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Safety and clinical efficacy of granulocyte and monocyte adsorptive apheresis therapy for ulcerative colitis

Authors:
  • Yokkaichi Hazu Medical Center

Abstract

Active ulcerative colitis (UC) is frequently associated with infiltration 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 filled 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 five consecutive weeks (a total of five apheresis sessions) has been a standard protocol. Several studies used modified 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, flushing, 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 efficacy as the first-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 definite efficacy 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.
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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,
In 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
in 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 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 ve consecutive weeks (a total of ve apheresis
sessions) has been a standard protocol. Several studies
used modi 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, 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
ef cacy as the 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 de nite ef 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 ef cacy; Granulocyte and monocyte
adsorptive apheresis; Leukocytapheresis; Safety;
Ulcerative colitis
Yamamoto T, Umegae S, Matsumoto K. Safety and clinical
ef 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 in 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 in ammation and patient status in UC. Recently,
leukocytapheresis has been tried as a novel approach for
UC[4,5].
Clinical ef 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 signi 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 ef 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, 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)
Ef 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 ve consecutive weeks; session time, 60 min; blood ow rate, 30 mL/min.
2This study was a randomized controlled trial comparing ef 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 out ow
from Antecubital vein
Bubble
detector
Adacolumn
Drip
chamber
Anticoagulant
administration port
Blood in 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 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 in ow line. Vital signs are
continuously monitored during the apheresis by dialysis
staff. One apheresis session (session time, 60 min; blood
ow rate, 30 mL/min) per week for 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 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 In 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 ef 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 ef 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 ( ve apheresis sessions for
ve consecutive weeks; session time, 60 min; blood 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 rst 6 mo of follow-up.
Higher remission or improvement rates have been
reported using the modi 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
ow rate, 30 mL/min); for patients with severe diseases,
two sessions per week for the rst three weeks and then
weekly session for five weeks; for the other patients,
weekly session for the rst ve weeks and after an interval
of one week, weekly session for another 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 ef 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 signi 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 signi 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 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 ef 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 in ux of new leukocytes into the
systemic circulation from the marginal pools, principally
the bone marrow during apheresis. Thus, the ef 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 in 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 signi cantly increased
in the peripheral blood after apheresis. These observations
suggest that selective granulocyte and monocyte adsorp-
tion is associated with modi ed peripheral blood leukocyte
function favorable to patients with UC which re 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
ef cacy as the rst-line therapy for steroid-naive patients
or patients who have the 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 de nite ef 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
ef cacy of GMCAP for Crohn’s disease[16,31-34]. One study
reported that a ve-session protocol of GMCAP seemed
to be ef 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 ( ve apheresis sessions for ve consecutive
weeks). After GMCAP therapy, signi 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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S- Editor Guo SY L- Editor Elsevier HK E- Editor Bi L
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et al.
Leukocytapheresis for ulcerative colitis 525
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... The initial protocol for GMA involved one session (60 min duration) per week for 5 weeks [38]. Two studies from Japan reported superior clinical outcomes with a more intensive twice-weekly GMA regimen [39,40]. ...
... No serious AEs have been reported to date with its use. Common AEs reported in early studies were headache, dizziness, nausea, flushing, and fever with an incidence of 5-27% [38]. A similar safety profile was observed during real-world use in Japan. ...
Article
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Introduction: Inflammatory bowel disease (IBD) is a chronic immune-mediated disease of the gastrointestinal tract comprising Crohn's disease (CD) and ulcerative colitis (UC). Whereas any part of the digestive tract can be affected in CD, mucosal inflammation in UC is limited to the colon. Differences and similarities between the two conditions are reflected by their pathophysiology. Areas covered: An overview of immunological aspects, pharmacological management and biomarkers of IBD is provided. The role of adsorptive granulocyte and monocyte apheresis (GMA) is reviewed including its primary and secondary effects on the immune system, as well as clinical studies in IBD (mainly UC), and potential biomarkers for adsorptive GMA. Expert opinion: In UC, adsorptive GMA with Adacolumn (Adacolumn®, JIMRO Co., Ltd. Takasaki, Gunma, Japan) selectively depletes elevated myeloid lineage leukocytes and has a range of beneficial secondary immune effects. Adsorptive GMA is a safe and effective non-pharmacological treatment option for UC. Pilot studies have reported promising results for adsorptive GMA in combination with biological agents, although larger studies are required. Fecal calprotectin concentrations, neutrophil counts in histological samples and/or the neutrophil/lymphocyte ratio in peripheral blood may prove to be useful biomarkers for predicting GMA effectiveness in the future.
... Granulocyte and monocyte adsorption apheresis (GMCAP) was first reviewed for use in ulcerative colitis. It uses an extracorporeal column filled with cellulose acetate beads that can adsorb granulocytes and monocytes [71]. The ability to reduce the amount of circulating leukocytes can help decrease inflammation and tissue damage that can be caused by the recruitment of neutrophils in PG. ...
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Pyoderma gangrenosum is a rare inflammatory skin disease classified within the group of neutrophilic dermatoses and clinically characterized by painful, rapidly evolving cutaneous ulcers with undermined, irregular, erythematous-violaceous edges. Pyoderma gangrenosum pathogenesis is complex and involves a profound dysregulation of components of both innate and adaptive immunity in genetically predisposed individuals, with the follicular unit increasingly recognized as the putative initial target. T helper 17/T helper 1-skewed inflammation and exaggerated inflammasome activation lead to a dysregulated neutrophil-dominant milieu with high levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-1α, IL-8, IL-12, IL-15, IL-17, IL-23, and IL-36. Low-evidence studies and a lack of validated diagnostic and response criteria have hindered the discovery and validation of new effective treatments for pyoderma gangrenosum. We review established and emerging treatments for pyoderma gangrenosum. A therapeutic algorithm based on available evidence is also provided. For emerging treatments, we review target molecules and their role in the pathogenesis of pyoderma gangrenosum.
... Granulocyte and monocyte adsorptive apheresis (GMA) is an extracorporeal blood circulation method performed with the Adacolumn (JIMRO, Takasaki, Japan), utilized to selectively remove active granulocytes and monocytes from peripheral blood, and numerous studies have reported good therapeutic efficacy and safety of once-a-week GMA (weekly GMA) treatments in CSdependent as well as -refractory UC patients. (20)(21)(22)(23)(24)(25)(26) Previous reports have shown that the clinical efficacy of GMA for active UC patients is superior to that of CS. (19,27) Moreover, a recent meta-analysis revealed GMA to be a safe and effective therapy for UC patients, with higher rates of clinical remission and response as compared to CS shown. (28) However, an important issue is that weekly GMA requires several weeks for induction of clinical remission. ...
Article
This study examined the long-term maintenance rate after inducing remission by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids (CS) and GMA re-treatment efficacy in the same patients upon relapse with ulcerative colitis. Patients who achieved clinical remission and mucosal healing (MH) by first-time intensive GMA (first GMA) without CS were enrolled. The cumulative non-relapse survival rate up to week 156 was calculated. Patients with relapse during the maintenance period underwent second-time intensive GMA (second GMA) without CS. Clinical remission and MH rates following second GMA were compared to those following first GMA in the same patients. Of the 84 patients enrolled, 78 were followed until week 156 and 34 demonstrated relapse. The cumulative non-relapse survival rate by week 156 was 56.4%. Clinical remission and MH rates after second GMA did not differ from those after first GMA in the same patients (week 6: clinical remission, 100% vs 88.4%, p = 0.134; MH, 100% vs 84.8%, p = 0.074). In conclusion, MH induction by intensive GMA without use of CS in ulcerative colitis patients contributes to subsequent long-term clinical remission maintenance. GMA re-treatment efficacy was comparable to that of first GMA in the same patients who had relapse.
... Recently, extracorporeal apheresis of CD16 positive monocytes has been reported to reduce the severity of inflammatory bowel disease. 38 In the near future, we hope that these or similar monocyte-targeted therapies may prove beneficial in the prevention of atrial fibrosis. ...
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Background: Inflammation, such as that associated with intermediate CD14++CD16+ monocytes and atrial structural remodeling (SRM), may be important in the recurrence of atrial fibrillation (AF) after catheter ablation. However, the relationship between the intermediate CD14++CD16+ monocytes, SRM, and AF recurrence is unclear. Methods: Twenty-four patients with AF were enrolled. The proportion of intermediate monocytes (PIM) was assessed prior to ablation by flow cytometry. As a surrogate marker of SRM, the volume ratio (VR) of signal intensity > 1 standard deviation on late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) was calculated. We investigated whether PIM correlated with SRM on LGE-MRI and determined the optimal cutoff value for predicting AF recurrence. Results: Univariate analysis revealed positive correlations between PIM and BNP with SRM (PIM: r = 0.593, p = 0.002; BNP: r = 0.567, p = 0.004). Multivariable analysis revealed that PIM was independently associated with VR on LGE-MRI (β = 0.522; p = 0.033). The finding of an area under the receiver operating characteristic curve of 0.750 revealed that a VR ≥ 13.3% on LGE-MRI as the optimal cutoff value to predict AF recurrence with 80% sensitivity and 71% specificity, which was associated with PIM ≥ 10.0%. Conclusion: Intermediate monocytes were significantly positively correlated with SRM. PIM ≥ 10% was associated with a VR ≥ 13.3% on LGE-MRI, which predicted AF recurrence after catheter ablation. This article is protected by copyright. All rights reserved.
... Although the roughness may not have been a factor on PC or PVC, we see that it may have been an issue for PS since platelet aggregate coverage was less predictable (Table 2). Fouling on polymers is known to be increased by an elevated level of surface roughness [41,42]. Thus, the results would be comparable with PVC and PC if PS had a Ra of ~0.1. ...
... Furthermore, there is a lack of randomized controlled trials, which could evaluate the effect of LCAP in the management of UC. Data from uncontrolled studies showed a high response rate in corticosteroid-naive patients and remission rate of 50% in patients with steroid-dependent or steroid-refractory UC [14][15][16][17][18][19][20] . Studies have shown that LCAP not only improves clinical symptoms but also is effective in the induction of mucosal healing 21 . ...
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Ulcerative colitis (UC) is a multifactorial disease of unknown precise etiology and immunopathogenesis. Peripheral blood granulocytes and monocytes/macrophages are the major sources of cytokines, which regulate inflammation. Leukocytapheresis (LCAP) is a method where blood is processed by apheresis system that removes lymphocytes and plasma before being returned to the body. We report the first case in Croatia where we used LCAP in the treatment of a patient with severe steroid-dependent UC. After 12 LCAP procedures, good clinical response was obtained and there were no significant adverse side effects noticed. The patient remained in clinical remission over two years in which he underwent regular follow ups at outpatient clinic. Over a 10-year follow-up period after LCAP, the patient had only occasional clinical symptoms of disease activity. The clinical course was complicated with the development of metastatic colorectal carcinoma, which points to the importance of regular disease monitoring rather than the increased risk of malignant disease after LCAP. Patients with UC are a demanding group of patients that warrant the search for novel treatment strategies other than conventional pharmacological therapies. Although LCAP is still not a common treatment modality in our daily practice, data from recent studies suggest it to be an effective and safe procedure in the management of active UC patients.
Chapter
Inflammatory bowel diseases (IBD) have become a major focus for gastroenterologists worldwide, with the increasing incidence and complexity of cases, which pose therapeutic challenges. Currently available approaches fail in controlling the disease activity in a significant proportion of patients and some of the therapies are associated with significant adverse events. Although new molecules are on the horizon and treatment strategies have been optimized, novel therapeutic tools are much needed in IBD for patients who fail to attain control of the disease. Apheresis is now a common non-pharmacological therapeutic modality used in several pathologies, IBD also. In the current review, we summarize currently available evidence with respect to selective apheresis in IBD.
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Inflammation has been suggested to play a key role in the pathogenesis of atrial fibrillation (AF). Our hypothesis was that this inflammation, mediated by intermediate monocytes and toll-like receptor 4 (TLR4), causes the formation and expansion of low-voltage zones (LVZs). Prior to ablation, the monocyte subsets of 78 AF patients and TLR4 expression of 66 AF patients were analyzed via a flow cytometric analysis. Based on the CD14/CD16 expression, the monocytes were divided into three subsets: classical, intermediate, and non-classical. At the beginning of the ablation session, voltage mapping was performed. LVZs were defined as all bipolar electrogram amplitudes of < 0.5 mV. Correlations between the flow cytometric analysis results and presence of LVZs, as well as the total area of the LVZ, were examined. Patients with LVZs clearly had a higher proportion of intermediate monocytes (10.0 ± 3.6% vs. 7.2 ± 2.7%, p < 0.001) than those without LVZs. TLR4 was much more frequently expressed in the intermediate monocytes than other two monocyte subsets (p < 0.001). Moreover, the TLR4 expression level in intermediate monocytes correlated positively with the total area of the LVZs (r = 0.267, p = 0.030), especially in patients with paroxysmal AF (r = 0.365, p = 0.015). The intermediate monocytes and TLR4 expression positively correlated with LVZs in AF patients.
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Crespo et al. comment on the influence of immunomodulators and biological drugs on ulcerative colitis and SARS-CoV-2 infection. Granulo-monocytoapheresis is a treatment used in ulcerative colitis outbreaks, whose mechanism of action is to selectively retain activated granulocytes and monocytes, in order to reduce the inflammatory process.
Article
Objectives: Current options for patients with steroid-dependent, chronic-active ulcerative colitis (UC) with insufficient response/intolerance to immunosuppressants (ISs) and/or biologics are limited. The aim of this study was to assess the long-term outcome of granulocyte/monocyte adsorptive (GMA) apheresis (Adacolumn®) in this population. Materials and methods: Ninety five adults with steroid-dependent active UC and insufficient response/intolerance to IS and/or TNF inhibitors received 5–8 aphereses in a single induction series of ≤10 weeks. Endpoints included rates of remission (clinical activity index [CAI] ≤ 4) at weeks 24 and 48. Results: Of 94 patients (ITT population), remission and response rates were 34.0% and 44.7% at week 24, and 33.0% and 39.4% at week 48. Among 30 patients with prior failure of IS and biologics, 33.3% and 20.0% were in remission at weeks 24 and 48. At both weeks, 19.2% of patients achieved steroid-free remission. Sustained remission or response occurred in 27.7% of patients at 48 weeks. The cumulative colectomy rate at week 96 was 23.4%. Safety was consistent with previous findings. Conclusions: This study confirms findings of the 12-week interim analysis and demonstrates that GMA apheresis provides a safe and beneficial long-term outcome for patients with chronic active UC resistant/intolerant to IS and/or TNF inhibitors.
Article
Active ulcerative colitis (UC) is characterized by activation and infiltration of granulocytes and monocytes/macrophages into the colonic mucosa. The infiltrated leukocytes can cause mucosal damage by releasing degradative proteases, reactive oxygen derivatives, and proinflammatory cytokines. The aim of this trial (conducted in 14 specialist centers) was to assess safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active UC most of whom were refractory to conventional drug therapy. We used a new adsorptive type extracorporeal column (G-1 Adacolumn) filled with cellulose acetate beads (carriers) of 2 mm in diameter, which selectively adsorb granulocytes and monocytes/macrophages. Patients (n = 53) received five apheresis sessions, each of 60 minutes duration, flow rate 30 ml per minute for 5 consecutive weeks in combination with 24.4 ± 3.60 mg prednisolone (mean ± SE per patient per day, baseline dose). During 60 minutes apheresis, 26% of granulocytes, 19.5% of monocytes and 2% of lymphocytes adsorbed to the carriers. At week 7, 58.5% of patients had remission or improved, the dose of prednisolone was reduced to 14.2 ± 2.25 mg (n = 37). The apheresis treatment was fairly safe, only eight non-severe side effects (in 5 patients) were reported. Based on our results, we believe that in patients with active severe UC, patients who are refractory to conventional drugs, granulocyte and monocyte adsorption apheresis is a useful adjunct to conventional therapy. This procedure should have the potential to allow tapering the dose of corticosteroids, shorten the time to remission and delay relapse. J. Clin. Apheresis. 16:1-9, 2001. © 2001 Wiley-Liss, Inc.
Article
We have studied the effects of granulocyte apheresis in 18 patients with ulcerative colitis and 6 with Crohn's disease who had failed to respond to conventional therapy. Patients were treated with weekly apheresis using a granulocyte removal column (GI, Otsuka Pharmaceutical Co., Ltd., London, U.K.). We found a mean reduction in circulating granulocytes of 1.29 × 109 cells/L with no significant alterations in red blood cell monocyte, total lymphocyte, absolute T-helper, or T-cytotoxic lymphocyte counts. There were no significant changes in complement levels or immunoglobulin subclasses. There was a signifycant increase in granulocyte adhesion and a reduction in L-selectin expression. The removal of granulocytes is unlikely to explain the effect of granulocytapheresis. The markedly increased expression of αm integrin/Mac-1 and low L-selectin expression alter the capability of granulocytes to migrate to sites of inflammation and may be responsible for the improvement observed in patients treated with granulocyte apheresis.
Article
To determine immunosuppression by leukocy-tapheresis, we studied the immune profiles of filter-passed lymphocytes (FPLs) in patients with ulcerative colitis. These patients were treated with a leukocytapheresis (LCAP) filter of granulocyte apheresis (GCAP) column. Cytokine profiles or FPLs and peripheral blood mononuclear cells (PBMCs) were examined using interleukin (IL)-4 and interferon-gamma (IFN-7) immunoassay with lectin stimulation. The IL-4 production of LCAP FPLs was significantly higher than in prefilter PBMCs and GCAP column-passed lymphocytes (median: 540 pg/ml 106 cells versus 4.7 and 2.9, respectively, p = 0.001). IL-4 production in PBMCs was increased after LCAP. IFN-γ production was not increased in the FPLs. The IL-4 immune deviation was not shown in the patients treated with GCAP. LCAP FPLs showed increased CD4+DR- cells and decreases CD4+DR+ cells in comparison to PBMCs. LCAP FPLs could produce IL-4 and may lead to bystander suppression.
Article
Quantification of disease severity was studied in 72 patients with ulcerative colitis, who had undergone total 85 clinical courses. We performed a multiple stepwise regression analysis, according to Truelove and Witts' classification, with disease severity as a dependent variable, and with 18 clinical, laboratory, and endoscopic parameters as independent variables. Results showed that disease severity in patients with ulcerative colitis is significantly influenced by five factors, namely, bloody stool, bowel movements, erythrocyte sedimentation rate (ESR), hemoglobin (Hb), and serum albumin. The activity index (AI) developed for ulcerative colitis is expressed as follows: AI = 60 x blood stool + 13 x bowel movements + 0.5 x ESR - 4 x HB - 15 x albumin + 200. Index values below 150, values between 150 and 220, and values above 220 nearly corresponded to mild, moderate, and severe disease, respectively, in Truelove and Witts' classification. We believe that the activity index is useful in evaluation of the effect of medical treatment in patients with ulcerative colitis. Its most important value will be in therapeutic trials.
Article
Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) of unknown etiology. They are characterized by an activation of intestinal mononuclear cells. Cytokines play a crucial role in the regulation of the functions of these cells. An increased synthesis of the cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha), which are primarily synthesized by activated monocytes/macrophages has been described in patients with IBD. The synthesis of interleukin-2 (IL-2) and of interferon gamma (IFN gamma), which are produced by lymphocytes, on the other hand, has been found to be decreased. The published data are, however, not quite consistent. In patients with IBD there is not only a stimulation of the local cytokine production in the gut. The blood levels and the synthesis of the cytokines IL-1, IL-6 and TNF alpha by peripheral blood mononuclear cells are also increased, in particular in patients with Crohn's disease. Drugs, which are commonly used for the treatment of IBD impair the synthesis of these cytokines in monocytes/macrophages.
Article
The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insufficient efficacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be "much improved" by the study physician compared to 22 of the 77 patients (29%) on placebo (p = 0.001). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo (p = 0.0001). Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.
Article
A 5-day intensive intravenous regimen for the treatment of severe attacks of ulcerative colitis has been developed, and the results in forty-nine patients treated in this way in a 5-year period are described. Thirty-six patients were in complete remission at the end of the 5-day course. Four showed clinical improvement without remission, and they all required urgent surgery within the next 6 weeks. The remainder were unchanged by the intravenous regimen and required emergency surgery. This regimen gives a higher remission-rate than has been recorded previously, and failure to respond provides a simple and straightforward indication for surgery without further delay. When used in the treatment of first attacks of the disease, the regimen gives a considerable chance of a prolonged remission. Two-thirds of the first-attack patients who went into remission remained symptom-free during the period of follow-up, which averaged more than 3 years.