein of one hand, and returned to the patient
via antecubital vein of the contralateral hand. GMCAP, granulocyte, and monocyte/
macrophage adsorptive apheresis.
Drip chamber
air outlet port
←
Venous pressure gauge
Adamonitor
Bubble detector
Pump
Blood outfl ow
from Antecubital vein
Bubble
detector
Adacolumn
Drip
chamber
←
Anticoagulant
administration port
←
Blood infl ow via
Antecubital vein
←
←
www.wjgnet.com
performed in out-patient clinic for patients with mild
symptoms, and patients with severe symptoms were
hospitalized for GMCAP. The process of performing
GMCAP is relatively simple. Prior to apheresis, the system
is primed by saline-containing anticoagulant, nafamostat
mesilate or heparin, and during apheresis saline containing
those anticoagulants is continuously administered into
the column. Blood is drawn into the column from the
antecubital vein of one hand, and returned to the patient
via antecubital vein of the contralateral hand, without
using a shunt. The commonly used apheresis time and
blood fl ow rate are 60 min and 30 mL/min, respectively.
During these procedures, the carriers adsorb about 65% of
granulocytes, 55% of monocytes and 2% of lymphocytes
from the blood in the column[7]. After completion of
each apheresis session, the residual blood in the column
and circuit lines is returned to the patient by infusing
physiological saline at the blood infl ow line. Vital signs are
continuously monitored during the apheresis by dialysis
staff. One apheresis session (session time, 60 min; blood
fl ow rate, 30 mL/min) per week for fi ve consecutive weeks
(a total of five apheresis sessions) has been a standard
protocol. Recently, other protocols with two sessions per
week or a total of 10 apheresis sessions have been used for
patients with severe UC. Furthermore, apheresis sessions
longer than 60 min and apheresis with a higher blood
flow rate have been tried for severe diseases. In several
institutions, the efficacy of the protocol with a longer
session time and higher blood fl ow rate is being compared
with that of the standard protocol[17].
Indications for GMCAP
According to the Guidelines of the Investigation and
Research Committee of Infl ammatory Bowel Disease of
the Ministry of Health and Welfare of Japan, GMCAP
has been mainly used for patients with steroid-refractory
(no or little improvement after high dose steroid therapy)
and steroid-dependent (inability to decrease the steroid
dosage) moderate-to-severe UC. For the majority of
patients, corticosteroids were given during GMCAP
therapy as concomitant medications. In contrast, steroid-
naive patients with milder UC were also treated with
GMCAP[11,12,15].
Adverse effects
No serious adverse effects were reported during and after
GMCAP therapy, and almost all patients could complete
the treatment course. From the data in the previous
trials[9-18], adverse effects were observed in 5%-27% of
patients (Table 1). Typical adverse reactions were dizziness,
nausea, headache, flushing, and fever. These symptoms
lasted from only a couple of minutes to a couple of
hours. Fever could be treated with antifebrile, and
headache could be prevented with painkillers before the
apheresis. Infectious problems due to GMCAP were rarely
reported[16]. In our study, one patient developed a mild liver
dysfunction probably due to an anticoagulant, nafamostat
mesilate[15]. Thereafter, heparin was used instead. The liver
dysfunction normalized without any special treatment.
Clinical effi cacy
Patients were followed up regularly during and after
GMCAP therapy, and the final efficacy assessment was
performed at one or two weeks after the last apheresis
session[9-18]. The effi cacy of GMCAP was evaluated using
clinical activity index or disease activity index scores[19-21].
In a prospective multicenter trial in Japan[9], 53 patients
refractory to conventional drug therapy were treated with
the standard GMCAP protocol (fi ve apheresis sessions for
fi ve consecutive weeks; session time, 60 min; blood fl ow
rate, 30 mL/min) in combination with prednisolone. After
the treatment, 21% and 37% of patients achieved remission
and improvement (without remission), respectively, and
the mean daily dose of prednisolone per patient was
reduced from 24.4 mg at enrollment to 14.2 mg after
GMCAP therapy. In another prospective multicenter study
in Korea[18], 27 patients with moderate-to-severe active
UC refractory to conventional drugs were treated with the
standard GMCAP protocol. Clinical improvement was
observed in 70% of patients (44% markedly improved),
and tapering down or discontinuation of steroids was
possible in 56% of concomitant steroid users. Naganuma
et al[13] treated 44 steroid-refractory or -dependent patients
with the standard GMCAP protocol. Twenty-four patients
(55%) obtained remission, 9 (20%) showed a clinical
response (without remission), and 11 (25%) remained
unchanged. Only 20% of patients with severe steroid-
refractory UC achieved remission, whereas 70% of
patients with moderate steroid-refractory UC achieved
remission. In 90% of patients with steroid-dependent UC,
the daily dose of corticosteroids could be tapered during
GMCAP therapy. In the long-term, 61% of patients who
achieved clinical improvement or remission maintained
remission, whereas 39% had relapsed. Approximately half
of the relapsed patients were successfully treated with
repeat GMCAP therapy. The Spanish Group for the Study
of Crohn’s Disease and Ulcerative Colitis (GETECCU)[16]
conducted a prospective, open, pilot study including 26
patients with steroid-dependent inflammatory bowel
disease (UC, 14; Crohn’s disease, 12). Patients were started
on 60 mg/d of prednisone; after one week, GMCAP
therapy with the standard protocol was started. The steroid
dose was tapered weekly if there was clinical improvement.
Remission was achieved in 62% and 70% of patients with
UC and Crohn’s disease, respectively. During a median
follow-up of 12.6 mo, 6 of 8 UC patients maintained their
clinical remission; however, only one Crohn’s disease patient
remained in remission after the fi rst 6 mo of follow-up.
Higher remission or improvement rates have been
reported using the modifi ed GMCAP protocols. Hanai et
al[11] examined 31 patients with steroid-refractory UC and
eight steroid-naive patients who were treated with a total
of 10 or 11 GMCAP sessions (session time, 60 min; blood
fl ow rate, 30 mL/min); for patients with severe diseases,
two sessions per week for the fi rst three weeks and then
weekly session for five weeks; for the other patients,
weekly session for the fi rst fi ve weeks and after an interval
of one week, weekly session for another fi ve weeks. After
the treatment, 81% of steroid-refractory and 88% of
522 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol January 28, 2006 Volume 12 Number 4
steroid-naive patients achieved remission, and 79% of
patients maintained their remission during 12 mo. The
same research group[14] conducted a randomized controlled
trial comparing the effi cacy of GMCAP and prednisolone.
Sixty-nine steroid-dependent patients were randomly
assigned to two groups; 46 patients were given 11 GMCAP
sessions (session time, 60 min; flow rate, 30 mL/min)
over 10 wk in combination with prednisolone (GMCAP
group), and the other 23 patients were treated with 30
mg/d of prednisolone (prednisolone group). Prednisolone
was tapered or discontinued with improvement of
disease in both the groups. At 12 wk after the treatment,
83% of patients in the GMCAP group and 65% in the
prednisolone group achieved remission and the difference
was not statistically signifi cant. During the 12 wk of the
treatment, the cumulative amount of prednisolone received
per patient was 1 157 mg in the GMCAP group, which
was signifi cantly lower than 1 938 mg in the prednisolone
group. Kanke et al[17] treated 60 patients with active UC
with 10 GMCAP sessions with different duration (60 or
90 min) and frequency (one or two sessions per week)
of apheresis. There was an association between the fi nal
disease activity and the duration of apheresis, and twice
a week was superior to one session per week for the
improvement of disease activity. Furthermore, twice a
week or 90 min was superior to one session per week or
60 min for improvement of clinical symptoms such as
diarrhea, abdominal pain, and bloody stools.
GMCAP has been also used for steroid-naive patients
or patients with milder UC[12,15]. Suzuki et al[12] treated 20
steroid-naive patients with active UC with 6-10 GMCAP
sessions (two sessions per week; session time, 60 min;
blood flow rate, 30 mL/min). Seventeen patients (85%)
achieved remission, and 60% had maintained their
remission during eight months. In our study[15], GMCAP
therapy with the standard protocol (no concomitant
steroid medications) was performed for 30 patients with
mild-to-moderately active distal UC. Clinical symptoms
significantly improved after the third apheresis session.
Clinical remission was achieved in 21 patients (70%), and
clinical improvement (without remission) was recognized
in 5 patients (17%). In 4 patients (13%), clinical response
was not recognized. GMCAP was not effective for patients
with long disease duration and those who had been
treated with high-dose steroids. All of the 21 patients who
achieved clinical remission were able to maintain remission
during the 12-wk follow-up after GMCAP. The effi cacy of
GMCAP for pediatric UC has been reported. Tomomasa
et al[10] retrospectively reviewed 12 steroid-refractory
children who were treated with weekly GMCAP for 5-10
consecutive weeks. In eight patients, clinical symptoms
improved after two apheresis sessions. The dose of steroid
was tapered during GMCAP therapy by 50%. Four of
the eight patients relapsed 3.5 mo after the last apheresis
session, the other four patients remained in remission up
to 22.8 mo.
DISCUSSION
A lot of research is going on to clarify the detailed mecha-
nism of GMCAP on UC[7,22-29]. Although during GMCAP,
the carriers adsorb 65% of granulocytes, 55% of mono-
cytes and 2% of lymphocytes from the blood in the column,
the number of these leukocytes in the systemic circula-
tion did not fall immediately after the apheresis[7]. This
can be explained by an infl ux of new leukocytes into the
systemic circulation from the marginal pools, principally
the bone marrow during apheresis. Thus, the effi cacy of
GMCAP cannot be fully explained on the basis of reduc-
ing leukocytes. Rembacken et al[4] found that the markedly
increased expression of α(m) integrin/Mac-1 and low
L-selectin expression alter the capability of granulocytes
to migrate to infl ammatory sites. Kashiwagi et al[23] found
a significant suppression of proinflammatory cytokines
(interleukin [IL]-1β, IL-6, IL-8 and tumor necrosis factor
[TNF]-α production) by leukocytes, neutrophils chemo-
taxis, down-regulation of leukocyte adhesion molecule
(L-selectin) and neutrophil adhesion to IL-1β-activated
endothelial cells after GMCAP for UC. Furthermore, the
number of CD10-negative premature granulocytes in-
creased, indicating increased turnover of these cells in the
systemic circulation. Takeda et al[27] found that granulocyte
adsorption to cellulose acetate beads required plasma IgG,
the complement C3 and was inhibited by an antibody to
leukocytes CD18. Furthermore, hepatocyte growth factor
and IL-1 receptor antagonist (IL-1ra) which have strong
anti-inflammatory actions were released by granulocytes
that adhered to cellulose acetate beads. Hanai et al[28] found
that TNF-α receptors I and II were signifi cantly increased
in the peripheral blood after apheresis. These observations
suggest that selective granulocyte and monocyte adsorp-
tion is associated with modifi ed peripheral blood leukocyte
function favorable to patients with UC which refl ect leu-
kocyte hyperactivity. Further investigations are necessary
to explain the precise mechanism of GMCAP.
No serious adverse effects were reported during and
after GMCAP therapy, and almost all patients could
complete the treatment course[9-18]. GMCAP is fairly
safe and well tolerated. The clinical remission and
improvement rates were different among the studies
because many factors such as the indications of GMCAP,
disease activity before GMCAP, protocol of GMCAP
(frequency, duration and a total number of apheresis),
concomitant medications, and the method of efficacy
assessment were different. However, the data from the
previous trials suggest that GMCAP is a useful alternative
therapy for patients with steroid-refractory or -dependent
UC. GMCAP should have the potential to allow tapering
the dose of steroids, and is useful for shortening the time
to remission and avoiding re-administration of steroids
at the time of relapse. Furthermore, GMCAP may have
effi cacy as the fi rst-line therapy for steroid-naive patients
or patients who have the fi rst attack of UC.
The modified apheresis protocols with two sessions
per week, with 90-min session, or a total of 10 apheresis
sessions seem to be more effective than the standard
protocol (weekly, 60-min apheresis and a total of five
sessions). The modified protocol should be used for
patients with more severe diseases, and patients with
milder diseases can be treated with the standard protocol.
However, the most appropriate frequency and duration of
apheresis, and number of apheresis sessions still remain
Yamamoto T
et al.
Leukocytapheresis for ulcerative colitis 523
www.wjgnet.com
unknown. Although several patients maintained their
remission after GMCAP therapy, the long-term efficacy
of GMCAP should be assessed in future. Furthermore,
whether GMCAP is useful as maintenance therapy during
remission needs to be assessed. Most of the previous
studies were uncontrolled trials; only one study was a
randomized, open-labeled, controlled trial comparing
GMCAP and predonisolone[14]. To assess a defi nite effi cacy
of GMCAP, well-designed randomized controlled trials are
necessary. In the United States and Canada, a randomized,
prospective, double-blinded, placebo-controlled (sham-
controlled) study to evaluate the safety and effectiveness
of the Adacolumn apheresis system for the treatment of
moderate-to-severe UC is being conducted[30].
There have been few studies which examined the
effi cacy of GMCAP for Crohn’s disease[16,31-34]. One study
reported that a fi ve-session protocol of GMCAP seemed
to be effi cient in the treatment of steroid-dependent UC,
but not in Crohn’s disease[16]. In contrast, several studies
reported that GMCAP was useful to decrease the disease
activity in patients with Crohn’s disease[31-34]. Kusaka
et al[33] treated six patients with active Crohn’s disease
unresponsive to conventional medications with GMCAP
(five apheresis sessions for five consecutive weeks).
The Crohn’s disease activity index (CDAI) significantly
decreased after GMCAP therapy. Three of the six patients
responded to the therapy, and one patient could be induced
to remission. Fukuda et al[34] treated 21 patients with a
CDAI of >200 and unresponsive to standard medication
with GMCAP (fi ve apheresis sessions for fi ve consecutive
weeks). After GMCAP therapy, signifi cant improvements
in CDAI scores were observed. GMCAP could be effective
for inducing remission and improving the quality of life
in patients with active Crohn’s disease that is refractory to
conventional therapy. However, further clinical studies are
necessary to assess the efficacy of leukocytapheresis for
Crohn’s disease because the number of patients included
in the previous studies was quite small.
A serious problem with GMCAP is cost; a single session
of GMCAP costs ¥145 000 ($1 300). Because of high
cost, GMCAP therapy may not be favorable as a first-
line alternative to steroids in patients with active UC. Up
to now, the most common medication for UC has been
steroids[35,36]. When the patient does not respond to steroids
and the disease is progressing, surgery is implemented as
the last option. Most patients experience adverse effects
associated with high dose and long-term administration
of steroids and hence, they could have a poor quality
of life[35,36]. Patients with active UC can be successfully
treated with leukocytapheresis, without the usage of
corticosteroids, which is good news for both patients and
physicians because the prolonged use of steroids may be
limited and patient compliance diminished by potential
adverse effects. If GMCAP prevents hospital admission,
re-administration of steroids and surgery, and it improves
and maintains a quality of life of the patients, GMCAP
may prove to be cost-effective. The future of GMCAP in
the treatment of UC requires further evaluation.
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