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The clinical efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with Crohn’s disease: A multicenter retrospective cohort study

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Background: A remission induction therapy of granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn was given to patients with active Crohn’s disease (CD). However, establishing an appropriate treatment strategy for GMA in patients with active CD remains unclear. Methods: This multicenter retrospective cohort study encompassed patients with CD who underwent GMA in seven independent institutions in Japan from January 2010 to March 2023. All clinical data were obtained from medical records. This study aimed to evaluate the clinical efficacy, safety, and subsequent clinical progression after GMA in patients with CD. Result: This study enrolled 173 patients with active inflammatory bowel disease who underwent GMA with Adacolumn, and among them, 16 patients with CD with mild to moderate disease activity were analyzed. Concomitant medication, including steroids, immunomodulators, and biologics, was used in 93.7% of all cases. The overall remission and response rates were 25.0% and 68.8%, respectively. The response rate between groups concerning the frequency and total GMA sessions revealed no significant difference. Six (37.5%) patients experienced adverse events (AEs). All AEs were related to the trouble in blood access and recovered soon without any sequelae. Regarding the factors associated with response to GMA, the responder group had a significantly longer disease duration (336 vs 44 months, p = 0.036) and exhibited a relatively lower rate of intestinal strictures and a median score of a simple endoscopic score for CD (SES-CD) (9.1 vs 60 %, p = 0.063 and 10 vs 21.5, p = 0.091, respectively). Further, all patients responding to GMA received biologics that were continuously used before and after GMA. Furthermore, 36.4% of patients remained on the same biologics 52 weeks after GMA. Notably, all patients who continued the same biologics had previously experienced a loss of response to anti-tumor necrosis factor-α agent. Conclusion: Therefore, GMA may exhibit heightened effectiveness in patients with moderately active CD without severe endoscopic activity. Moreover, it represents a potential novel therapeutic option for refractory CD, particularly with insufficient response to biologics.
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The clinical ecacy and safety of granulocyte and
monocyte adsorptive apheresis in patients with
Crohns disease: A multicenter retrospective cohort
study
Nobuhiro Ueno ( u-eno@asahikawa-med.ac.jp )
Asahikawa Medical University Hospital
Seisuke Saito
Furano Hospital
Masahiro Sato
Asahikawa Medical University
Yuya Sugiyama
Asahikawa Medical University
Yu Kobayashi
Asahikawa Medical University
Yuki Murakami
Asahikawa Medical University
Kohjiro Sugimura
Nakashibetsu Town Hospital
Takahiro Sasaki
Asahikawa Medical University
Aki Sakatani
Asahikawa Medical University
Keitaro Takahashi
Asahikawa Medical University
Kazuyuki Tanaka
Asahikawa Kosei General Hospital
Shinya Serikawa
Nayoro City General Hospital
Katsuyoshi Ando
Asahikawa Medical University
Shin Kashima
Asahikawa Medical University
Momotaro Muto
Engaru Kosei General Hospital
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Yuhei Inaba
Asahikawa City Hospital
Kentaro Moriichi
Asahikawa Medical University
Hiroki Tanabe
Asahikawa Medical University
Toshikatsu Okumura
Asahikawa Medical University
Mikihiro Fujiya
Asahikawa Medical University
Research Article
Keywords: Crohns disease, Granulocyte and monocyte apheresis, Clinical response, Biologics, Loss of
response, Biomarker
Posted Date: June 16th, 2023
DOI: https://doi.org/10.21203/rs.3.rs-3037827/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License. 
Read Full License
Page 3/23
Abstract
Background: A remission induction therapy of granulocyte and monocyte adsorptive apheresis (GMA)
with Adacolumn was given to patients with active Crohn’s disease (CD). However, establishing an
appropriate treatment strategy for GMA in patients with active CD remains unclear.
Methods: This multicenter retrospective cohort study encompassed patients with CD who underwent
GMA in seven independent institutions in Japan from January 2010 to March 2023. All clinical data were
obtained from medical records. This study aimed to evaluate the clinical ecacy, safety, and subsequent
clinical progression after GMA in patients with CD.
Result: This study enrolled 173 patients with active inammatory bowel disease who underwent GMA
with Adacolumn, and among them, 16 patients with CD with mild to moderate disease activity were
analyzed. Concomitant medication, including steroids, immunomodulators, and biologics, was used in
93.7% of all cases. The overall remission and response rates were 25.0% and 68.8%, respectively. The
response rate between groups concerning the frequency and total GMA sessions revealed no signicant
difference. Six (37.5%) patients experienced adverse events (AEs). All AEs were related to the trouble in
blood access and recovered soon without any sequelae. Regarding the factors associated with response
to GMA, the responder group had a signicantly longer disease duration (336 vs 44 months,
p
= 0.036)
and exhibited a relatively lower rate of intestinal strictures and a median score of a simple endoscopic
score for CD (SES-CD) (9.1 vs 60 %,
p
= 0.063 and 10 vs 21.5,
p
= 0.091, respectively). Further, all patients
responding to GMA received biologics that were continuously used before and after GMA. Furthermore,
36.4% of patients remained on the same biologics 52 weeks after GMA. Notably, all patients who
continued the same biologics had previously experienced a loss of response to anti-tumor necrosis
factor-α agent.
Conclusion: Therefore, GMA may exhibit heightened effectiveness in patients with moderately active CD
without severe endoscopic activity. Moreover, it represents a potential novel therapeutic option for
refractory CD, particularly with insucient response to biologics.
Introduction
Crohn’s disease (CD) is a gastrointestinal tract idiopathic and chronic inammatory disease. The
introduction of early immunosuppression to prevent irreversible bowel damage and disability is central to
the therapeutic strategy.1 Anti-tumor necrosis factor α (anti-TNF-α) agent administration is a crucial
component of the therapeutic regimen for patients with CD. However, approximately one-third of patients
with CD experience a loss of response (LOR) and require dose escalation after anti-TNF-α therapy
initiation.2
Granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn (JIMRO Co., Takasaki, Japan)
has been used as a nonpharmacological treatment modality for patients with active inammatory bowel
disease (IBD) in Japan. The mechanism of GMA involves Adacolumn, which is lled with cellulose
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acetate beads, interacting with fragment crystallizable gamma receptors expressed at the surface of
activated leukocytes and selectively adsorbing granulocytes and monocytes from the systemic
circulation.3 GMA is mainly used for patients with ulcerative colitis (UC) in remission induction therapy,
and numerous studies have reported its clinical ecacy and safety.
Recent studies have described the combined ecacy of GMA with biologics in patients with UC with
refractory cases4–6 and/or LOR to anti-TNF-α agent cases.7–8 However, clinical data on GMA for patients
with CD are signicantly less, and its clinical position in therapeutic strategy remains unclear. Therefore,
this study aimed to examine the ecacy, safety, and subsequent clinical course after GMA and to clarify
the appropriate treatment strategy in patients with CD.
Material and methods
Study design and ethics
This multicenter retrospective cohort study included all patients with active IBD who underwent GMA with
Adacolumn in seven independent institutions in Hokkaido, Japan, from January 2010 to March 2023.
These institutions included Furano Hospital, Nakashibestsu Town General Hospital, Nayoro City General
Hospital, Engaru Kosei General Hospital, Asahikawa Kosei General Hospital, Asahikawa City Hospital, and
Asahikawa Medical University Hospital. The ethics committees of Asahikawa Medical University
(approval no. 21004) and of each institution reviewed and approved the research methodology following
the Helsinki Declaration (1964, and later versions).
Data collection
CD diagnosis for all patients was based on the criteria established by the Japanese Ministry of Health,
Labor and Welfare. Patients with CD with stoma were excluded from this study because these patients
cannot calculate the CD activity index (CDAI). All clinical data were obtained from medical records.
Baseline characteristics, including age, gender, extent of CD according to the Montreal classication,
disease course, disease duration, body weight, intestinal complication, including stricture, stula, perianal
lesion, and short bowel syndrome, clinical history, CDAI, simple endoscopic score for CD (SES-CD), white
blood cell (WBC) count, hemoglobin level (g/dL), platelet count, serum total protein (TP) level (g/dL),
serum albumin (ALB) level (g/dL), C-reactive protein (CRP) level (mg/dL), enteral nutrition, concomitant
medications, including 5-aminosalicylic acid (5-ASA), corticosteroid/budesonide, immunomodulators,
biologics, and duration of biologic administration during the entry into GMA were collected. Follow-up
clinical data after GMA, including CDAI, WBC count, hemoglobin level (g/dL), platelet count, TP level
(g/dL), ALB level (g/dL), and CRP level (mg/dL), were also collected to assess the clinical ecacy of
GMA. These follow-up clinical data were determined within 7 days from the last GMA, or the day on which
GMA was canceled. In addition, enteral nutrition, maintenance medications after GMA, including 5-ASA,
corticosteroids, immunomodulators, and biologics and the duration of continued maintenance
medication until 52 weeks were collected to evaluate the sustained ecacy after GMA.
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GMA treatment strategy with Adacolumn
The Japan Ministry of Health approved GMA with Adacolumn (JIMRO Co., Takasaki, Japan) as a
remission induction therapy for all patients with active IBD. The participating institutes contraindicated
GMA in patients with a neutrophil count of < 1500/mm3; hemoglobin of < 8 g/dL; a history of allergic
reaction to anticoagulant; or a serious cardiac, pulmonary, hepatic, or renal disorder. The standard GMA
treatment plan involved 10 sessions with Adacolumn twice a week for ve consecutive weeks. The blood
via venipuncture of an antecubital vein entered Adacolumn and then returned to the patient via the
column outow line. The GMA protocol consisted of ltering 1800 mL per session at a rate of 30 mL/min.
All GMA data, including the total number of sessions, frequency, and AEs, were obtained from the medical
records.
Endpoints and denitions
Clinical outcomes were evaluated within 7 days after GMA initiation and at 52 weeks thereafter.
Evaluation items included the response rate (RR) following GMA, AEs, the change in laboratory test
values before and after GMA, and the duration of sustained ecacy until 52 weeks. The clinical factors
associated with the response to GMA and the change maintenance therapy up to 52 weeks were
statistically investigated to elucidate these evaluation items. Patients missing certain clinical information
at a certain point were still included in this study.
Clinical response was dened as a decrease of > 30% in CDAI score from the baseline after GMA, while
clinical remission was dened as a decreased CDAI score of < 150 after GMA. Relapse was dened as a
CDAI of  150 or a change in the maintenance medication following GMA. Primary non-response to
biologics was dened as an inadequate response to biologics during the remission induction therapy,
while LOR to biologics was dened as relapse despite the continuous biologic administration in the
maintenance therapy.
Statistical analyses
Numerical data are presented as either median with minimum–maximum or interquartile ranges (IQR).
The Mann–Whitney U-test or Fisher’s test was used to compare the demographic characteristics of
patients with and without responses. The Wilcoxon test was used to compare laboratory test values
before and after GMA. Kaplan–Meier methods were used to estimate sustained clinical ecacy after
GMA. The Mann–Whitney U-test or Fishers test was used to analyze demographic parameters that affect
the duration of continued maintenance medication after GMA. A
p
-value of < 0.05 was considered
statistically signicant. All statistical analyses were performed using Statistical Package for the Social
Sciences for Windows (SPSS Inc., Chicago, IL, USA).
Results
Baseline characteristics of all patients
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This retrospective cohort study enrolled 173 patients with active IBD who underwent GMA with
Adacolumn. Among them, 156 patients with active UC and one with CD who underwent ileostomy were
excluded, leaving a total of 16 patients for analysis (Fig.1). Table1 shows the baseline characteristics of
these patients. The median age (min–max) was 45 (16–63) years, and 13 (81.3%) patients were male.
Moreover, 2 (12.5%) patients had ileal type and 14 (87.5%) had ileocolonic type according to the Montreal
classication. All 16 (100%) patients had CD relapse. The median disease duration (IQR) was 157 (58.3–
370.1) months. The median body weight was 51.1 (48.8–55.6). Four (25.0%) patients had intestinal
strictures, 1 (6.3%) had enterocutaneous stula, 10 (62.5%) had perianal lesions, and 5 (31.3%) had short
bowel syndrome. The median CDAI and SES-CD were 255 (235.5–327.9) and 10 (9–19), respectively. The
median WBC count, hemoglobin value, platelet count, TP value, ALB value, and CRP value were 6615
(5132.5–7715), 10.1 (9.8–10.4) g/dL, 26.3 (19.4–34.3), 6.9 (6.3–7.1) g/dL, 2.8 (2.5–3.2) g/dL, and 0.38
(0.11–1.31) mg/dL, respectively. Enteral nutrition was performed in 11 (68.8%) patients. GMA was
concomitantly conducted with 5-ASA in 8 (50.0%), corticosteroid/budesonide in 6 (37.5%),
immunomodulators in 5 (31.3%), anti-TNF-α agent in 13 (81.3%), ustekinumab in 1 (6.3%), and
vedolizumab in 1 (6.3%) patient. Among the 15 patients who received biologics, two with vedolizumab or
ustekinumab had primary non-response to biologics, and 13 with anti-TNF-α agents were LOR to
biologics. The median biologic administration duration was 58 (4.5–79).
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Table 1
Baseline characteristics of all patients.
Variables
Age, years median (IQR) 45 (16–63)
Gender, male N (%) 13 (81.3)
Extent of CD (Montreal classication)
L1 ileal N (%) 2 (12.5)
L3 ileocolonic N (%) 14 (87.5)
Disease course
Relapse/Remitting N (%) 16 (100)
Duration of disease, month median (IQR) 157 (58.3-370.1)
Body weight, kg median (IQR) 51.1 (48.8–55.6)
Stricture N (%) 4 (25.0)
Fistula N (%) 1 (6.3)
Perianal lesion N (%) 10 (62.5)
Short bowel syndrome N (%) 5 (31.3)
Disease activity at entry
CDAI median (IQR) 255 (235.5-327.9)
SES-CD median (IQR) 10 (9–19)
Laboratory data at entry
WBC count median (IQR) 6615 (5132.5–7715)
Hemoglobin, g/dL median (IQR) 10.1 (9.8–10.4)
Platelet count median (IQR) 26.3 (19.4–34.3)
TP, g/dL median (IQR) 6.9 (6.3–7.1)
ALB, g/dL median (IQR) 2.8 (2.5–3.2)
CRP, mg/dL median (IQR) 0.38 (0.11–1.31)
Enteral nutrition N (%) 11 (68.8)
Concomitant medication with GMA
5-aminosalicylic acid N (%) 8 (50.0)
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Variables
Corticosteroid/Budesonide N (%) 6 (37.5)
Immunomodulators N (%) 5 (31.3)
Anti-TNF-alpha agent N (%) 13 (81.3)
Ustekinumab N (%) 1 (6.3)
Vedolizumab N (%) 1 (6.3)
Primary non-response to biologics N (%) 2 (12.5)
Loss of response to biologics N (%) 13 (81.3)
Duration of administration of biologics, month (N = 15) median (IQR) 58 (4.5–79)
Overall clinical ecacy and safety of GMA
Figure 2 summarized all data about GMA, including the clinical ecacy, frequency, and total number of
sessions. Clinical assessments were conducted on all 16 patients, of whom four achieved clinical
remission while 11 responded to GMA. The overall remission rate (ReR) and RR were 25.0% and 68.8%,
respectively (Fig.2A). Concerning the GMA regimen, 6 (37.5%) patients received GMA once a week, while
10 (62.5%) received GMA twice a week. RR for once a week and twice a week were 83.3% and 60.0%,
respectively (Fig.2B). Seven (43.8%) patients underwent 5 sessions of GMA, and 9 (56.2%) patients
underwent 10 sessions of GMA. The total number of GMA sessions depended on the disease activity of
CD, patient tolerance, and GMA therapy response. RR for 5 and 10 GMA sessions were 66.7% and 77.8%,
respectively (Fig.2C). All 16 patients received ltering of 1,800 mL per session at a rate of 30 mL/min in
each GMA session. RR was not signicantly different between groups concerning the frequency and total
session of GMA. However, ReR for twice a week and 10 sessions of GMA was higher than that for once a
week and ve sessions of GMA.
This study revealed AEs in 6 (37.5%) patients during and after GMA. Table2 lists all AEs. Five patients
had diculty in securing blood vessels during GMA and one developed vascular pain (not vasculitis)
after GMA. All AEs were related to the trouble in blood access, and physical AEs were not observed. These
cases were all mild and recovered soon without any sequelae, but GMA was discontinued in two patients
after the fth GMA session due to the patient’s refusal. Four patients completed all planned GMA
sessions.
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Table 2
All adverse events during and after GMA.
Variables All cases continued GMA canceled GMA
All AEs N (%) 6 (37.5) 4 (25) 2 (12.5)
Diculty in securing blood vessels N (%) 5 (31.3) 4 (25) 1 (6.3)
Vascular pain N (%) 1 (6.3) 0 (0) 1 (6.3)
Identication of clinical factors associated with response to
GMA
Patients were divided into the responder and non-responder groups based on their clinical activity
assessed by the CDAI after GMA. Table3 shows the clinical factors associated with response to GMA.
The disease duration was signicantly longer in the responder group (336 vs 44 months,
p
 = 0.036).
Moreover, the rate of intestinal strictures and the median of SES-CD were relatively lower in the responder
group (9.1 vs 60%,
p
 = 0.063 and 10 vs 21.5,
p
 = 0.091, respectively). The remaining clinical factors did
not exhibit any signicant differences between the two groups.
Page 10/23
Table 3
The clinical factors associated with response to GMA.
Variables Responder (N=
11) Non-responder (N
=5) p
value
Age, years median
(IQR) 52 (31.5–58.5) 22 (22–51) 0.126
Gender, male N (%) 10 (90.9) 3 (60) 0.214
Extent of CD (Montreal classication)
L1 ileal N (%) 2 (18.2) 0 (0) 1.000
L3 ileocolonic N (%) 9 (81.8) 5 (100) -
Duration of disease, month median
(IQR) 336 (109–378) 44 (18–97) 0.036
Body weight, kg median
(IQR) 50.1 (48.7–
53.3) 50.5 (47.9–51.7) 0.533
Stricture N (%) 1 (9.1) 3 (60) 0.063
Fistula N (%) 0 (0) 1 (20) 0.313
Perianal lesion N (%) 7 (63.6) 3 (60) 1.000
Short bowel syndrome N (%) 5 (45.5) 0 (0) 0.119
Disease activity at entry
CDAI median
(IQR) 260 (241.1-
345.1) 237 (213-288.7) 0.282
SES-CD median
(IQR) 10 (8.5–14.5) 21.5 (20.3–22.8) 0.091
Laboratory data at entry
WBC count median
(IQR) 6830 (5125–
7655) 6400 (5690–
8910) 0.692
Hemoglobin, g/dL median
(IQR) 10.1 (9.6–10.3) 10.2 (10.1–11.4) 0.332
Platelet median
(IQR) 21.6 (19.1–
31.7) 34.1 (24.5–39.1) 0.234
TP, g/dL median
(IQR) 6.8 (6.2–7.1) 7.2 (6.9–7.3) 0.257
ALB, g/dL median
(IQR) 2.9 (2.5–3.3) 2.7 (2.5–3.2) 0.775
CRP, mg/dL median
(IQR) 0.22 (0.1–1.2) 0.42 (0.33–1.28) 0.648
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Variables Responder (N=
11) Non-responder (N
=5) p
value
Enteral nutrition N (%) 9 (81.8) 2 (40) 0.245
Concomitant medication with GMA
5-aminosalicylic acid N (%) 4 (36.4) 4 (80) 0.282
Corticosteroid N (%) 5 (45.5) 1 (20) 0.588
Immunomodulators N (%) 2 (18.2) 3 (60) 0.245
Anti-TNF-alpha agent (loss of
response) N (%) 10 (90.9) 3 (60) 0.214
Ustekinumab (primary non-
response) N (%) 0 (0) 1 (20) 0.313
Vedolizumab (primary non-
response) N (%) 1 (9.1) 0 (0) 1.000
Duration of administration of
biologics, month
median
(IQR) 69 (6.5–79) 9 (2.5–56.8) 0.472
The Change in laboratory test values before and after GMA
The change in laboratory test values before and after GMA were compared in all patients, responders, and
non-responders (Fig.3). No signicant difference was found in WBC count, hemoglobin level, platelet
count, and TP level before and after GMA in all patients, responders, and non-responders. However, the
ALB level after GMA was signicantly higher than that before GMA in all patients (2.8 to 3.1,
p
 = 0.039),
but not in responders and non-responders. In addition, the CRP level was signicantly higher after GMA
than that before GMA only in non-responders (0.42 to 1.14,
p
 = 0.043), but not in all patients and
responders. Blood transfusions were performed in two patients, and no one received albumin products.
Sustained clinical ecacy after GMA
Eleven patients who exhibited a response to GMA were followed up for 52 weeks. Table4 shows the post-
GMA characteristics of these patients. Of the cohort, one patient (9.1%) had intestinal strictures, none had
enterocutaneous stula (0%), 7 (63.6%) had perianal lesions, and 5 (45.5%) had short bowel syndrome.
The median CDAI was 165.7 (139.9–196.2). The median WBC count, hemoglobin value, platelet count,
TP value, ALB value, and CRP value were 6530 (5850–8505), 10.4 (9.6–11.7) g/dL, 20.5 (17–33.6), 7
(6.9–7.3) g/dL, 3.1 (2.7–3.7) g/dL, and 0.41 (0.10–0.61) mg/dL, respectively. Enteral nutrition was
employed in 9 (81.8%) patients. Following GMA, 5-ASA was prescribed for maintenance medication in 4
(36.3%) patients, corticosteroid/budesonide in 1 (9.1%), immunomodulators in 4 (36.3%), anti-TNF-α
agent was administered in 10 (90.9%), and vedolizumab in 1 (9.1%). All patients who responded to GMA
were administered biologics, and these patients continued the same biologics as before GMA. Of the
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cohort, one patient discontinued immunomodulators during GMA, one patient initiated budesonide, and
three patients received immunomodulators on biologics following GMA.
Table 4
The post-GMA characteristics of all patients.
Variables
Stricture N (%) 1 (9.1)
Fistula N (%) 0 (0)
Perianal stula N (%) 7 (63.6)
Short bowel syndrome N (%) 5 (45.5)
Disease activity at entry
CDAI median (IQR) 165.7 (139.9-196.2)
Laboratory data at entry
WBC count median (IQR) 6530 (5850–8505)
Hemoglobin g/dL median (IQR) 10.4 (9.6–11.7)
Platelet count median (IQR) 20.5 (17-33.6)
TP, g/dL median (IQR) 7 (6.9–7.3)
ALB, g/dL median (IQR) 3.1 (2.7–3.7)
CRP, mg/dL median (IQR) 0.41 (0.10–0.61)
Enteral nutrition N (%) 9 (81.8)
Maintenance medication after GMA
5-aminosalicylic acid N (%) 4 (36.3)
Corticosteroid/Budesonide N (%) 1 (9.1)
Immunomodulators N (%) 4 (36.3)
Anti-TNF-alpha agent (loss of response) N (%) 10 (90.9)
Vedolizumab (primary non-response) N (%) 1 (100)
The same biologics were continued in four of the 11 (36.4%) patients up to 52 weeks. The median time of
continuous same biologics following GMA was 30 weeks (Fig.4). Patients monitored for up to 52 weeks
after GMA were divided into two groups based on their biologic treatment regimen, including those who
continued with the same biologics and those who switched biologics. Table5 outlines the clinical factors
potentially associated with switching biologics after GMA. No signicant differences were observed
Page 13/23
between the groups based on these clinical factors. However, all four patients who continued the same
biologics were LOR to anti-TNF-α agents.
Page 14/23
Table 5
The clinical factors potentially associated with switching biologics after GMA.
Variables Continued same
biologics (N=4) Switched
biologics (N=7) p-
value
Stricture N (%) 1 (25) 0 (0) 0.364
Perianal stula N (%) 3 (75) 4 (57.1) 1.000
Short bowel syndrome N (%) 2 (50) 3 (42.9) 1.000
Disease activity at entry
CDAI median
(IQR) 182.9 (147.2-215.1) 165.7 (132.7-
173.2) 0.571
Laboratory data at entry
WBC count median
(IQR) 6240 (5930–7450) 6820 (5200–
8505) 0.850
Hemoglobin, g/dL median
(IQR) 9.6 (8.7–10.6) 11.2 (9.9–12.1) 0.185
Platelet count median
(IQR) 19.8 (18-23.4) 23.8 (16.7–35.8) 0.571
TP, g/dL median
(IQR) 6.9 (6.6–7.2) 7.2 (6.9–7.3) 0.635
ALB, g/dL median
(IQR) 3.1 (2.7–3.6) 3.1 (2.9–3.6) 0.925
CRP, mg/dL median
(IQR) 0.23 (0.1–0.43) 0.51 (0.24–0.96) 0.286
Enteral nutrition N (%) 4 (100) 5 (71.4) 0.491
Concomitant medication with
biologics
5-aminosalicylic acid N (%) 1 (25) 3 (42.9) 1.000
Corticosteroid/Budesonide N (%) 0 (0) 1 (14.3) 1.000
Immunomodulators N (%) 1 (25) 3 (42.9) 1.000
Biologics
Anti-TNF-alpha agent (loss
of response) N (%) 4 (100) 6 (85.7) 1.000
Vedolizumab (primary non-
response) N (%) 0 (0) 1 (14.3) 1.000
Discussion
Page 15/23
This multicenter retrospective cohort study evaluated the clinical ecacy and safety, including
subsequent clinical progression, after GMA in patients with active CD. Our ndings indicate that GMA is
associated with a high RR and favorable safety prole, underscoring that serum ALB and CRP levels may
serve as valuable biomarkers for predicting clinical ecacy. Notably, GMA demonstrated ecacy even in
patients who have experienced a LOR to biologic, indicating that GMA enables long term continuous use
of the same biologics to restore their ecacy.
This study enrolled 173 patients with active IBD who underwent GMA with Adacolumn from seven
independent institutes, but only 17 (9.8%) patients had active CD. The analysis included 16 cases with a
median CDAI (IQR) of 255 (235.5–327.9) and a median SES-CD of 10 (9–19). All these patients
presented with active lesions in the small intestine, and most cases received concomitant medication,
including steroids/budesonide, immunomodulators, and biologics. Furthermore, these patients exhibited
ineffectiveness in response to biologics, including both primary non-response and LOR to biologics. The
overall ReR and RR were 25.0% and 68.8%, respectively, even in such refractory cases. GMA combined
with biologics has been reported to be effective in a small number of refractory CD cases.9,10 These
indicate that GMA is a considerable treatment even in combination with biologics for patients with
moderately active disease although GMA utilization for active CD in real world clinical practice remains
limited.
ReR for twice a week and 10 sessions of GMA was higher than that for once a week and ve sessions of
GMA although with no signicant difference in RR between groups regarding the frequency and total
session of GMA. All of the AEs observed in this study were attributed to issues related to blood access,
and physical symptoms were not reported. These cases were all mild and recovered soon; however, GMA
was discontinued in two cases. Fukuda et al. rst reported signicant improvements from baseline to
week seven in the CDAI (
p
 = 0.0005) in 21 patients with mild to moderate active CD who received GMA as
an adjunct to ongoing medication for ve sessions.11 In contrast, Sands et al. conducted a randomized
double-blind control study, involving 235 patients with moderate to severely active CD, and demonstrated
no clinical ecacy for 10 sessions of GMA (RR, GMA vs. sham; 28.0% vs. 26.9%).12 A validation study of
the GMA protocol by Yoshimura et al. revealed that intensive GMA (10 sessions, twice a week) was not
superior to weekly GMA (10 sessions, once a week), but the time to clinical remission was signicantly
shorter in the former without an increase in AEs.13 Fukuchi et al. reported high rates of clinical remission
(81.8%) at 52 weeks in 22 corticosteroid and biologics-naive patients with early diagnosed CD who
received intensive GMA (10 sessions, twice a week) and immunomodulators without serious AEs.14
Conversely, a small number of consecutive patients with refractory CD who received intensive GMA (10
sessions, twice a week) combined with biologics achieved clinical remission at week 10.9,10 Additionally,
GMA has been widely recognized as a safe and well-tolerated treatment for UC.15,16 Thus, intensive GMA
is considered an effective treatment in patients with CD with mild to moderately active disease although
clinical ecacy of GMA for patients with CD was controversial. GMA has also demonstrated a safe
prole in patients with CD; however, securing blood vessels is considered the most important issue to
complete intensive GMA, especially in patients with dehydration, undernourishment, and anemia.
Page 16/23
The analysis of factors associated with response to GMA revealed a signicantly longer disease duration
in the responder group (336 vs 44 months,
p
 = 0.036). Additionally, the responder group exhibited a
relatively lower rate of intestinal strictures and a median score of SES-CD (9.1 vs 60%,
p
 = 0.063 and 10 vs
21.5,
p
 = 0.091, respectively). Our previous study regarding patients with UC revealed that the clinical
remission group had a signicantly longer disease duration compared to the non-clinical remission
group17 while no previous reports have described clinical factors related to GMA response in patients with
CD. Moreover, several large cohort studies have indicated that GMA does not respond well to severe
endoscopic activity in patients with UC.6,15,16 The results of the present study align with these previous
studies conducted on patients with UC and may apply to select the patient suitable for GMA. However,
objective biomarkers are necessary to predict GMA responsiveness because disease activity and
endoscopic activity scores are subjective assessments. We have previously reported that fecal
calprotectin is a useful biomarker for estimating the clinical ecacy of GMA in patients with UC.17 The
present study revealed a signicantly higher ALB level after GMA than that before GMA in all patients
who did not receive albumin products. Moreover, the CRP level after GMA was signicantly higher than
that before GMA only in non-responders. These items may serve as biomarkers for GMA clinical ecacy
evaluation. Among these, CRP is known to be upregulated in IBD, especially CD, compared to UC,18 and
maybe a potential biomarker for predicting the effectiveness of GMA in patients with active CD.
Furthermore, we investigated the sustained clinical ecacy after GMA up to 52 weeks. All patients who
responded to GMA were administrated biologics, and these patients continued the same biologics as
before GMA. The same biologics were continued in four of the 11 (36.4%) patients up to 52 weeks.
Notably, all patients who continued the same biologics had previously experienced LOR to anti-TNF-α
agents. Yokoyama et al. revealed that GMA therapy decreased serum anti-iniximab antibody levels in
patients with IBD who had LOR to iniximab.8 These results suggest that GMA may contribute to
restoring a therapeutic effect in a proportion of patients with CD who lost response to biologics, allowing
for long term continuous use of the same biologics. Limited information is available on the subsequent
clinical progression after GMA. Fukuchi et al. reported 81.8% in sustained clinical remission at 52 weeks
with corticosteroid- and biologic-naive early diagnosed CD receiving intensive GMA and
immunomodulators.11 The usefulness of immunomodulators as maintenance therapy after GMA is
controversial in patients with UC. Ishiguro et al. reported the effectiveness of GMA in corticosteroid-naive
patients, and the sustained ecacy was greater in those who did not receive immunomodulators during
GMA.19 Our previous report revealed that immunomodulators after GMA contributed to sustaining clinical
remission up to 52 weeks in patients with UC receiving biologics as maintenance therapy.6 This study
revealed that concomitant use of immunomodulators did not affect the long term ecacy of biologics. A
substantial number of cases are needed to assess the additional effect of immunomodulators on
biologics after GMA in patients with active CD.
Our ndings, as well as previous studies, suggest that GMA may exhibit more effectiveness in cases with
moderate active disease without severe endoscopic activity. It could potentially serve as a therapeutic
option for refractory CD, particularly in individuals who have not adequately responded to biologics.
Page 17/23
However, certain limitations associated with our study should be acknowledged. Specically, this was a
retrospective cohort study with a small number of patients whose clinical information was not perfectly
collected on some points. Moreover, treatment plans are separately determined by each physician, and
assessing the disease and endoscopic activity of the patients varied. Furthermore, concomitant
medications were collected only during admission, thereby excluding the medications initiated during
GMA. Furthermore, the dose and the frequency of each concomitant medication during and after GMA
were not investigated. Further investigations employing prospective observational studies on a larger
scale are warranted to establish a comprehensive therapeutic strategy.
Conclusion
To our best knowledge, this is the rst study demonstrating the effectiveness of GMA, even in patients
with refractory CD with LOR to biologic therapy. GMA may facilitate the continuous and long term use of
the same biologics to restore their ecacy in selected cases. We propose that GMA may exhibit
heightened effectiveness in patients with moderately active CD without signicant endoscopic activity.
Moreover, it represents a potential novel therapeutic option for refractory CD, particularly among those
with insucient response to biologic treatments.
Abbreviations
CD: Crohns disease; anti-TNF-α: anti-tumor necrosis factor α; LOR: loss of response; GMA: granulocyte
and monocyte adsorptive apheresis; IBD: inammatory bowel disease; UC: ulcerative colitis; CDAI: Crohns
disease activity index; SES-CD: simple endoscopic score for Crohns disease; WBC: white blood cell; TP:
total protein; ALB: albumin; CRP: C-reactive protein; 5-ASA: 5-aminosalicylic acid; AEs: adverse events; RR:
response rate; IQR: interquartile ranges; ReR: remission rate
Declarations
Ethics approval and consent to participate
The need for informed consent was waived by ethics committee of Asahikawa Medical University
(approval no. 21004) because it is a study which uses only information such as medical records without
using samples.
Consent for publication
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author
upon reasonable request.
Page 18/23
Competing interests
N. Ueno has received personal fees from JIMRO Co. Ltd. and Alfresa Pharma Corporation; grants and
personal fees from Pzer Inc. T. Okumura has received grants from AbbVie Inc, Nippon Kayaku Co. Ltd.,
and Hokkaido Welfare Federation of Agricultural Cooperatives. M. Fujiya received grants from JIMRO Co.
Ltd., ZERIA Pharmaceutical Co. Ltd., K Kissei Pharmaceutical Co. Ltd. Kyowa Kirin Co.,Ltd. and Kamui
Pharma Inc.; grants and personal fees from AbbVie Inc, AYUMI Pharmaceutical Corporation, EA Pharma
Co. Ltd., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma
Corporation, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd.
Pzer Inc, Nobelpharma Co., Ltd. and Alfresa Pharma Corporation; and personal fees from Viatris Inc., ,
Olympus Co. Ltd. S. Saito, M. Sato, Y. Sugiyama, Y. Kobayashi, Y. Murakami, K. Sugimura, T. Sasaki, A.
Sakatani, K. Takahashi, K. Tanaka, S. Serikawa, K Ando, S. Kashima, M. Muto, Y. Inaba, K. Moriichi, and H.
Tanabe have no conicts of interest to declare.
Funding
This study has no funding sources.
Authors’ contributions
NU developed study design. All authors treated inammatory bowel disease patients in each hospital.
SeS, MS, YS, YK, YM, KS, AS, KaT, ShS, KA, MM, and YI collected all clinical data and calculated partial
Mayo score. TS, KeT, KaT, ShS, KA, SK, YI, KM, and HT performed endoscopy and calculated MES. NU and
MF analyzed and interpretated all clinical data. NU, TO and MF drafted manuscript and all author revised
it. All authors have approved the nal version of this manuscript.
Acknowledgements
We extend our heartfelt gratitude to the esteemed physicians and esteemed medical personnel at Furano
Hospital, Nakashibestu Town General Hospital, Nayoro City General Hospital, Engaru Kosei General
Hospital, Asahikawa Kosei General Hospital, Asahikawa City Hospital, and Asahikawa Medical University
Hospital for their collaborative efforts in the comprehensive care of individuals aicted with
inammatory bowel disease.
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Figures
Figure 1
Patients enrolled in this study.
This retrospective cohort study enrolled 173 patients with active IBD who underwent GMA with
Adacolumn. Among them, 156 with active UC and one with CD who underwent ileostomy were excluded,
leaving a total of 16 patients for analysis.
Page 22/23
Figure 2
Clinical ecacy and frequency and the total number of GMA sessions.
The overall remission rate (ReR) and response rate (RR) were 25.0% and 68.8%, respectively. RR for once
a week and twice a week were 83.3% and 60.0%, and for 5 and 10 sessions of GMA were 66.7% and
77.8%, respectively. No signicant difference was found in RR between groups concerning the frequency
and total session of GMA.
Figure 3
Page 23/23
Change in laboratory test values before and after GMA.
No signicant difference was found in WBC count, hemoglobin level, platelet count, and TP level before
and after GMA in all patients, responders, and non-responders. However, the ALB level after GMA was
signicantly higher than that before GMA in all patients, but not in responders and non-responders.
Moreover, the CRP level after GMA was signicantly higher than that before GMA only in non-responders,
but not in all patients and responders.
Figure 4
The proportion of patients who remained on the same biologics after GMA up to 52 weeks.
The same biologics were continued in three of the 11 patients up to 52 weeks. The proportion of patients
who remained on the same biologics after GMA at 52 weeks was 36.4% and the median time of
continuous same biologics following GMA was 30 weeks.
ResearchGate has not been able to resolve any citations for this publication.
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Adalimumab (ADA) is applied to induce remission in patients with Crohn's disease (CD) naïve to chimeric anti-tumor necrosis factor-α (anti-TNF-α), infliximab or patients with loss of response to scheduled maintenance infliximab. Adsorptive granulocyte and monocyte apheresis (GMA) depletes elevated/activated myeloid lineage leucocytes as sources of inflammatory cytokines and has been used to treat patients with CD. This study was to investigate the efficacy of intensive GMA in combination with ADA as remission induction therapy in cases of CD refractory to medications including anti-TNF-α therapies. Between December 2010 and February 2012, 5 consecutive cases with refractory CD were treated with intensive GMA (2 sessions per week) plus ADA to induce remission. CD activity index (CDAI), C-reactive protein (CRP), and endoscopic findings based on the simple endoscopic score for CD (SES-CD) at baseline and 10 weeks post 5 ADA injections were applied to determine treatment efficacy outcomes. At week 10 post ADA treatment, clinical remission together with normal CRP levels were achieved in all 5 cases, while SES-CD scores reflected marked improvement in 3 cases and partial improvement in 2 cases who had extensive deep longitudinal CD lesions. The CDAI and CRP values at baseline were 324 ± 118 and 4.9 ± 3.3 mg/dl, respectively. The corresponding values after treatment were 100 ± 28 (p = 0.024) and 0.2 ± 0.2 mg/dl (p = 0.038). In these 5 cases with medication-refractory CD, combination therapy with intensive GMA followed by 5 ADA shots appeared to be an effective and safe intervention for inducing clinical remission.
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Background and aim: In inflammatory bowel disease (IBD) patients, antibody-to-infliximab (ATI) generation is responsible for loss of response (LOR) and infusion reaction (IR) to infliximab. An immuno-therapeutic approach is considered an option to overcome LOR. Granulocyte/monocyte adsorptive apheresis (GMA) using an Adacolumn has been shown to have clinical efficacy together with immunomodulatory effects in IBD patients. Methods: We developed an ATI-CAI assay utilizing a C1q immobilized plate and applied it to measure ATI in patients who were receiving infliximab, including 56 with sustained response, 76 with LOR, and 6 with IR. Furthermore, 14 patients with LOR and 2 with paradoxical skin reactions who received infliximab+GMA combination therapy were analyzed. Results: Fourteen patients with LOR, 7 with Crohn's disease, and 7 with ulcerative colitis showed significantly improved clinical indices (P=0.0009), and decreased ATI (P=0.0171) and interleukin-6 (P=0.0537) levels at week 8 following initiation of infliximab+GMA therapy. Nine patients who received combination therapy achieved remission, which was maintained to week 24 with infliximab alone. Additionally, cutaneous lesions in 2 patients with IR were improved. ATI-CAI assay efficiency was not influenced by infliximab concentration during the test. Pre- and post-infliximab infusion ATI levels were not different. Patients with ATI greater than the 0.153 μg/mL cut-off value were likely to experience LOR (odds ratio 3.0). Conclusions: Patients who received infliximab+GMA therapy appeared to regain clinical response to infliximab by a decrease in ATI level. Furthermore, the concentration of infliximab in the test did not influence ATI measurement, though was associated with clinical response.
Article
Objectives: To assess the effectiveness and safety of combining granulocyte-monocyte apheresis (GMA) and vedolizumab (VDZ) in patients with refractory ulcerative colitis (UC). Methods: This retrospective, multicentre pilot study included all UC patients receiving both GMA and VDZ. We recorded data on GMA sessions, demographic characteristics, and clinical response. Effectiveness was assessed 1 and 6 months after finishing the GMA using the partial Mayo score, C-reactive protein, and fecal calprotectin levels. Data were also compiled on VDZ intensification, use of new immunomodulators and colectomy during follow-up. Results: Eight patients were included (mean age 46 years; 63% female; mean disease duration, 132 months; 50% E3). GMA was started after a loss of response to VDZ in all cases (25% primary nonresponse and 75% secondary loss of response). All had previously received anti-TNF agents. VDZ was prescribed as the second-, third-, or fourth-line biologic in 37%, 50%, and 13% of cases, respectively. Patients had a mean baseline partial Mayo score of 7.5 (SD 2.1) and received a median of 15 GMA sessions (range 5-38). After a median follow-up of 7.5 months (IQR 5-12), partial Mayo score decreased after 1 and 6 months (P = .01 and .06, respectively). Three patients (38%) achieved steroid-free clinical remission and five (63%) withdrew VDZ. Colectomy rate was 38%. No adverse events were observed during the combination therapy. Conclusions: This small case series suggests that combining GMA with VDZ could be a treatment option in selected cases of UC with an inadequate response to this biologic agent.
Article
Objective: To evaluate the effectiveness and safety of the combination of granulocyte–monocyte apheresis (GMA) after loss of response (LOR) to anti-tumor necrosis factor (TNF) agents in ulcerative colitis (UC). Materials and methods: A retrospective, multicenter study was performed in 11 inflammatory bowel disease (IBD) Units. Clinical remission was defined as a partial Mayo score ≤2. The effectiveness of the treatment was evaluated by the partial Mayo score and the rate of anti-TNF intensification, switch, swap or colectomy. Results: Forty-seven patients with ulcerative colitis were included (mean age 35 years, mean disease duration 52 months, 66% male and 59% extensive colitis). Twenty-three subjects were receiving infliximab, eighteen adalimumab and six golimumab. GMA was combined after a primary non-response (49%) or secondary loss of response (51%) to anti-TNF therapy. We observed a significant decrease in partial Mayo score and fecal calprotectin after GMA. Fifteen patients (32%) responded to the combination therapy without anti-TNF intensification, switch, swap or colectomy. Eight patients (17%) underwent colectomy. Two patients (4%) presented adverse events related to the technique. Conclusions: Combination of GMA and anti-tumor necrosis factor is a safe and effective treatment after the loss of response to this biologic agents, with a significant decrease of the clinical disease activity and biomarkers, in a population with limited therapeutic alternatives.
Article
Ustekinumab is applied to induce clinical remission in patients with Crohn's disease. Granulocyte and monocyte absorptive apheresis depletes activated myeloid lineage leukocytes and has been applied for active Crohn's disease. This study retrospectively examined the efficacy and safety of combining intensive granulocyte and monocyte absorptive apheresis and ustekinumab for remission induction therapy in refractory Crohn's disease. Between June and September 2017, three consecutive cases (two females) with refractory Crohn's disease were treated with intensive granulocyte and monocyte absorptive apheresis plus ustekinumab. Crohn's disease activity index, and simple endoscopic score for Crohn's disease at baseline and 10 weeks were applied as treatment efficacy outcomes. In all three cases, at week 10, clinical remission was achieved, while simple endoscopic score for Crohn's disease reflected no improvement. Thus, combination therapy with intensive granulocyte and monocyte absorptive apheresis plus ustekinumab appeared to represent a safe and effective intervention for inducing clinical remission.
Article
Background To review the frequency with which anti-TNF-α loses its effect and dose “intensification” is required for Crohn’s disease (CD) treatment. Methods Electronic databases were searched for eligible studies. Raw data from studies meeting inclusion criteria were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes. ResultsEighty-six eligible studies were included. Estimates of loss of response (LOR) incidence ranged from 8 to 71%. The random effects pooled incidence of LOR with a median follow-up of 1-year was 33% (95% CI 29–38, 55 studies, n = 6135). The effect estimate based on data from patients with infliximab was 33% (95% CI 27-40), 30% (95% CI 22–39) for adalimumab, and 41% (95% CI 30–53) for certolizumabpegol. Overall, the mean percentage of patients’ LOR to anti-TNFs was 38.5%. The annual risk for LOR was 20.9% per patient-year. The random-effects pooled rate of need for dose intensification with a median follow-up of 1 year was 34% (95% CI 28–41, 38 studies, n = 10,690). The effect estimate for infliximab was 38% (95% CI 28–50), 36% (95% CI 30–43) for adalimumab, and 2% (95% CI 2–3) for certolizumab-pegol. The mean percentage of patients who needed an anti-TNF dose escalation was 23% with an annual risk of 18.5% per patient-year. There was no evidence of publication bias for incidence of LOR but not for the dose intensification (p = 0.001). Conclusions Overall, around one-third of CD patients experience a LOR and required dose intensification in primary anti-TNF-α responders.