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Keywords:

  • ulcerative colitis;
  • clinical remission;
  • endoscopic inflammation;
  • mucosal healing;
  • granulocyte and monocyte/macrophage adsorptive apheresis

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Background:

During active ulcerative colitis (UC), vast numbers of granulocytes, monocytes/macrophages (GM) infiltrate the mucosal tissue and can potentially exacerbate inflammation and injury. Accordingly, we were interested to see if selective depletion of GM by adsorption (GMA) impacts mucosal healing (MH) in UC patients.

Methods:

In all, 124 patients with clinically and endoscopically active UC received 5 or 10 GMA sessions at one or two sessions/week. The endoscopic severity of mucosal inflammation at entry and 1 week after the last GMA session were scored as follows: 0 = normal mucosa and inactive disease; 1 = mild inflammation; 2 = moderate inflammation; 3 = severe inflammation. Likewise, a score 0 or 1 at post-GMA course was defined as MH.

Results:

At entry the endoscopic severity of the mucosal inflammation was 2 in 100 patients (81%) and 3 in 24 patients (19%). Following the course of GMA, 56 patients (45%) achieved clinical remission (normal stool frequency and no rectal bleeding). Thirty-four of these 56 responders achieved MH; 32 (94%) of the 34 patients with MH had an endoscopic score of 2 (moderate inflammation) at entry. The maintained clinical remission rate was significantly higher in the 34 patients who achieved MH as compared with 22 patients who achieved clinical remission without MH (P = 0.0005).

Conclusions:

MH is achieved more frequently in patients with moderate than with severe endoscopic severity at entry. Further, patients with MH have a reduced risk of future clinical relapse as compared with patients who achieve remission without MH. (Inflamm Bowel Dis 2010)

In the management of ulcerative colitis (UC), a number of studies have shown mucosal healing (MH) as a disappearance of endoscopic inflammation in a fraction of patients treated with different medications.1–3 Thus, in patients with mild-to-moderate UC, MH was reported after delayed and sustained release mesalamine.1, 2 Recently, the Active Ulcerative Colitis Trial (ACT) I and II studies were performed in patients with moderate-to-severe UC who had a clinical history of treatment failure with either 5-aminosalicylic acid (5-ASA) or antimetabolite therapy.3 The ACT I trial showed that MH was achieved by significantly more patients in the infliximab (IFX) groups (5 mg/kg, 62.0% and 10 mg/kg, 59.0% at week 8) than in the placebo group (33.9%).5 The ACT II trial reported similar results (5 mg/kg, 60.3% and 10 mg/kg, 61.7% at week 8 versus placebo, 30.9%).3

The principal goal of treatment in patients with UC has been induction and maintenance of remission. However, nowadays an increasing number of physicians view MH as an important sign of treatment efficacy and a prognostic marker of long-term disease management.4, 5 In line with this thinking, a recent population-based study found that MH after 1-year treatment was predictive of reduced subsequent disease activity and a decreased need for active treatment of inflammatory bowel disease (IBD).6 In patients with UC, MH was associated with a significantly lower risk of future colectomy.

In Japan, multiple open-label studies found that selective granulocyte/monocyte adsorption (GMA) to eliminate the extra load of leukocytes was safe and therapeutically effective in patients with active UC.7–15 Additional evidence to support a therapeutic benefit from GMA in the management of patients with active UC should lead to a reduced need for pharmacologic preparations like corticosteroids, cyclosporine, and biologicals, which are associated with serious adverse effects. However, the impact of GMA on mucosal inflammation in patients with active UC has not yet been fully reported. The primary objective of this study was to investigate the incidence of MH following a course of GMA and the impact of MH on the maintenance rate of clinical remission in patients who responded to this therapy. We were also interested in the predictive factors of MH during the course of GMA therapy as well as clinical efficacy and safety of this treatment.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This was a prospective cohort study undertaken at the Yokkaichi Social Insurance Hospital, a referral center treating a large number of patients with IBD in the Mie Prefecture of Japan. The study was carried out in accordance with principles of good clinical practice, the Declaration of Helsinki, and the study protocol was reviewed and approved by our Institutional Review Board.

Patients

Between July 2002 and August 2008, 147 patients received GMA therapy in our hospital. Patients who met the following inclusion and exclusion criteria were selected for this study. Inclusion criteria were: 1) age between 15 and 75; 2) endoscopic and histologic diagnosis of UC, not having indeterminate colitis; 3) colonic involvement; 4) a Disease Activity Index (DAI)16 score of ≥6; 5) an endoscopy subscore (according to “mucosal appearance” section of the DAI) ≥2; 6) receiving one or more of the following medications: sulfasalazine, mesalamine, corticosteroids, or immunosuppressants, or had not received the above medications due to intolerance or had been found to be nonresponders; and 7) agreed to have endoscopic examinations at entry and after the treatment. The DAI16 we used is a 12-point scoring system which includes “stool frequency,” “rectal bleeding,” “mucosal appearance,” and “physician's overall assessment of disease activity.” The endoscopy subscore was according to the “mucosal appearance” section of the DAI: score 0 = normal mucosa and inactive disease; score 1 = mild inflammation (erythema, decreased vascular pattern, mild friability); score 2 = moderate inflammation (marked erythema, absence of vascular pattern, friability and erosions); and score 3 = severe inflammation (spontaneous bleeding and ulcerations). Exclusion criteria were: 1) patients with evidence of toxic megacolon or fulminant colitis; 2) could not have endoscopic examination due to serious conditions such as peritonitis and sepsis; 3) with malignancy; 4) with serious concomitant cerebral, pulmonary, cardiac, hepatic, or renal disease; 5) laboratory abnormalities including leukocyte count <3000/mm3 or hemoglobin (Hb) <7.0 g/dL; 6) a known bleeding disorder or were receiving concomitant anticoagulant therapy other than for the GMA procedure; and 7) a history of hypersensitivity reaction during an apheresis. Twenty-three of the 147 patients could not be included due to serious conditions, having mild disease (DAI <6), or an endoscopic score of 1. In all, 124 consecutive patients who met the inclusion and exclusion criteria were investigated in this study. Table 1 shows baseline demographic characteristics of the 124 eligible patients.

Table 1. Baseline Demographic Characteristics of 124 Eligible Patients with UC Who Received GMA Therapy
  • UC, ulcerative colitis; GMA, granulocyte and monocyte/macrophage adsorptive apheresis; DAI, disease activity index.16

  • a

    Extending to the splenic flexure.

Age (mean ± SE)37 ± 3.5 years
Male : female72 : 52
Duration of UC before entry (mean ± SE)48 ± 9.5 months
Number of prior relapses (n) 
 023
 1–469
 ≥532
Duration of the current exacerbation before entry (mean ± SE)6 ± 0.6 weeks
Clinical disease severity (n) 
 Severe (DAI score ≥ 9)52
 Moderate (6 ≤ DAI score < 9)72
Endoscopic severity (n) 
 Severe (score 3)24
 Moderate (score 2)100
Medication for the current exacerbation (n) 
 Sulphasalazine or mesalamine119
 Corticosteroids72
 Azathioprine15
Extraintestinal manifestations (n) 
 Arthritis16
 Pyoderma gangrenosum5
Extent of disease (n) 
 Pancolitis40
 Left-sided colitisa57
 Proctosigmoiditis27

GMA Therapy

Patients with moderately active disease (6 ≤DAI score <9) were treated in our outpatient facility, while those with severe disease (DAI score ≥9) were treated as inpatients. GMA therapy was done with the Adacolumn, which is an adsorptive carrier based granulocyte/monocyte apheresis device with a volume of 335 mL, filled with about 220 g cellulose acetate beads of 2 mm diameter as the column adsorptive carriers.17 GMA was administered at two sessions/week in patients with severely active disease, and weekly in patients with moderately active disease. Earlier studies7–12 reported that GMA was well tolerated, with a good safety profile and one study12 found that GMA at 90 minutes/session was superior to 60 minutes/session. Based on these reports, during this study the GMA session time was changed from 60 minutes, at 30 mL/minute (July 2002 to May 2005) to 90 minutes/session, at 30 mL/minute (June 2005 to August 2008). Patients who achieved clinical improvement (a decrease in stool frequency or rectal bleeding) after five GMA sessions, but did not achieve clinical remission (normal stool frequency and no rectal bleeding) were given five additional GMA sessions. Patients who worsened or remained unchanged were not given additional GMA sessions; instead, they could receive conventional medications or surgery if necessary. In patients who were receiving corticosteroids at entry, the dose of steroids was to be tapered or discontinued in line with clinical improvement during the GMA treatment. Patients receiving sulfasalazine, mesalamine or immunosuppressants at entry could continue at the same dosage.

Assessment of Efficacy and Safety

Clinical assessment was made weekly during the GMA treatment. Adverse events, stool frequency, consistency, presence or absence of abdominal pain, tenesmus, rectal bleeding, and mucus discharge were recorded. At entry and after treatment, endoscopic examinations and hematology data were obtained for all patients. Clinical laboratory values included differential leukocyte count, Hb, platelet count, C-reactive protein (CRP), total protein, albumin, creatinine, urea, sodium, potassium, chloride, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactic dehydrogenase (LDH), total bilirubin, and blood cholesterol.

The DAI scores were compared at entry (within 1 week before the first GMA session) and 1 week after the last GMA session. Clinical remission was defined as a score of 0 in the clinical section (stool frequency and rectal bleeding) of the DAI (normal stool frequency and no rectal bleeding). At entry (within 1 week before the first GMA session), in all patients, complete endoscopic evaluation up to the cecum or the terminal ileum was performed mainly for determining the extent of UC and identifying the most severely affected segment. At endoscopy after the GMA therapy (1 week after the last session), mainly the most affected segment at entry was observed. To assess the endoscopic efficacy of the treatment, endoscopic severity of the most inflamed segment was compared before and after the GMA therapy. MH was defined as a score of 0 or 1 in the mucosal appearance section of the DAI after the treatment.

Follow-up

After the GMA therapy, all patients except those who required colectomy were medically followed for longer than 1 year. For patients who achieved clinical remission with the GMA therapy, the dose of corticosteroids was to be tapered or discontinued if they were still on steroids at the end of the GMA therapy. Medications with sulfasalazine, mesalamine, and/or immunosuppressants were continued at the same dose unless a clinical relapse occurred. Patients who did not respond to the GMA therapy were treated with an increased dose of corticosteroids, immunosuppressants, or colectomy.

Statistical Analysis

Comparison of frequencies was by using the chi-square test with Yates' correction. Continuous data are presented as the mean ± SE values. The mean values between two groups were compared using the unpaired t-test. To search for factors that might have affected MH during the course of GMA therapy, both univariate (chi-square test) and multivariate (multiple regression) analyses were done. The cumulative proportion of patients in remission after the GMA therapy was calculated by the Kaplan–Meier method, and compared between groups using the log-rank test. P < 0.05 was considered significant. StatView-J 5.0 was used for the statistical analyses of the data.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Clinical Efficacy and Treatment Safety

Clinical outcomes of GMA therapy are summarized in Table 2. During the GMA therapy, 18 patients (15%) showed worsening UC symptoms such as bloody stool ≥20 times/day, high fever (39–40°C), and abdominal discomfort with peritoneal involvement. In these 18 patients, GMA therapy was discontinued and the patients underwent emergency colectomy. The other 106 patients completed the GMA treatment course; of these, 46 received a total of five GMA sessions each and 60 received 10 sessions each. After the GMA therapy, 56 patients (45%) achieved clinical remission (normal stool frequency and no rectal bleeding), and 29 patients (23%) showed clinical improvement (a decrease in stool frequency or rectal bleeding) without complete remission. The other 21 patients (17%) did not respond to the GMA therapy. The clinical remission rate was significantly higher in patients with moderately active disease at entry than in those with severely active disease (70% versus 11%; P < 0.0001). In this study the clinical efficacy of GMA was not significantly affected by the GMA session time (60 versus 90 minutes).

Table 2. Clinical Outcomes of GMA Therapy in 124 Patients with UC
Clinical Disease SeveritySession Time: 60 : 90 MinutesNumber of Sessions:a 5 : 10Clinical Outcomes
Discontinuation of GMA Therapy (Emergency Colectomy)RemissionImprovedNo Response
  • In each subgroup the number of patients is presented.

  • a

    Eighteen patients who required emergency colectomy during GMA therapy were excluded.

Severe (n=52)18 : 34 3 : 3415 (29%)6 (11%)16 (31%)15 (29%)
Moderate (n=72)25 : 4743 : 263 (4%)50 (70%)13 (18%)6 (8%)
Total (n=124)43 : 8146 : 6018 (15%)56 (45%)29 (23%)21 (17%)

Adverse events were observed in 30 patients (24%). These included: transient headache in 17 patients; fever (37–38°C) in 12; feeling of fatigue in 7; dizziness or nausea in 6; transient abdominal pain with tenesmus and diarrhea in 2; and mild liver dysfunction related to anticoagulant in 1 (several patients experienced more than one adverse event). These adverse events were not serious, and all except patients who required emergency colectomy due to deterioration of UC completed the GMA treatment course.

Mucosal Healing

At entry the endoscopic severity score of the most severely affected segment was 2 in 100 patients (81%) and 3 in 24 patients (19%). In all, 102 patients had endoscopic examination after the GMA therapy (1 week after last session). The remaining 22 patients could not have endoscopy because these included the 18 patients who underwent colectomy (see above) and four who had serious deterioration of UC at the end of the GMA therapy. The changes in endoscopic severity before and after the GMA therapy are presented in Figure 1. Following the course of GMA therapy, 36 patients showed endoscopic improvement (a decrease in the endoscopic score). Among the 36 patients with endoscopic improvement, 34 patients achieved MH (endoscopic score of 0 or 1). Typical endoscopic findings in patients who achieved MH are presented in Figure 2. The other 66 patients did not respond to the GMA therapy endoscopically (no change or an increase in the endoscopic score). Thirty-two (94%) of the 34 patients who achieved MH had an endoscopic score of 2 (moderate inflammation) at entry. Further, all 34 patients with MH achieved clinical remission as well, while 22 patients achieved clinical remission without MH.

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Figure 1. Changes in endoscopic severity scores before and after a course of GMA therapy.

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Figure 2. Representative endoscopic findings at entry and post-GMA course in three patients who achieved MH.

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Factors affecting the likelihood of MH during the course of GMA therapy were also investigated. Age, gender, duration of UC, number of prior relapses, duration of current exacerbation, medications for the current exacerbation, extraintestinal manifestations, clinical severity and extent of UC, and time of one GMA session did not appear to affect the likelihood of MH (Table 3). In contrast, moderate endoscopic inflammation (score 2, marked erythema, absence of vascular pattern, friability, and erosions) was significantly associated with a higher rate of MH as compared with severe endoscopic inflammation (score 3, ulcerations and spontaneous bleeding).

Table 3. Factors Thought to Determine the Likelihood of MH During GMA Therapy
 MH n (%)Univariate Analysis, PaMultivariate Analysis, Pb
  • MH, mucosal healing.

  • a

    The chi-square test.

  • b

    Multiple regression analysis.

Age at entry 0.670.52
 ≤37 years (n = 64)16 (25)  
 >37 years (n = 60)18 (30)  
Gender 0.470.17
 Male (n = 72)22 (31)  
 Female (n = 52)12 (23)  
Duration of UC before entry 0.370.27
 ≤4 years (n = 63)20 (32)  
 >4 years (n = 61)14 (23)  
Number of prior relapses 0.300.41
 ≤4 (n = 92)28 (30)  
 ≥5 (n = 32)6 (19)  
Duration of the current exacerbation before entry 0.370.43
 ≤6 weeks (n = 63)20 (32)  
 >6 weeks (n = 61)14 (23)  
Clinical disease severity at entry 0.130.21
 Severe (n = 52)10 (19)  
 Moderate (n = 72)24 (33)  
Endoscopic severity at entry 0.040.049
 Severe (n = 24)2 (8)  
 Moderate (n = 100)32 (32)  
Corticosteroid therapy at entry 0.610.82
 Yes (n = 72)18 (25)  
 No (n = 52)16 (31)  
Azathioprine therapy at entry 0.810.75
 Yes (n = 15)5 (33)  
 No (n = 109)29 (27)  
Extraintestinal manifestations 0.500.47
 Presence (n = 21)4 (19)  
 Absence (n = 103)30 (29)  
Extent of disease 0.610.75
 Pancolitis (n = 40)10 (25)  
 Left-sided colitis (n = 57)18 (32)  
 Proctosigmoiditis (n = 27)6 (22)  
Time of one GMA session 0.990.88
 60 minutes (n = 43)12 (28)  
 90 minutes (n = 81)22 (27)  

To investigate a likely impact of MH during the GMA therapy on future clinical course, the maintenance rate of clinical remission was compared between the 34 patients who achieved MH (MH group) and the 22 patients who achieved clinical remission without MH (non-MH group). Medication with sulfasalazine, mesalamine, or immunosuppressants were continued at the same dose until a clinical relapse was observed. With a mean follow-up of 22 months, 30 patients (88%) in the MH group and 9 patients (41%) in the non-MH group maintained clinical remission (P = 0.0005). The cumulative proportion of patients in remission was also significantly higher in the MH group than in the non-MH group (P = 0.0005, Fig. 3). Patient demographic factors including age, gender, duration and extent of UC, extraintestinal manifestations, and maintenance medications were not significantly different between the groups. Seventeen patients who developed clinical relapse were treated with corticosteroids, immunosuppressants, or received additional GMA sessions, and 12 of these 17 patients achieved remission again. Five patients who had unremitting UC opted for colectomy at the end of this study.

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Figure 3. The Kaplan–Meier plot showing the cumulative fraction of patients in remission following the course of GMA therapy. The cumulative proportion of patients in remission was significantly higher in the MH group than in the non-MH group (P = 0.0005).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Recently, several studies have reported MH in a fraction of patients with UC who were treated with drug-based medications including novel biologics.1–3 However, as yet, a broadly accepted and used criterion for MH has not been validated.5 In this investigation an endoscopic score ≥2 was the criterion for study inclusion, and an absolute subscore of 0 or 1 was defined as MH. This definition of MH was used in the ASCEND and ACT trials as well, and yet, patients with continued mucosal edema, loss of vascular patterns, and friability were considered to have achieved MH.1, 3 Clearly, further studies are necessary to define MH more appropriately.

In the present investigation we had a relatively large number of patients with various levels of disease activity to investigate the possibility of MH following GMA therapy and its impact on the future clinical course of the disease. We ascertained that GMA treatment was safe and well tolerated, which is in line with hitherto reports.7–15, 18 During this study, 15% of patients underwent an emergency colectomy because of deterioration of UC, and 17% did not respond to the GMA. Both of these figures are higher than in previous GMA studies.7–15 At the last assessment timepoint the clinical remission rate was 45%, which appeared to be much lower than in the previous Japanese studies.7–15 The low remission rate in this investigation could be because only patients with moderate or severe endoscopic disease score were included, excluding those with a mild endoscopic disease score. In this patient population, 34 patients (27%) achieved MH about 1 week after the last GMA session. Most patients who achieved MH had moderate endoscopic inflammation (marked erythema, absence of vascular pattern, friability, and erosions) at entry. Therefore, MH was achieved more frequently in patients with moderate than with severe endoscopic severity at entry. Other clinical parameters such as duration of UC, type of concomitant medications, severity, the extent of UC, and time of GMA did not seem to be relevant. These data suggest that patients with severe endoscopic inflammation are not likely to achieve MH during GMA therapy, and may benefit from alternative medications like biologics and immunosuppressants.

During the first half of the study period, GMA time was set at 60 minutes/session, and was subsequently changed to 90 minutes/session. However, data analyses did not show any significant difference between 60 minutes and 90 minutes for clinical or endoscopic efficacy. Likewise, as stated in Patients and Methods, GMA was given at two sessions/week to patients with severely active disease, and weekly for those with moderately active disease. Therefore, data on the efficacy of one session/week versus two sessions/week could not be compared logically because the results were affected by disease severity and not by the frequency of GMA per se. Further studies are warranted to better understand the impact of GMA session time and frequency on the efficacy of this nondrug-based treatment strategy.

Meucci et al19 assessed rates of clinical remission among 78 patients with UC who received oral and topical 5-ASA/mesalamine. At 6 weeks, 75% of patients were in clinical remission, with endoscopic activity present in only 9% of these patients. Further, the cumulative rate of relapse at 1 year was 23% in patients who had achieved both clinical and endoscopic remission at 6 weeks, as opposed to 80% in patients with clinical remission alone. In the present study we were interested to see the impact of MH during GMA therapy on future clinical course. Albeit a small number of patients, our results clearly showed that MH was associated with maintaining long-term remission. Our impression is that the majority of patients without MH cannot maintain clinical remission in the long-term. In our current practice, azathioprine is given to patients who achieve clinical remission without MH during GMA therapy.

In conclusion, to our knowledge this is the first study with a major focus on MH during GMA therapy of patients with active UC. MH is achieved more frequently in patients with moderate than with severe endoscopic severity at entry. Patients who achieve MH have a reduced risk of future clinical relapse as compared with patients who achieve clinical remission without MH. Further, clinical data from a large number of studies (albeit mostly open trials) indicate that GMA with Adacolumn is an effective nonpharmacologic medication for patients with active UC.7–15, 20–22 Given that GMA has no serious adverse side effect, improved efficacy outcomes from controlled studies should lead to a reduced need for drug-based medication, sparing patients from side effects of pharmacologics.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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    Direct Link:
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