Active ulcerative colitis (UC) is characterized by activation and infiltration of granulocytes and monocytes/macrophages into the colonic mucosa. The infiltrated leukocytes can cause mucosal damage by releasing degradative proteases, reactive oxygen derivatives, and proinflammatory cytokines. The aim of this trial (conducted in 14 specialist centers) was to assess safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active UC most of whom were refractory to conventional drug therapy. We used a new adsorptive type extracorporeal column (G-1 Adacolumn) filled with cellulose acetate beads (carriers) of 2 mm in diameter, which selectively adsorb granulocytes and monocytes/macrophages. Patients (n = 53) received five apheresis sessions, each of 60 minutes duration, flow rate 30 ml per minute for 5 consecutive weeks in combination with 24.4 +/- 3.60 mg prednisolone (mean +/- SE per patient per day, baseline dose). During 60 minutes apheresis, 26% of granulocytes, 19.5% of monocytes and 2% of lymphocytes adsorbed to the carriers. At week 7, 58.5% of patients had remission or improved, the dose of prednisolone was reduced to 14.2 +/- 2.25 mg (n = 37). The apheresis treatment was fairly safe, only eight non-severe side effects (in 5 patients) were reported. Based on our results, we believe that in patients with active severe UC, patients who are refractory to conventional drugs, granulocyte and monocyte adsorption apheresis is a useful adjunct to conventional therapy. This procedure should have the potential to allow tapering the dose of corticosteroids, shorten the time to remission and delay relapse.

The administration of steroids is not always effective for the treatment of ulcerative colitis (UC). Their long-term use often causes adverse effects which sometimes result in their stoppage and acute exacerbation. Therefore, an alternative treatment is necessary in order to decrease steroid dosage and avoid the clinical problems associated with steroids. Methods The effectiveness and adverse effects of a leukocytapheresis (LCAP) were investigated in a controlled multicenter trial with randomized assignment of 76 active-stage UC patients in two groups. In the LCAP group (39 patients), LCAP weekly for 5 weeks as an intensive therapy was added to the on-going drug therapy, while steroids were maintained but not increased, and then LCAP was gradually reduced to once every 4 weeks as a maintenance therapy. In the high dose prednisolone (h-PSL) group (37 patients), PSL was added or increased 30 approximately 40 mg/day for moderately severe and 60 approximately 80 mg/day for severe patients and then gradually tapered. Findings The LCAP group showed a significantly higher effectiveness (74% vs. 38%; p=0.005) and lower incidence of adverse effects (24% vs. 68%; p<0.001). The patients were able to continue the trial for a longer period in the LCAP group than the h-PSL group (p=0.012). Clinical activity and endoscopic indexes showed the LCAP group had better improvements than the h-PSL group. Interpretation The results of the trial show that LCAP permits a reduction in total PSL dosage and is more effective and safer than high-dose PSL administration for intensive therapy, and LCAP may maintain remission longer than PSL.

Leukocytapheresis (LCAP), performed with a leukocyte removal filter, was administered five times, at 1-week intervals, for 5 weeks of intensive therapy and five times, at approximately 1-month intervals, for approximately 5 months of maintenance therapy, to 13 patients with inflammatory bowel disease (IBD) diagnosed as ulcerative colitis (UC) in 8 and Crohn's disease (CD) in 5. Clinical and blood examinations showed no side effects in any of the patients. During the intensive therapy, excellent or moderate clinical response was recognized in 11 of the 13 patients (84.6%), of whom 6 had a dramatic response; the excellent or moderate clinical response continued throughout the maintenance therapy in 8 of the patients (61.5%). Flow cytometry showed that the patients who had improved generally had high values for percentages of HLADR+, HLADR+CD3+, and HLADR+CD8+ cells before the first LCAP, and that these values and the C-reactive protein levels and erythrocyte sedimentation rates had decreased to the normal range by the end of both intensive and maintenance therapy. In the patients who showed poor response, in contrast, all the above values had been at or near normal before the initial LCAP administration. The clinical improvement in the absence of any additional medical treatment suggests that LCAP has the capacity to influence the causal mechanism(s) of IBD and that IBD is strongly associated with the cell-mediated immune response.

The importance of tumor necrosis factor (TNF)-alpha and the TNF receptor gene polymorphisms in the etipathogenesis of inflammatory bowel disease (IBD) has not been elucidated. DNA from peripheral blood samples was obtained from 124 patients with Crohn's disease (CD), 106 patients with ulcerative colitis (UC), and 111 unrelated healthy controls. We examined two single nucleotide polymorphisms (SNPs) of the TNF-alpha gene, TNF (-308 G/A and -238 G/A), an SNP of the TNF receptor superfamily member 1A gene, TNFRSF1A(also known as TNFR1), at codon 12 in exon 1 (CCA/CCG), and two SNPs of the 1B gene, TNFRSF1B (also known as TNFR2), (1466 A/G and 1493 C/T). There was a difference in the carrier frequency for haplotype AG (-308 A, -238 G) between UC patients and the controls (OR=4.76, 95% CI=1.53-14.74, P<0.01). We found a significant difference in carrier frequency for haplotype AT (1466 A, 1493 T) of the TNFRSF1B gene between CD patients and the controls (OR=2.13, 95% CI=1.08-4.21, P<0.05). The significance proved to be greater in CD patients with both internal and external fistula (OR=4.8, 95% CI=1.73-13.33, P<0.01), and in those who were poor responders ( n=22) to our treatments, which consisted of nutritional therapy, medical therapy and surgical therapy (OR=9.24, 95% CI=3.37-25.36, P<0.001). This study suggests that one of the genes responsible for UC may be the TNF gene, or an adjacent gene, and that TNFRSF1B gene polymorphisms contribute greatly to the increased onset risk of CD and to the disease behavior.

Inflammatory and/or autoimmune diseases like ulcerative colitis (UC) or Crohn's disease (CD) are debilitating chronic disorders that poorly respond to pharmacological interventions. Further, drug therapy has adverse effects that add to disease complications. The current thinking is that disorders like inflammatory bowel disease (IBD) reflect an over exuberant immune activation driven by cytokines including TNF-alpha. Major sources of cytokines include myeloid leukocytes (granulocytes, monocytes/macrophages), which in IBD are elevated with activation behavior and are found in vast numbers within the inflamed intestinal mucosa. Accordingly, myeloid cells should be the targets of therapy. Adacolumn is filled with cellulose acetate beads that selectively adsorb and deplete myeloid cells and a small fraction of lymphocytes (FcgammaR and complement receptors bearing cells). In one study, 20 steroid naive patients with moderate (n = 14) or severe (n = 6) UC according to Rachmilewitz despite 1.5-2.25 g/day of 5-aminosalicylic acid received 6 to 10 Adacolumn sessions at 2 sessions/week. Efficacy was assessed 1 week after the last session. The majority of patients responded to 6 sessions, 17 (85%) achieved remission. In 2 of the 3 non-responders, CAI was 8 and 12 in 1; all 3 had deep colonic ulcers at study initiation. Decreases were seen in total leukocytes (P = 0.003), % neutrophils (P = 0.003), % monocytes (P = 0.004), an increase in lymphocytes (P = 0.001), decreases in C-reactive protein (P = 0.0002), and rises in blood levels of soluble TNF-alpha receptors I (P = 0.0007), II (P = 0.0045). In a separate study, a case with very severe steroid refractory UC who received up to 11 sessions responded well and avoided colectomy. Further, myeloid cell purging with Adacolumn has been associated with the release of IL-1 receptor antagonist, suppression of TNF-alpha, IL-1beta, IL-6, IL-8, down-modulation of L-selectin and the chemokine receptor CXCR3. In conclusion, selective depletion of myeloid cells appears to induce anti-inflammatory effects and represents a non-pharmacological treatment for patients with active IBD. The treatment has a clear drug-sparing role. Changes in blood levels of inflammatory and anti-inflammatory factors are thought to contribute to the efficacy of this procedure.