Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone

Ulcerative colitis (UC) is one of the two major phenotypes of the chronic inflammatory bowel disease (IBD); the other major phenotype of IBD is Crohn’s disease [1, 2]. UC afflicts millions of individuals throughout the world, causing symptoms like fever, weight loss, diarrhoea, rectal bleeding and abdominal discomfort, which impair individual’s activities and quality of life. Currently, there is no permanent cure for UC, the treatments focus on controlling the disease activity with pharmacologics, often at high doses over long periods of time [1, 3, 4]. Corticosteroids like prednisolone (PSL) have had a major role in the treatment of UC since the pioneering trials by Truelove, and colleagues several decades ago [5, 6]. However, when used in chronic, remitting-relapsing conditions like UC, corticosteroids cause adverse side effects, steroid dependency and refractoriness [1, 3]. It is known that long-term administration of corticosteroids potentially increases the development of osteoporosis, and cataracts as adverse side effects, which are more likely at higher corticosteroid doses [7–9]. Accordingly, in one major study, the incidence of severe adverse events was higher in the high dose PSL group as compared with the low dose group [9].

There is evolving evidence for myeloid lineage leucocytes (granulocytes and monocytes) as major factors in the immunopathogenesis of UC. Thus, patients with UC may harbour elevated peripheral neutrophils [10] in the presence of compromised lymphocytes [11–13]. Further, in UC, neutrophils show activation behavior [14] and prolonged survival [15]. Factors known to promote neutrophil survival include inflammatory cytokines [16], and paradoxically corticosteroids [17]. Indeed, neutrophil activation and prolonged survival is a feature of persistent intestinal inflammation and histological examinations of the mucosal tissue in biopsy specimens from patients with active UC reveals a spectrum of pathologic manifestations among which presence of neutrophils accounts not only for the morphologic lesions of UC, but also for the prevailing patterns of mucosal inflammation [1, 14, 15, 18]. When activated, granulocytes together with monocytes/macrophages produce an array of pleiotropic cytokines like tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12, IL-23 which are strongly inflammatory [19–23]. These have given rise to the inference that elevated and activated granulocytes and monocytes should be targets of therapy in UC. Based on theses observations, the Adacolumn has been developed for selective depletion of granulocytes and monocytes by adsorption (GMA).

In the early 2000, following a major multicentre clinical trial [24, 25], GMA was introduced into the Japan national health reimbursement scheme as remission induction therapy for patients with UC. Subsequently, investigators reported high remission rates and good safety profile for GMA [26–30], but disappointing trial outcomes have been reported as well [31]. In this study, we aimed to assess the efficacy, safety and treatment cost in two cohorts of patients with active UC treated with GMA or with PSL as remission induction therapy.

The major focus of this study was on the safety, efficacy, and the medication cost analyses in patients with active UC being treated by GMA as a non-pharmacologic intervention (GMA group) or with the corticosteroid, PSL (PSL group). All included patients had already achieved remission following these interventions and were reviewed retrospectively. This was possible for the fact that all patients were registered at our hospital and had been treated by the physicians who are the authors of this article. Further, for the analyses we undertook in this study, patients who had achieved remission were included to allow us to see the sustainability of remission achieved with these two interventions. The outcomes might be summarised as follows. As the first treatment end point, we considered UC symptoms, which patients consider as the most serious cause of impaired activities and quality of life. These included diarrhoea, rectal bleeding, and abdominal discomfort. The average time to the cessation of at least one of these symptoms was not significantly different between the patients who received PSL and those who received GMA. The second treatment end point we considered was clinical remission. Similar to the first end point, the average time to remission was not significantly different between the two groups. Further, the efficacy outcomes in terms of CAI reflected the outcomes we monitored as time to the cessation of major UC symptoms and UC remission. The sustainability of remission was another significant consideration in this study. To see this, we applied the Kaplan-Meier survival analysis of remission maintenance during a 600 day follow-up. The rate of relapse was not significantly different between the two groups.

Regarding the cumulative amount of PSL, in the GMA group, patients had relapsed while not being on a corticosteroid (were steroid naïve for that relapse). These patients received GMA as the only medication for that flare up except that AZA could be continued if a patient had started well in advance of receiving GMA. Nonetheless, we calculated the total amount of PSL patients in the two groups had received for the duration of UC disease. Our calculations did not show any significant difference in the amount of corticosteroid patients had received before the start of the medications factored into this investigation (GMA and PSL). This was because, like the patients in the GMA group, patients in the PSL group had relapsed while not being on a corticosteroid. Further, for this investigation, we ensured that all patients in the GMA group remain corticosteroid free during the follow-up time as well and in the PSL group, the dose of PSL was tapered when patients improve and discontinued when patients achieved remission. Accordingly, the cumulative amount of PSL during the present study was 0mg in the GMA group and 1122.4 mg per patient in the PSL group, clearly showing that GMA spares patients from corticosteroids. Similarly, our safety evaluation showed the data to be very much in favour of GMA with just a few transient and non-serious adverse side effects, which is in line with earlier reports on the safety of GMA in patients with UC [10, 12, 25–33]. In contrast, over 40% of patients in the PSL group developed adverse events. However our figures from the calculations of the medication cost was in favour of PSL as this is a relatively inexpensive medication as compared with the single use Adacolumns required for GMA. Our impression is that this cost difference is more than offset by the safety of GMA [36].

Following the publication of the first clinical trial of GMA in patients with UC [24], several investigators from Japan, Europe, and the USA [12, 27–30, 37–43], have reported varying efficacy outcomes ranging from an impressive 85% [12] to a statistically insignificant level [31] Except [31, 37, 38, 41], most other studies did not include a control arm, relying on patients’ disease activity at baseline to serve as a control parameter to judge treatment efficacy [12, 27–30]. Among controlled studies, Maiden et al., used GMA to suppress clinical relapse in one arm, while the control arm received no treatment [14]. At the end of a 6-month follow-up, both the relapse rate and time to clinical relapse were significantly better in the GMA arm [14]. Further, intensive GMA involving two sessions per week was found to be more effective than the routinely applied weekly GMA sessions [44]. Likewise, there are reports saying that patients with deep colonic lesions and extensive loss of the mucosal tissue at the lesion sites show very poor response to GMA [12, 29, 43], while first episode and steroid naïve cases respond well and avoid corticosteroids [12, 29, 39].

The results of this study showed that GMA as a non-pharmacologic treatment intervention in patients with UC produced efficacy equivalent to the corticosteroid, PSL and was without safety concern. In view of serious adverse side effects associated with long-term administration of drugs, GMA is very much favoured by patients for its safety profile. In particular, young and elderly patients should benefit most from GMA as a replacement for corticosteroids and other potentially unsafe medications including biologics. However, the results of this study require further support by a prospective controlled study in large cohorts of patients.