Abby R. Saniabadi

Adacolumn, an adsorptive carrier based granulocyte and monocyte apheresis device for the treatment of inflammatory and refractory diseases associated with leukocytes

Abstract:  Apheresis has been recognized both economically and therapeuticallyas a novel approach for the treatment of inflammatory diseases,and certain others, which respond poorly to drug therapy. This reportis about Adacolumn, an adsorptive carrier based granulocyteand monocyte apheresis device with a volume of 335 mL,filled with about 220 g of cellulose acetate beads of 2 mmdiameter as the column adsorptive carriers. Pre‐ and post‐columnleukocyte counts have shown that the carriers adsorb about 65% ofgranulocytes, 55% of monocytes and 2% of lymphocytesfrom the blood in the column. Additionally, after apheresis, thereis a marked decrease in inflammatory cytokines (TNF‐α,IL‐1β, IL‐6 and IL‐8) produced by blood leukocytes,together with down‐modulation of l‐selectinand the chemokine receptor CXCR3. Adacolumn has been used to treatpatients with rheumatoid arthritis, ulcerative colitis and HIV infection. Typicalapheresis sessions have been 4–10, at a frequency of oneor two sessions per week. Treatment of patients with Adacolumn hasbeen associated with very promising efficacy and safety data. Accordingly,in Japan, Adacolumn has been approved by the Ministry of Healthfor the treatment of ulcerative colitis. Furthermore, Adacolumnmet the required quality and safety standards for medical devices andreceived an EC certification (CE‐mark) from TUV in 1999. However,although Adacolumn carriers are very efficient in depleting excessand activated granulocytes and monocytes/macrophages, theclinical efficacy associated with Adacolumn apheresis cannot befully explained on the basis of reducing granulocytes and monocytesper se. Hence, a long lasting effect on inflammatory cytokine generation,chemokine activities or immunomodulation is likely, but the precisemechanisms involved are not fully understood yet.

Immunomodulatory Effects of Granulocyte and Monocyte Adsorption Apheresis as a Treatment for Patients with Ulcerative Colitis

Our aim was to understand the mechanism of immunological changes associated with the use of an adsorptive-type extracorporeal device (Adacolumn) that has been developed for selective adsorption of granulocytes and monocytes/macrophages from peripheral blood of patients with active ulcerative colitis. The column is filled with carriers (G-1 beads) that have a diameter of 2 mm and are made of cellulose diacetate. In peripheral blood treated with the G-1 beads or peripheral blood from patients with active ulcerative colitis following granulocyte and monocyte adsorption apheresis, a significant suppression of proinflammatory cytokines (tissue necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-8) production by leukocytes, neutrophil chemotaxis, down-regulation of leukocyte adhesion molecule (L-selectin) and neutrophil adhesion to interleukin-1β-activated endothelial cells were observed. Furthermore, after granulocyte adsorption therapy, the number of CD10-negative premature granulocytes increased, indicating increased turnover of these cells in the circulation. Our observations suggest that selective granulocyte and monocyte adsorption is associated with modified peripheral blood leukocyte function favorable to patients with ulcerative colitis and possibly other autoimmune disorders which reflect leukocyte hyperactivity.

Selective Granulocyte and Monocyte Adsorptive Apheresis as a First-Line Treatment for Steroid Naïve Patients with Active Ulcerative Colitis: A Prospective Uncontrolled Study

Corticosteroid therapy of ulcerative colitis (UC) is associated with frequent adverse side effects and poor quality of life. Recently, adsorptive granulocyte and monocyte/macrophage apheresis has shown efficacy in patients with severe steroid refractory UC. The objective of this study was to investigate if, instead of corticosteroids, adsorptive leukocytapheresis has efficacy as the first-line therapy for steroid-naïve patients with active UC. Twenty patients, aged 15–49 years, with a mean clinical activity index (CAI) of 8.6 were recruited. Adsorptive leukocytapheresis was done with Adacolumn, which contains cellulose acetate beads as adsorptive carriers for granulocytes and monocytes (FcγR and complement receptors expressing leukocytes). Each patient received 6 to 10 leukocytapheresis sessions of 60-min duration, at 2 sessions/week. Efficacy was assessed 1 week after the last session. Post treatment, the mean CAI was 3.0 (P = 0001), and 17 of 20 patients (85%) were in remission. There were significant falls in C-reactive protein (P = 0.0003), total white cell counts (P = 0.003), neutrophils (P = 0.0029), and monocytes (P = 0.0038), an increase in lymphocytes (P = 0.001), and increases in the blood levels of soluble TNF-α receptors I (P = 0.0007) and II (P = 0.0045) in the column outflow (blood return to the patients). Further, at 8 months, 60% of patients had maintained their remission. No severe side effects were reported. In conclusion, adsorptive leukocytapheresis should reduce corticosteroid therapy in patients with moderate UC; cases with early-stage active disease may benefit most.

Adsorptive Granulocyte and Monocyte Apheresis versus Prednisolone in Patients with Corticosteroid-Dependent Moderately Severe Ulcerative Colitis

Background/Aim: Active ulcerative colitis (UC) is often associated with increased peripheral granulocytes and monocytes/macrophages which show activation behavior and prolonged survival time. Further, mucosal granulocyte level parallels intestinal inflammation and can predict UC relapse. Accordingly, our aim was to see if adsorptive granulocyte/monocyte apheresis (GMA) can promote remission and spare steroid in patients with steroid-dependent (SD) UC. Methods: 69 SD patients, at the time of relapse, were randomly assigned to groups I (n = 46) and II (n = 23). The mean dose of prednisolone (PSL) was 12 mg/day/patient, CAI (clinical activity index) 9.2 in both groups. Group I patients were given up to 11 GMA sessions over 10 weeks with Adacolumn; in group II, the mean dose of PSL was increased to 30 mg/day/patient. Results: At week 12, 83% of group I and 65% of group II patients were in remission, CAI in group I was 1.7 (p < 0.001) and in group II, 2.5 (p < 0.001). Further, during the 12 weeks of treatment, the cumulative amount of PSL received per patient was 1,157 mg in group I and 1,938 mg in group II (p = 0.001). Conclusions: GMA appeared to be an effective adjunct to standard drug therapy of moderately severe UC by promoting remission and sparing steroids.

Studies on the mechanisms of leukocyte adhesion to cellulose acetate beads: an in vitro model to assess the efficacy of cellulose acetate carrier-based granulocyte and monocyte adsorptive apheresis.

Abstract: Granulocyte and monocyte adsorptive apheresis (GMA) using a column filled with cellulose acetate (CA) beads (carriers) has been associated with a significant clinical efficacy in patients with rheumatoid arthritis and ulcerative colitis. To obtain further understanding on the mechanisms of disease modification by cellulose acetate‐carrier‐based GMA, in the present study, we investigated the mechanisms of granulocyte and monocyte adhesion to CA beads following exposure of human peripheral blood to the carriers at 37°C for up to 60 min under controlled conditions. Cellulose acetate beads selectively adsorbed granulocytes, monocytes, CD19+ (B cells) and CD56+ (NK cells) lymphocyte subpopulations. The granulocyte and monocyte adsorption was inhibited by heat‐inactivated plasma and EDTA, indicating that the adsorption was plasma protein (immunoglobulin, complement) and calcium dependent. Accordingly, granulocyte and monocyte adsorption was markedly enhanced by coating the carriers with IgG. Similarly, C3b was adsorbed onto the CA beads as a marker of complement activation. The results indicated that IgG and active complement fragments mediated leukocyte adhesion to CA beads via the FcγR and/or leukocyte complement receptor like CR3. Additionally, CA beads induced loss of expression of TNF receptors on CD16+ granulocytes and CD14+ monocytes, but not on CD3+ lymphocytes. In conclusion, CA beads might be an appropriate biomaterial for inducing extracorporeal immunomodulation as a treatment for auto‐immune diseases which are associated with pathological leukocyte activity.

Relationship Between Fecal Calprotectin, Intestinal Inflammation, and Peripheral Blood Neutrophils in Patients with Active Ulcerative Colitis

Active ulcerative colitis (UC) is associated with elevated granulocytes and monocytes/macrophages (GM) which show activation behavior and increased survival time. Further, fecal calprotectin (a stable neutrophil protein) level parallels intestinal inflammation and can predict UC relapse. Since GM are major sources of inflammatory cytokines and chemokines, they are suspected to have roles in the initiation and perpetuation of UC. Our objective was to investigated relationships between peripheral blood (PB) neutrophils, calprotectin, and UC disease activity. Full PB and calprotectin were determined in 69 healthy controls and 31 patients with UC, then 7 randomly selected patients received GM adsorptive apheresis (GMA) with Adacolumn, 10 sessions of 60-min duration each. Patients with UC had higher neutrophil counts (P<0.001), but lower lymphocyte counts (P<0.001) compared with controls. Further, fecal calprotectin levels showed a correlation with UC clinical activity index (CAI; P<0.001) and mucosal inflammation (P<0.001). Following GMA, there were falls in neutrophils (P<0.02), CAI (P<0.02) and calprotectin (P<0.02). In conclusion, GM appear to contribute to intestinal inflammation and UC activity and reduction of these cells by GMA should benefit patients with active UC. Further, the correlations among calprotectin, UC activities, and PB neutrophils should serve as the basis for preemptive actions to control this disease.

Association of plasma triglyceride-rich lipoprotein remnants with coronary atherosclerosis in cases of sudden cardiac death

Among the risk factors for coronary atherosclerosis, elevated LDL-C level is best known. The action of lipoprotein lipase on triglyceride-rich lipoproteins produces remnant lipoprotein particles enriched in cholesterol and apolipoprotein E (apo E). Apo E serves as the ligand for uptake of remnant lipoproteins via the LDL-receptor or the remnant receptor. In this study, postmortem plasma total cholesterol, triglycerides (TG), VLDL-C, HDL-C, lipoprotein (a) [Lp(a)] and remnant-like lipoprotein particles (RLP)-cholesterol, RLP-TG, apolipoproteins B, C III and E were measured, together with LDL-C to assess their potential contribution to the severity of coronary and aortic atherosclerosis of the 197 cases of sudden death (132 cardiac death and 65 non-cardiac death). In all cases, the severity of coronary atherosclerosis was determined at postmortem pathological examination. RLP-cholesterol (RLP-C) and LDL-C concentrations were significantly higher in cases with advanced coronary atherosclerosis compared with those without coronary atherosclerosis; respective median values were 13.5 vs 8.4 mg/dl (P < 0.001) and 140 vs 115 mg/dl (P < 0.05). RLP-C levels were more strongly correlated with the severity score of coronary atherosclerosis than LDL-C.

Correlation of Serum Soluble TNF-|[alpha]| Receptors I and II Levels with Disease Activity in Patients with Ulcerative Colitis

OBJECTIVES:TNF-α has a major role in inflammatory bowel disease via two receptors, p55 (RI) and p75 (RII) expressed on many cell types, in particular neutrophils and monocytes (GM). Upon activation of these leukocytes, RI and RII are shed into the medium and can neutralize TNF. Accordingly, soluble RI and RII (s-RI/RII) are believed to have potent antiinflammatory actions. Further, in active UC, GM are elevated with activation behavior and recently adsorptive GM apheresis (GMA) in patients with severe UC was associated with a dramatic efficacy. In this study, we investigated the effects of GMA on serum s-RI/RII.METHODS:Thirty-one patients with UC, clinical activity index (CAI) 11.1 were treated with GMA by using the Adacolumn. In the column, leukocytes which bear the FcγR and complement receptors adhere to the column apheresis carriers (neutrophils, monocytes, and a small fraction of lymphocytes). One GMA session was 60 min at 30 mL/min and each patient could receive up to 11 sessions over 8 wk. Serum s-RI/II were measured in the blood at the column inflow (peripheral blood, time 0 and 60 min) and outflow at 60 min.RESULTS:Serum s-RI/RII showed strong correlation with CAI, r = 0.849 (p < 0.001) and r = 0.867 (p < 0.001), respectively and were greater than when patients were in remission or the levels in controls (p < 0.001). s-RI/RII at the column outflow were higher compared with inflow (p < 0.05) suggesting that RI/RII were shed from leukocytes which adhere to the carriers. Similarly s-RI/RII were significantly increased in the peripheral blood at the end of the 60 min GMA session compared with time 0. After 11 GMA sessions, CAI fell to remission level in 26 of 31 patients accompanied by falls of s-RI/RII.CONCLUSIONS:The sources of s-RI/RII are believed to be activated monocytes and neutrophils with further release when these leukocytes adhere to the column carriers. s-RI/RII released during GMA should contribute to the clinical efficacy of this procedure.

CASE REPORT: Therapeutic Efficacy of Granulocyte and Monocyte Adsorption Apheresis in Severe Active Ulcerative Colitis

Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease that appears with varying severity. The disease is associated with activation of the immune system and inflammatory responses (1– 3). Patients with acute severe fulminant flares of UC require hospitalization for intensive therapy, and for many years, the standard medication has been oral, rectal or intravenous corticosteroids (4–6). In about 40% of these cases, the intensive therapy does not induce remission and patients who fail to respond to intravenous steroid have historically undergone colectomy (5, 6). Therefore, there is a need for new effective therapies to reduce the number of patients who require colectomy. Factors that initiate and perpetuate UC are not well understood, but a major role for granulocytes and monocytes is indicated by their density within the inflamed mucosa; one hallmark of active UC is crypt abscess containing an abundance of neutrophils, macrophages, and other inflammatory leukocytes (2, 3, 5). Leukocytes have the potential to initiate and amplify inflammation via their proinflammatory cytokines (2, 3, 7) and cause tissue injury by releasing proteases and oxygen derivatives (8). Furthermore, recently fecal levels of neutrophils and a neutrophil-derived protein (calprotectin) have been measured as markers of intestinal inflammation and predictors of UC relapse (9–11). This indicates that during remission, neutrophils infiltrate the intestinal mucosa and have a major role in mucosal inflammation and UC relapse. With this information in mind, we thought that patients with severe UC who do not respond to standard medications and patients with unstable remission might respond to reduction of inflammatory leukocytes by selective apheresis.

Treatment of pyoderma gangrenosum associated with Crohn's disease.

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