Concomitant pharmacologic medications influence the clinical outcomes of granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis: A multicenter retrospective cohort study

doi:10.21203/rs.3.rs-1599678/v1

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Concomitant pharmacologic medications influence the clinical outcomes of granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis: A multicenter retrospective cohort study

https://doi.org/10.21203/rs.3.rs-1599678/v1

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Background: Granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn has been widely used as a remission induction therapy for patients with active ulcerative colitis (UC). However, an appropriate GMA treatment strategy related to concomitant medication in patients with active UC has not been established. Herein, we investigated the influence of concomitant medications in the remission induction of GMA in patients with active UC.

Methods: This multicenter retrospective cohort study included patients with UC who underwent GMA in five independent institutions in Japan from January 2011 to July 2021. Clinical factors associated with clinical remission (CR) were analyzed statistically.

Result: A total of 133 patients with active UC who underwent GMA were included. Seventy-four patients achieved a CR after GMA. The overall CR rate was 55.6%. The multivariable analysis revealed that concomitant medication with 5-aminosalicylic acid, Mayo endoscopic subscore (MES), and concomitant medication with immunosuppressors (IMs) remained as predictors of CR after GMA (p = 0.027, odds ratio [OR] 0.157; p = 0.017, OR 2.983; and p = 0.008, OR 3.361, respectively). In the subgroup analysis in patients with MES 2, concomitant medication with IMs was demonstrated as a significant negative factor of CR after GMA (p = 0.042, OR 2.823). Seventy-four patients who achieved CR after GMA were followed up for 52 weeks. CR was sustained in 24 of 74 patients (32%), and the median remission time was 30 weeks. In the multivariable analysis, the maintenance therapy with IMs was demonstrated as a significant positive factor of sustained CR up to 52 weeks (p = 0.038, OR 2.214). The rate of sustained CR in patients with 5-ASA and IMs was not different when compared with that in patients with 5-ASA only (p = 0.248). On the other hands, the rate of sustained CR in patients with biologics and IMs was significantly higher than that in patients with biologics only (p = 0.002).

Conclusion: GMA was more effective for patients with active UC that relapsed under treatment without IM. Furthermore, the addition of IMs should be considered in patients on maintenance therapy with biologics after GMA.

Ulcerative colitis

Granulocyte and monocyte apheresis

Clinical remission

Immunosuppressors

Biologics

Loss of response

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colonic mucosa and is characterized by alternating periods of relapse and remission.⁽¹⁾ Therefore, patients with UC require life-long medications, including immunosuppressive therapy.

Granulocyte and monocyte adsorptive apheresis (GMA) with an Adacolumn (JIMRO Co., Takasaki, Japan) has been applied as a nonpharmacological treatment strategy and is widely used in the remission induction therapy for patients with active UC in Asia and European Union. The mechanism underlying GMA involves the Adacolumn, which is filled with cellulose acetate (CA) beads, interacting with fragment crystallizable-gamma receptor (FcγR) expressed at the surface of activated leukocytes and selectively adsorbing granulocytes and monocytes from the systemic circulation.⁽²⁾ Numerous reports have described the clinical efficacy and safety of GMA in patients with active UC.^(3)–(22) Previous reports have demonstrated that patients who were most likely to respond to GMA tended to be first attack cases and were steroid-naïve with short disease duration and low disease activity.^(9)–(14) However, GMA has been reported to enable the evaluation of clinical efficacy for refractory UC such as steroid-dependent UC and immunosuppressor (IM)-resistant UC.^(6)(15)(16) Moreover, recent studies have described the combined efficacy of GMA with biologics^(17)–(20) and tofacitinib⁽²¹⁾ in patients with refractory UC. In addition, the combination of GMA with antitumor necrosis factor (TNF) alpha agents has decreased clinical activity and biomarkers even in cases with lost responses to antiTNF-alpha agents.⁽²²⁾ Yokoyama et al. demonstrated that patients with inflammatory bowel disease (IBD) experiencing a loss of response to infliximab appeared to regain clinical response to infliximab after undergoing GMA, as shown by a decrease in the antibody-to-infliximab level.⁽²³⁾ However, no clinical study has compared each concomitant medication in GMA therapy.

Thus, GMA with Adacolumn is considered to potentially exert sufficient effectiveness not only in mild active UC cases but also in refractory cases, such as those dependent on steroids, those resistant to IMs and/or biologics, and even those that lost response to biologics. However, an appropriate GMA treatment strategy related to concomitant medication in patients with active UC has not been established. In this retrospective multicenter cohort study, we investigated whether concomitant pharmacologic medications influence the clinical outcomes of GMA with Adacolumn in patients with active UC.

Study design and ethics

This multicenter retrospective cohort study included patients with active UC who underwent GMA with Adacolumn in five independent institutions in Hokkaido, Japan, from January 2011 to July 2021. These institutions included Nayoro City General Hospital, Engaru Kosei General Hospital, Asahikawa Kosei General Hospital, Asahikawa City Hospital, and Asahikawa Medical University.

The research protocol was reviewed and approved by the ethics committees of Asahikawa Medical University (approval no. 21004) and of each institution in accordance with Helsinki Declaration (1964, and later versions)..

Data collection

All patients were diagnosed with UC based on the criteria of the Japanese Ministry of Health, Labor and Welfare. There were no exclusion criteria. All clinical data were collected from medical records. The baseline characteristics were age, gender, extent of UC according to the Montreal classification, disease course, disease duration, body weight, clinical history, drug allergy, partial Mayo score (PMS); a total of three subscores [0–9]; stool frequency [0–3], rectal bleeding [0–3] and Physician’s global assessment [0–3],⁽²⁴⁾ Mayo endoscopic subscore (MES) [0–3];⁽²⁵⁾ Matts pathological grade [1–5],⁽²⁶⁾ white blood cell (WBC) count, C-reactive protein (CRP) level (mg/dL), fecal calprotectin (FC) level (mg/kg), and concomitant medications including 5-aminosalicylic acid (5-ASA), corticosteroids, IMs, biologics, and calcineurin inhibitor at the start of GMA. Medications initiated during GMA were not included as concomitant medications. In patients treated with IM, additional laboratory data were collected, including lymphocyte count, mean corpuscular volume (MCV) of red blood cells (fl), serum total protein (TP) level (g/dL), serum albumin (ALB) level (g/dL), and serum immunoglobulin G (IgG) level (mg/dL). Follow-up clinical data after GMA, which were determined within 7 days from the last GMA or the day GMA was canceled, included PMS [0–9], MES [0–3], Matts pathological grade [1–5], WBC count, CRP level (mg/dL), and FC level (mg/kg). Furthermore, the duration of sustained clinical remission (CR) until 52 weeks and maintenance therapy after GMA including 5-ASA, IM, and biologics were collected.

GMA therapy with Adacolumn

GMA with Adacolumn (JIMRO Co., Takasaki, Japan) is approved as a remission induction therapy for patients with active UC by the Japan Ministry of Health. In this study, all patients received 5–10 sessions of GMA with Adacolumn once or twice a week for 5–10 consecutive weeks. In each patient, the blood via venipuncture of an antecubital vein entered the Adacolumn and then returned to the patient via the column outflow line. The GMA regimen consisted of a standard protocol, filtering 1800–3000 mL per session at a rate of 30 mL/min.

Endpoints and definitions

Clinical outcomes were assessed after GMA and at 52 weeks thereafter. The primary endpoint was the influence of concomitant medication on the CR after GMA. The secondary endpoints were the influence of maintenance therapy on the sustained CR after GMA up to 52 weeks. To clarify these endpoints, the clinical factors associated with the CR after GMA and up to 52 weeks were statistically investigated. Patients were also included even if the clinical information needed for this study was missing at a certain point.

CR was defined as PMS of ≤ 2 and ≤ 1 for all subscores. Relapse was defined PMS of ≥ 3. 5-ASA intolerance was defined as discontinuation of 5-ASA because of allergy or adverse events. A primary nonresponse to biologics occurs when a patient did not respond well to biologics during the remission induction therapy. Loss of response to biologics was defined as relapse despite continuous administration of biologics in the maintenance therapy.

Statistical analyses

Numerical data are presented as medians with minimum–maximum or interquartile ranges (IQR). The comparison of demographic characteristics between the CR and nonCR groups was performed using the Mann–Whitney U-test. Factors associated with CR after GMA were evaluated by univariate logistic regression analysis. Relevant demographic features with P < 0.10 in the univariable analysis were entered into the multivariate model to identify independent predictors of CR. Sustained CR was estimated by the Kaplan–Meier estimator graphs and the log-rank test. Post GMA demographic parameters that affect the duration of sustained CR were assessed by Cox proportional hazards model. Relevant demographic features with p < 0.10 in the univariable analysis were entered into the multivariate model to identify independent predictors of sustained CR; p < 0.05 was considered significant. Each statistical analysis was performed using the SPSS Statistics for Windows (SPSS Inc., Chicago, IL, USA).

Baseline characteristics of all patients

A total of 133 patients with active UC who underwent GMA with Adacolumn were included in this retrospective cohort study. The baseline characteristics of these patients are shown in Table 1. The median age (min–max) was 46 (15–82) years, and 62 patients (46.6%) were male. Moreover, 97 (72.9%) patients had pancolitis, 33 (24.8%) had left-sided colitis, 1 had proctitis, and 2 had others according to the Montreal classification. Eight patients (6.0%) experienced the first UC attack, whereas 125 (93.9) patients had UC relapse. The median disease duration (IQR) was 58 (22.5–117.2) months. The median body weight (IQR) was 54.1 (47.5–62.3). The median PMS (IQR), MES (IQR), and Matts pathological grade (IQR) were 6 (5–7), 2 (2–3), and 3 (3–4.2), respectively. The median WBC count (IQR), CRP value (IQR), and FC value (IQR) were 7320 (5490–9770), 0.61 (0.1–1.79) mg/dL, and 7031 (2427.9–18480.5) mg/kg, respectively. GMA was conducted concomitantly with 5-ASA in 119 (89.4%) patients, corticosteroids in 56 (42.1%), IMs in 42 (31.5%), antiTNF-alpha agent in 42 (31.5%), vedolizumab in 2 (1.5%), and calcineurin inhibitor in 8 (6.0%). Fourteen patients expressed 5-ASA intolerance. Fifteen patients (11.2%) were primary nonresponders to biologics including antiTNF-alpha agent and vedolizumab, and 29 patients expressed a loss of response to antiTNF-alpha agents.

Table 1

Baseline demographic variables in all patients (N = 133).
Variables
Age, years		Median (min–max)	46 (15–82)
Gender, male		N (%)	62 (46.6)
Extent of UC (Montreal classification)
	Pancolitis	N (%)	97 (72.9)
	Left-sided colitis	N (%)	33 (24.8)
	Proctitis	N (%)	1 (0.7)
	Others	N (%)	2 (1.5)
Disease course
	First attack	N (%)	8 (6.0)
	Relapse/remitting	N (%)	125 (93.9)
Duration of disease, month		median (IQR)	58 (22.5–117.2)
Body weight, kg		median (IQR)	54.1 (47.5–62.3)
Disease activity at entry
	PMS	median (IQR)	6 (5–7)
	MES	median (IQR)	2 (2–3)
	Matts pathological grade	median (IQR)	3 (3–4.2)
Biomarker at entry
	WBC count	median (IQR)	7320 (5490–9770)
	CRP, mg/dL	median (IQR)	0.61 (0.1–1.79)
	FC, mg/kg (N = 39)	median (IQR)	7031 (2427.9–18480.5)
Concomitant medication with GMA
	5-ASA	N (%)	119 (89.4)
	Corticosteroid	N (%)	56 (42.1)
	IMs	N (%)	42 (31.5)
	AntiTNF-alpha agent	N (%)	42 (31.5)
	Vedolizumab	N (%)	2 (1.5)
	Calcineurin inhibitor	N (%)	8 (6.0)
5-ASA intolerance		N (%)	14 (10.5)
Primary nonresponse to biologics		N (%)	15 (11.2)
Loss of response for antiTNF-alpha agent		N (%)	29 (21.8)

Overall clinical efficacy of GMA

In two patients, GMA was canceled after the first GMA session because of severe headache and/or high fever. According to the clinical assessment, 74 patients achieved CR and 57 did not achieve CR (nonCR) after GMA. The overall CR rate was 55.6% (Fig. 1). Furthermore, the CR rates in patients who underwent GMA concomitant with 5-ASA, corticosteroids, IMs, biologics, and calcineurin inhibitor were 61%, 62.5%, 38%, 46.5%, and 87.5%, respectively.

Identification of clinical factors associated with CR after GMA

Patients were divided into the CR and nonCR groups following the assessment of the clinical activity based on the PMS after GMA. The clinical factors associated with CR after GMA are shown in Table 2. In the univariable analysis, concomitant medications with 5-ASA were significantly associated with higher CR rates (p = 0.007); furthermore, MES, concomitant medication with IMs, and loss of response to antiTNF-alpha agent were significantly associated with lower CR rates (p = 0.026, p = 0.004, and p = 0.042, respectively). In the multivariable analysis, concomitant medication with 5-ASA remained as a significantly independent positive factor (p = 0.027, odds ratio [OR] 0.157, 95% confidence interval [CI] 0.030–0.811). Furthermore, MES and concomitant medication with IMs remained as significant independent negative factors of CR after GMA (p = 0.017, OR 2.983, 95% CI 1.216–7.314 and p = 0.008, OR 3.361, 95% CI 1.375–8.216, respectively).

Table 2

Univariate and multivariable analyses of factors associated with clinical remission (CR) after GMA.
					Univariable analysis			Multivariable analysis
Variables			CR (N = 74)	NonCR (N = 57)	P value	OR	95% CI	P value	OR	95% CI
Age, years		Median (min–max)	46.5 (17–82)	45 (15–79)	0.995	1.000	0.980–1.020
Gender, male (vs. female)		N (%)	35 (47.2)	26 (45.6)	0.848	1.070	0.535–2.139
Extent of UC
	Pancolitis (vs. left-sided colitis and others)	N (%)	53 (71.6)	42 (73.6)	0.793	0.901	0.415–1.959
Disease course
	First attack (vs. relapse/remitting)	N (%)	6 (8.1)	2 (3.5)	0.291	2.418	0.469–12.464
Duration of disease, month		Median (IQR)	70 (21–131.2)	40 (23–96)	0.206	0.997	0.992–1.002
Body weight, kg		Median (IQR)	55.3 (48.6–64.0)	53.0 (46.0-59.8)	0.137	0.976	0.945–1.008
Disease activity at entry
	PMS of 3–6 (vs. 7–9)	N (%)	44 (59.4)	32 (56.1)	0.703	1.146	0.569–2.306
	MES of 2 (vs. 3)	N (%)	55 (74.3)	33 (57.8)	0.026	2.476	1.113–5.508	0.017	2.983	1.216–7.314
	Matts pathological grades 2, 3 (vs. 4, 5)	N (%)	24 (32.4)	16 (28.0)	0.322	1.588	0.635–3.970
Biomarker at entry
	WBC count	Median (IQR)	7650 (5755–9970)	7040 (5040–9300)	0.137	1.000	1.000–1.000
	CRP, mg/dL	Median (IQR)	0.43 (0.1–1.60)	0.93 (0.28–2.25)	0.638	1.027	0.920–1.146
	FC, mg/kg	Median (IQR)	10010.5 (2927.3–21319.2)	4715 (1218–10409)	0.116	1.000	1.000–1.000
Concomitant medication
	with 5-ASA (vs. without)	N (%)	72 (97.2)	46 (80.7)	0.007	0.116	0.025–0.548	0.027	0.157	0.030–0.811
	with corticosteroid (vs. without)	N (%)	35 (47.2)	21 (36.8)	0.231	0.650	0.321–1.316
	with IMs (vs. without)	N (%)	16 (21.6)	26 (45.6)	0.004	3.040	1.421–6.503	0.008	3.361	1.375–8.216
	with antiTNF-alpha agent (vs. without)	N (%)	19 (25.6)	22 (38.5)	0.116	1.820	0.863–3.836
	with vedolizumab (vs. without)	N (%)	1 (1.3)	1 (1.7)	0.852	1.304	0.080–21.300
	with calcineurin inhibitor (vs. without)	N (%)	7 (9.4)	1 (1.7)	0.103	0.171	0.020–1.431
	with a primary nonresponse to biologics (vs. without)	N (%)	9 (12.1)	6 (10.5)	0.771	0.850	0.284–2.543
	with a loss of response to antiTNF-alpha agent (vs. without)	N (%)	11 (14.8)	17 (29.8)	0.042	2.434	1.034–5.272	0.105	2.359	0.835–6.665

Identification of clinical factors associated with CR after GMA in patients with MES 2

Endoscopic activity is a known predictor of CR after GMA in a large cohort study.⁽¹¹⁾ In our study, we conducted a subgroup analysis of patients with MES 2, which indicated a moderately active UC. Clinical factors associated with CR after GMA are shown in Table 3. In the univariable analysis, concomitant medication with 5-ASA was significantly associated with higher CR rates (p = 0.085). Furthermore, concomitant medication with IMs and antiTNF-alpha agents and loss of response to antiTNF-alpha agents were significantly associated with lower CR rates (p = 0.010, p = 0.082, and p = 0.058, respectively). In the multivariable analysis, concomitant medication with IMs remained as a significant independent negative factor of CR after GMA (p = 0.042, OR 2.823, 95% CI 1.040–7.666).

Table 3

Univariate and multivariable analyses of factors associated with CR after GMA in patients with MES 2.
					Univariable analysis			Multivariable analysis
Variables			CR (N = 52)	NonCR (N = 33)	P value	OR	95% CI	P value	OR	95% CI
Age, years		Median (min-max)	46.5 (17–82)	44 (15–74)	0.477	0.991	0.966–1.016
Gender, male (vs. female)		N (%)	23 (44.2)	14 (42.4)	0.870	1.076	0.446–2.597
Extent of UC
	Pancolitis (vs. left-sided colitis and others)	N (%)	38 (73.0)	23 (69.6)	0.736	1.180	0.451–3.090
Duration of disease, month		Median (IQR)	70 (18.5–128.5)	37.5 (28–47.7)	0.247	0.996	0.989–1.003
Body weight, kg		Median (IQR)	55.25 (48.3–61.5)	52 (43.6–59.7)	0.139	0.965	0.920–1.012
Disease activity at entry
	PMS of 3–6 (vs. 7–9)	N (%)	33 (63.4)	32 (56.1)	0.763	0.868	0.347–2.174
	Matts pathological grades 2, 3 (vs. 4, 5)	N (%)	20 (38.4)	16 (47.0)	0.466	1.515	0.496–4.625
Biomarker at entry
	WBC count	Median (IQR)	7240 (5657.5–9947.5)	6610 (4900–9120)	0.148	1.000	1.000–1.000
	CRP, mg/dL	Median (IQR)	0.43 (0.09–1.62)	0.53 (0.14–1.03)	0.348	0.902	0.726–1.119
	FC, mg/kg	Median (IQR)	7517 (3046–25226)	4582 (2129.2–9724.2)	0.107	1.000	1.000–1.000
Concomitant medication
	with 5-ASA (vs. without)	N (%)	50 (96.1)	28 (84.8)	0.085	0.224	0.041–1.231	0.115	0.235	0.039–1.423
	with corticosteroid (vs. without)	N (%)	25 (48.0)	10 (30.3)	0.107	0.470	0.187–1.179
	with IMs (vs. without)	N (%)	11 (21.1)	16 (48.4)	0.010	3.508	1.352–9.102	0.042	2.823	1.040–7.666
	with antiTNF-alpha agent (vs. without)	N (%)	14 (26.9)	15 (45.4)	0.082	2.262	0.902–5.671	0.790	1.224	0.277–5.404
	with vedolizumab (vs. without)	N (%)	1 (1.9)	1 (3.0)	0.745	1.594	0.096–26.388
	with calcineurin inhibitor (vs. without)	N (%)	6 (11.5)	1 (3.0)	0.196	0.240	0.028–2.087
	with a primary nonresponse to biologics (vs. without)	N (%)	7 (13.4)	5 (15.1)	0.827	1.148	0.332–3.970
	with a loss of response for biologics (vs. without)	N (%)	8 (15.3)	11 (33.3)	0.058	2.750	0.967–7.817	0.356	2.184	0.416–11.478

Comparison of demographic variables between patients with IMs in CR and nonCR groups

We compared the body weight and laboratory data in patients with concomitant medication with IMs, as they may have a potential to influence the effectiveness of GMA. The result is shown in Table 4. No significant difference was found in the body weight, WBC count, lymphocyte count, MCV, TP, ALB, and IgG between the groups; however, the CRP value was significantly higher in the nonCR group (p = 0.021).

Table 4

Comparison of demographic variables between CR and nonCR in patients with IMs.
Variables		CR (N = 16)	NonCR (N = 26)	P value
Body weight, kg	Median (IQR)	61.7 (52.6–66.9)	55.1 (43.7–59.9)	0.286
WBC count	Median (IQR)	7645 (6012–7960)	6165 (4420–7880)	0.195
Lymphocyte count	Median (IQR)	1210 (1116–1634)	1400 (1004–1665)	0.907
MCV, fl	Median (IQR)	87.9 (84–91)	86.3 (81.6–93.6)	0.797
TP, g/dL	Median (IQR)	7.0 (6.6–7.3)	6.8 (6.0–7.1)	0.159
ALB, g/dL	Median (IQR)	4.0 (3.4–4.4)	3.6 (3.0–4.0)	0.082
CRP, mg/dL	Median (IQR)	0.09 (0.03–0.56)	0.67 (0.14–1.43)	0.021
IgG, mg/dL	Median (IQR)	1365.5 (996.2–1517.1)	1150(998.9–1549.1)	0.938

PostGMA characteristics of patients with CR

A total of 74 patients with active UC who underwent GMA achieved CR. The postGMA characteristics of the 74 eligible patients are shown in Table 5. The median PMS (IQR), MES (IQR), and Matts pathological grade (IQR) were 1 (1–2), 1 (1–2), and 3 (2–4), respectively. The median WBC count (IQR), CRP value (IQR), and FC value (IQR) were 6750 (5432.5–7755), 0.1 (0.03–0.18) mg/dL, and 469 (141.5–1230.5) mg/kg, respectively. The maintenance therapy after GMA included 5-ASA in 72 (97.2%) patients, IMs in 27 (36.4%), biologics in 20 (27.0%), and IM and biologics in 8 (10.8%).

Table 5

PostGMA demographic variables in patients with CR (N = 74).
Variables
Disease activity after GMA
	PMS	Median (IQR)	1 (1–2)
	MES	Median (IQR)	1 (1–2)
	Matts pathological grade	Median (IQR)	3 (2–4)
Biomarker after GMA
	WBC count	Median (IQR)	6750 (5432.5–7755)
	CRP, mg/dL	Median (IQR)	0.1 (0.03–0.18)
	FC, mg/kg	Median (IQR)	469 (141.5–1230.5)
Maintenance therapy after GMA
	5-ASA	N (%)	72 (97.2)
	IMs	N (%)	27 (36.4)
	Biologics	N (%)	20 (27.0)

Rate of patients sustained CR after GMA

Seventy-four patients who achieved CR after GMA were followed up for 52 weeks. CR was sustained in 24 of the 74 patients (32%), and the median remission time was 30 weeks. (Fig. 2A)

Clinical factors associated with sustained CR after GMA

The patients were divided into the CR and relapse groups following the assessment of the clinical activity based on the PMS after GMA up to 52 weeks. Clinical factors associated with sustained CR after GMA are shown in Table 6. In the univariable analysis, WBC count and maintenance therapy with IMs were significantly associated with a higher sustained CR rate (p = 0.034 and p = 0.023, respectively). In the multivariable analysis, maintenance therapy with IMs remained as a significant independent positive factor of sustained CR up to 52 weeks (p = 0.038, OR 2.214, 95% CI 1.046–4.638, respectively).

Table 6

Univariate and multivariable analyses of factors associated with relapse after GMA.
					Univariable analysis			Multivariable analysis
Variables			CR (N = 34)	Relapse (N = 40)	P value	OR	95% CI	P value	OR	95% CI
Disease activity after GMA
	PMS of 0, 1 ( vs. 2)	N (%)	22 (64.7)	23 (57.5)	0.379	1.327	0.707–2.491
	MES of 0, 1 ( vs. 2)	N (%)	15 (44.1)	17 (42.5)	0.640	0.834	0.390–1.782
	Matts pathological grades 1–3 ( vs. 4, 5)	N (%)	4 (11.7)	4 (10.0)	0.821	1.157	0.326–4.107
Biomarker after GMA
	WBC count < 6700 (vs. >6700)	N (%)	23 (67.6)	15 (37.5)	0.034	2.004	1.005–3.808	0.060	1.856	0.973–3.538
	CRP, mg/dL < 0.1 (vs. >0.1)	N (%)	20 (58.8)	25 (62.5)	0.589	0.838	0.441–1.591
	FC, mg/kg < 500 (vs. >500))	N (%)	5 (14.7)	5 (12.5)	0.549	0.645	0.154–2.704
Maintenance therapy after GMA
	with 5-ASA (vs. without)	N (%)	33 (97.0)	39 (97.5)	0.424	0.047	0.000–83.888
	with IMs (vs. without)	N (%)	18 (52.9)	9 (22.5)	0.023	2.373	1.1226–5.001	0.038	2.214	1.046–4.638
	with biologics (vs. without)	N (%)	7 (20.5)	13 (32.5)	0.215	0.654	0.335–1.279

Rate of sustained CR among patients with IM after GMA

CR was sustained in 14 of the 27 patients (51.8%) with IMs, and the proportion of sustained CR in patients with IMs was significantly higher than that in patients without IMs (p = 0.017). (Fig. 2B) We also evaluated the effectiveness of IMs on maintenance therapy with 5-ASA or biologics. CR was sustained in 11 of the 19 patients (57.8%) with 5-ASA and IMs, and the proportion of sustained CR in patients with 5-ASA and IMs was not different when compared with that in patients with 5-ASA only (p = 0.248). (Fig. 2C) CR was sustained in 6 of the 8 patients (75.0%) with biologics and IMs, and the proportion of sustained CR in patients with biologics and IMs was significantly higher than that in patients with biologics only (p = 0.002). (Fig. 2D) Furthermore, CR was sustained in 4 of the 5 patients (80.0%) with primary nonresponse to biologics and IMs, and the proportion of sustained CR in patients with primary nonresponse to biologics and IMs was significantly higher than that in patients with primary nonresponse to biologics only (p = 0.043). (Fig. 2E) CR was sustained in 2 of the 3 patients (66.6%) with loss of response to biologics and IMs, and the proportion of sustained CR in patients with loss of response to biologics and IMs was significantly higher than that in patients with loss of response to biologics only (p = 0.041). (Fig. 2F)

In this multicenter retrospective cohort study, we evaluated whether concomitant pharmacologic medications influence the rates of CR and sustained CR in patients with active UC who underwent GMA with Adacolumn. To the best of our knowledge, this is the first study to demonstrate that concomitant medication with IMs was a negative factor for the remission induction therapy by GMA. Moreover, maintenance therapy with IMs after GMA was a positive factor for sustained CR, especially in patients treated with biologics.

In this study, patients with moderately active and refractory UC were largely included based on the baseline characteristics. Moreover, 74 patients achieved CR after GMA, and the overall CR rate was 55.6%. Furthermore, the CR rates in patients who underwent GMA concomitant with 5-ASA, corticosteroids, IMs, biologics, and calcineurin inhibitors were 61%, 62.5%, 38%, 46.5%, and 87.5%, respectively. This clinical effectiveness was nearly equivalent to those in previous reports with refractory cases such as steroid-dependent and IM-resistant UC (CR rates of 71%, 36%, and 34%, respectively) ^(6)(15)(16). However, no clinical study has compared each concomitant medication in GMA therapy.

In the multivariable analysis of factors associated with CR after GMA, concomitant medication with 5-ASA or IMs and MES at the start of GMA were demonstrated as predictors of CR after GMA. In a large cohort study, Yamamoto et al. reported that patients with moderately to severely active UC who had severe endoscopic activity did not respond well to GMA.⁽¹¹⁾ Thus, the endoscopic activity, with deep mucosal lesions and extensive loss of the mucosal tissue, is already known as a negative factor of CR after GMA.^(8)(11) To evaluate the influence of concomitant medications, patients with severe endoscopic activity (MES of 3) that decreases the induction rate of GMA were excluded, and the subgroup of only patients with moderate endoscopic activity (MES of 2) was additionally investigated. In the multivariable analysis, concomitant medication with IMs was only demonstrated as a significant independent negative factor of CR after GMA.

In GMA, Adacolumn is filled with CA beads. The mechanisms of disease modification by CA beads, IgG, and C3-derived active complement fragments mediated leukocyte adhesion to CA beads. These plasma proteins on the CA beads interact with FcγR and/or leukocyte complement receptor-like CR3 expressed at the surface of activated granulocytes and monocytes. Thus, CA beads selectively adsorb granulocytes and monocytes from the systemic circulation.^(27)–(29) Activated granulocytes and monocytes absorbed on the CA beads degranulate and induce apoptosis in the Adacolumn. Consequently, GMA would decrease the number of neutrophils in the intestinal mucosa⁽³⁰⁾ and macrophages through the decline of proinflammatory monocytes in the peripheral blood.^(31)(32) Furthermore, apoptotic neutrophils that returned to the systemic circulation from Adacolumn are processed in secondary lymphoid organs, such as the spleen⁽³³⁾ and phagocytosed by CD19(+) B-cells. CD19(+) B-cells, which phagocytosed the apoptotic neutrophils are differentiated into regulatory B-cell and inhibit the activated lymphocytes by increasing the production of the immunosuppressive cytokine interleukin-10.^(34)(35) Regulatory T-cells are induced by dendritic cells that capture these apoptotic neutrophils.^(36)(37) These regulatory T-cells migrate into the inflammation site and then modulate the immune response by suppressing lymphocyte activation.⁽³⁸⁾ Thus, GMA is considered to exert a long-term antiinflammatory effect in patients with active UC. On the contrary, IMs, including azathioprine and a prodrug of 6-mercaptopurine (6-MP), are used to maintain remission and reduce antidrug antibody formation in the monoclonal antibody therapy of patients with IBD. Orally administered IMs are absorbed from the gut and metabolized nonenzymatically to 6-MP in the body. 6-MP is eventually metabolized to 6-thio-guanosine triphosphate (6-TGTP) and 6-thiodeoxyguanosine diphosphate (6-TdGDP). 6-TGTP is incorporated into the RNA, and 6-TdGDP is incorporated into the DNA, inhibiting RNA transcription and DNA replication, respectively, and leading to apoptosis.⁽³⁹⁾ 6-TGTP also causes apoptosis of lymphocytes by inhibiting GTPase Rac1.⁽⁴⁰⁾ Thus, IMs strongly exert immunosuppressive effects on patients with active UC. As mentioned above, a similar antiinflammatory effect between GMA and IMs might cause a lower induction rate in patients who underwent GMA concomitantly with IMs.

The measurement method of the concentration of IMs is not established; therefore, we always adjust the dosage of IMs while referring to the WBC count, lymphocyte count, and MCV value in clinical practice. In this study, concomitant medication with IMs was demonstrated as a negative factor for remission induction by GMA. Regarding the comparison between patients with IMs in the CR and nonCR groups, no significant difference was found in body weight, WBC count, lymphocyte count, MCV, TP, ALB, and IgG. However, the CRP value was significantly higher in the nonCR group. In this study, the medications initiated during GMA were not included as concomitant medications; therefore, IMs were continued before the start of GMA. Patients with IMs in the nonCR group might have decreased WBC count; nevertheless, the CRP value increased, because of the sufficient immunosuppressive effect of IMs. In this study, 42 patients have undergone GMA concomitant with IMs, and the CR rate in patients with IMs was 38% (16/42). In a previous clinical study, the CR rates in patients with resistance to IMs were 36% and 34%, respectively.^(15)(16) Thus, the clinical efficacy of GMA in patients with IMs in our study is not lower than that of patients in a previous clinical report. However, in our study, GMA that was conducted concomitantly with IMs was significantly associated with a lower CR rate than GMA with other concomitant medications. Thus, patients who experienced relapse under treatment with IMs did not respond well to GMA compared with those using other concomitant medications because of a similar antiinflammatory effect that restrained the inflammatory immune response through the suppression of activated lymphocytes between GMA and IMs.

Moreover, in this study, we investigated the clinical factors associated with sustained CR up to 52 weeks. CR was sustained in 24 of 74 patients, and the median remission time was 30 weeks. In the multivariable analysis of factors associated with sustained CR up to 52 weeks in this study, maintenance therapy with IMs was demonstrated as a significant independent positive factor of sustained CR up to 52 weeks. The rate of sustained CR in patients with IMs was significantly higher than that in patients without IMs. However, IMs are usually used to maintain remission and reduce antidrug antibody formation in monoclonal antibody therapy in patients with IBD. Therefore, the additional effectiveness of IMs on maintenance therapy with 5-ASA or biologics was investigated. As a result, the additional effectiveness of IMs was confirmed especially in patients with maintenance therapy using biologics, in both cases of primary nonresponse and loss of response to biologics. Ishiguro et al. reported that GMA was effective for patients who are corticosteroid-naïve, and the efficacy was sustained longer in those not receiving IMs during GMA.⁽¹²⁾ This prospective study included patients with UC who had received GMA as remission induction therapy after showing an inadequate response to 5-ASA preparations as first-line medications. Moreover, the rate of sustained CR in patients with 5-ASA and IMs was also not different from that in patients with 5-ASA only. These results indicate that IMs have no additional effects on 5-ASA preparation as maintenance remission therapy after the remission induction of GMA. On the contrary, Panaccione et al. demonstrated that patients with antiTNF alpha agent-naïve UC who received infliximab and azathioprine were more likely to achieve corticosteroid-free remission than those receiving either monotherapy because IMs are considered to reduce the antidrug antibody formation in monoclonal antibody therapy in patients with IBD.⁽⁴¹⁾ Even in the GMA therapy, apoptotic neutrophils that returned to the systemic circulation from Adacolumn activate the differentiation of regulatory B-cells and inhibit the activated lymphocytes.^(34)(35) Yokoyama et al. demonstrated that an antibody-to-infliximab level in the serum has decreased after GMA therapy in patients with IBD experiencing a loss of response to infliximab.⁽²³⁾ In our study, all patients with biologics as a maintenance therapy without IMs were in relapse within 26 weeks; therefore, we assumed that the clinical effectiveness through the reduction of antidrug antibody by GMA would be attenuated after GMA. Thus, we consider that the maintenance therapy with biologics and IMs after GMA well sustained a CR because of a similar immunosuppressive effect that reduces the production of antidrug antibodies from lymphocytes between GMA and IMs.

The strength of this study is attributed to the analysis of large data from multiple facilities, and it is the first to compare concomitant medications in GMA. However, it was associated with some limitations. Specifically, it was a retrospective cohort study, and patients whose clinical information needed for this study was missing for a certain point and each number of concomitant medications is low were also included. Further investigations with a prospective observation study are needed to establish the therapeutic strategy.

To the best of our knowledge, this is the first study to demonstrate that concomitant medication with IMs was a negative factor for the remission induction therapy by GMA, and the maintenance therapy with IM after GMA was a positive factor for sustained CR, especially in patients treated with biologics. We suggest that GMA was more effective on patients with active UC who were in relapse despite treatment without IM; furthermore, the addition of IMs should be considered in patients under maintenance therapy with biologics after GMA. This therapeutic strategy may contribute to making better decisions in the clinical treatment of patients with active UC.

UC: Ulcerative colitis, GMA: Granulocyte and monocyte adsorptive apheresis, CA: Cellulose acetate, FcγR: fragment crystallizable-gamma receptor, IM: immunosuppressors, TNF: Tumor necrosis factor, IBD: Inflammatory bowel disease, PMS: Partial Mayo score, MES: Mayo endoscopic subscore, WBC: white blood cell, CRP: C-reactive protein, FC: Fecal calprotectin, 5-ASA: 5-aminosalicylic acid, MCV: Mean corpuscular volume, TP: Total protein, ALB: Albumin, IgG: Immunoglobulin G, CR: Clinical remission, IQR: Interquartile ranges, nonCR: Not achieve CR, OR: Odds ratio, CI: Confidence interval, 6-TGTP: 6-thio-guanosine triphosphate, 6-TdGDP: 6-thiodeoxyguanosine diphosphate.

Ethics approval and consent to participate

This multicenter retrospective cohort study was conducted by Nayoro City General Hospital, Engaru Kosei General Hospital, Asahikawa Kosei General Hospital, Asahikawa City Hospital, and Asahikawa Medical University. The research protocol was reviewed and approved by the ethics committees of Asahikawa Medical University (approval no. 21004) and of each institution in accordance with Helsinki Declaration (1964, and later versions).

Consent for publication

This study is a retrospective observational cohort study and does not necessarily require written informed consent because it is a study which uses only information such as medical records without using samples. By disclosing information related to clinical research on our website, we will provide the subject with the opportunity to withdraw from using their own information.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

Y. Sugiyama, Y. Kobayashi, Y. Murakami, T. Iwama, T. Sasaki, T. Kunogi, A. Sakatani, K. Takahashi, K. Tanaka, S. Serikawa, K Ando, S. Kashima, M. Muto, Y. Inaba, K. Moriichi, and H. Tanabe have no conflicts of interest to declare. N. Ueno has received personal fees from JIMRO Co. Ltd. T. Okumura has received grants from AbbVie Inc, EISAI co. Ltd. and Hokkaido Welfare Federation of Agricultural Cooperatives. M. Fujiya received grants from JIMRO 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., and ZERIA Pharmaceutical Co. Ltd.; and personal fees from Aspen Japan K.K., Kissei Pharmaceutical Co. Ltd., Olympus Co. Ltd.

Funding

This study has no funding sources.

Authors' contributions

NU developed study design. All authors treated Ulcerative colitis patients in each hospital. YS, YK, YM, TI, TK, AS, KaT, SS, KA, MM, and YI collected all clinical data and calculated partial Mayo score. TS, KeT, KT, 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 final version of this manuscript.

Acknowledgements

We would like to thank Shohei Kuroda MD, Sho Onoda MD, Mika Yoshii MD, Kenichi Ishigaki MD, Kazuki Muro MD, Moe Yoshida MD, and Kyoko Uehara MD from Asahikawa Medical University; Seisuke Saito MD, Akihito Uehara MD, Hirotaka Nakata MD, Ryuji Sugiyama MD, Masaki Taruishi, MD, PhD, and Yusuke Saitoh, MD, PhD, from Asahikawa City Hospital; Ryunosuke Hayashi MD, Tomonobu Sato MD, and Mitsuru Goto MD from Asahikawa Kosei General Hospital; Shion Tachibana MD, Jyunpei Ikeda MD, Masashi Horiuchi MD, Mizue Muto MD, and Nobuyuki Yanagawa MD, PhD, from Engaru Kosei General Hospital; Ken Terasawa MD, Yuuki Miyazawa MD, and Yasuaki Suzuki MD, PhD, from Nayoro City General Hospital for their cooperative management of patients with UC.

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Competing interest reported. Y. Sugiyama, Y. Kobayashi, Y. Murakami, T. Iwama, T. Sasaki, T. Kunogi, A. Sakatani, K. Takahashi, K. Tanaka, S. Serikawa, K Ando, S. Kashima, M. Muto, Y. Inaba, K. Moriichi, and H. Tanabe have no conflicts of interest to declare. N. Ueno has received personal fees from JIMRO Co. Ltd. T. Okumura has received grants from AbbVie Inc, EISAI co. Ltd. and Hokkaido Welfare Federation of Agricultural Cooperatives. M. Fujiya received grants from JIMRO 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., and ZERIA Pharmaceutical Co. Ltd.; and personal fees from Aspen Japan K.K., Kissei Pharmaceutical Co. Ltd., Olympus Co. Ltd.

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Concomitant pharmacologic medications influence the clinical outcomes of granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis: A multicenter retrospective cohort study

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Abstract

Figures

Introduction

Material And Methods

Study design and ethics

Data collection

GMA therapy with Adacolumn

Endpoints and definitions

Statistical analyses

Results

Baseline characteristics of all patients

Overall clinical efficacy of GMA

Identification of clinical factors associated with CR after GMA

Identification of clinical factors associated with CR after GMA in patients with MES 2

Comparison of demographic variables between patients with IMs in CR and nonCR groups

PostGMA characteristics of patients with CR

Rate of patients sustained CR after GMA

Clinical factors associated with sustained CR after GMA

Rate of sustained CR among patients with IM after GMA

Discussion

Conclusion

Abbreviations

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References

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