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.
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- PATIENTS AND METHODS
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.