Optimization of processing conditions. Clinical effectiveness of LCAP and GMA should be regulated by blood volume for the procedure (Pv), procedure time, and procedure frequency (Qf). Pv can be calculated as: Pv = Blood flow speed (Qb) × Procedure time (Qt).
Basically, slower Qb should reinforce the leukocyte removal performance of the column. Cellsorba, the LCAP column, is unsuitable for proceeding under 20 mL/min of slow Qb conditions since the platelet removal characteristics of the column could cause formation of thromboses in the Cellsorba column.49 On the other hand, Adacolumn, the GMA column, aims to adsorb granulocytes, monocytes/macrophages and a smaller fraction of lymphocytes from the patient's peripheral whole blood on cellulose acetate beads that fill the device. These are the leukocytes that bear the so-called FcγR and complement receptors.4,8–10 Therefore, GMA should be suitable for processing under slow Qb conditions because GMA appears to remove fewer platelets than LCAP.
In spite of these facts, the Pv per extracorporeal hemofiltration session has been ignored in clinical settings. According to recent national surveys, the average body weight of US citizens is 78.9 kg;50 as compared with 58.2 kg for Japanese.51 The Pv per CAP session might be an equally relevant factor bearing in mind that the main function of CAP is to deplete elevated and activated leucocytes of the myeloid lineage, like CD14+CD16+ monocytes which are a major source of TNF-α.22,23 Up to now, however, CAP has been performed at a fixed PV of 3000 mL/session in LCAP and 1800 mL/session in GMA regardless of patient body weight (BW). Recently, we have published the first report for evaluating this point. We conducted open label prospective trials for evaluating the clinical response of BW-adjusted LCAP (BWA-LCAP)49 and GMA (BWA-GMA).52 The results showed that the average Pv in the BWA-LCAP, which was determined as 30 mL/kg × BW (1971 ± 330 mL) per session, provided significant improvements in both the clinical and endoscopic disease activity of UC. Further, these scores after 10 weekly sessions were not significantly different between the BWA-LCAP group and the conventional fixed 3000 mL/session group. However, a significantly higher incidence of adverse event was observed in the 3000 mL LCAP group as compared with the BWA-LCAP group (P < 0.01).49
Conversely, in order to determine the optimum Pv for GMA, 33 UC patients were successfully induced to remission with five weekly GMA sessions at a standard Pv of 1800 mL, and then divided into three groups according to their BW; high body weight (HBW) (≥ 65 kg, n = 11), 50 kg ≤ middle body weight (MBW) < 65 kg (n = 12), and low body weight (LBW) (≤ 50 kg, n = 10). The results indicated that, by the clinical activity index for UC, a significantly higher remission rate was achieved in the LBW (80%) versus MBW (33%) or HBW (27%) at 6 weeks after beginning weekly GMA (P < 0.03). Therefore, we have reported that the lower-limit of optimum Pv/kg should be higher than 39 mL/kg per session for BWA-GMA.52
Recently, Yoshimura et al. reported that GMA could achieve a significant higher clinical efficacy by up to twofold higher processed volume (≥ 60 mL/kg) without any safety concerns.53 We have to optimize the optimum Pv for GMA by adjusting Qt since Qb should be 30 mL/min because of its adsorption mechanism. However, then, we have to consider patient patience for longer Qt because the clinical performance of GMA should be inverse proportion to Qt.
Figure 4 is our hypothesized optimum therapeutic regime of CAP for active UC patients according to the obtained evidence. The optimum Pv of a single CAP session for UC patients should be 30 mL/kg in LCAP and 40 mL/kg in GMA. On the other hand, since established evidence indicates that both functional suppression of circulating leukocytes and the quantitative removal of activated leukocytes contribute to the efficacy of this non-pharmacological therapy,11 it has been hypothesized that there might be an inverse proportion between Qf and immunological effect of CAP. Therefore, twice or more a week procedure of GMA and LCAP (intensive GMA or LCAP) has been recommended, especially for patients experiencing a severe flare. Although there is not sufficient evidence obtained from CD patients, the optimum procedure condition for them should presently be the same as for UC. Nationwide multicenter trials have be planned and started so as to test this hypothesis.
Figure 4. Our hypothesized therapeutic regimen of extracorporeal leukocytapheresis (CAP) for active ulcerative colitis (UC) patients is shown. According to the result from a Japanese nationwide multicenter trial,11 therapeutic frequency should be fixed at twice (or more) a week. In addition, the procedure volume (Pv) has to be adjusted in each case according to their body weight (BW). We propose the optimum Pv values for filtration leukocytapheresis (LCAP) and granulocyte/monocyte apheresis (GMA) are 30 mL/kg per session49 and 40 mL/kg per session,52 respectively (this figure indicates a UC case with 60 kg BW).
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Extracorporeal leukocytapheresis for a long-term maintenance therapy. In the clinical setting, there is a need to establish an effective therapeutic strategy for long-term maintenance of remission without compromising safety. Further, it is reasonable if one can work with a strategy that is very effective as remission induction therapy and then use the same intervention as maintenance therapy as well. This approach has been used with Infliximab.54 CAP has the potential to achieve these intentions. There is evidence to support the clinical efficacy for monthly CAP as an adjunct maintenance therapy in UC patients with steroid-refractory background.3 With this background in mind, we have designed a prospective, single centre, randomized, sham-controlled, double-blind one-year trial with three arms to see if monthly GMA can suppress UC relapse in a population of patients who had achieved remission with a series of weekly GMA sessions.55 At week 48, the avoiding relapse rates (%AR) in True, Sham, and Control were 40%, 9.1%, and 18%, respectively. Interestingly, in patients who could taper their PSL dose to < 20 mg/day during remission induction, the %AR in True was better versus Shan (P < 0.03) or Control (P < 0.05). Future multicenter trials in large cohorts are needed to further strengthen our concept.