Gene Expression Analysis Using a High‐Resolution DNA Microarray of Peripheral Whole Blood Immediately Before and After Leukocytapheresis for Rheumatoid Arthritis

Leukocytapheresis (LCAP) is a safe, unique therapy pertaining to intractable rheumatoid arthritis (RA) even in cases of drug allergy or infectious states. To investigate how to represent LCAP efficacy, we have conducted gene expression analyses from the peripheral blood of RA patients treated with non‐woven polyethylene terephthalate filters. Peripheral blood samples were collected immediately before and after treatment from eight RA patients who received LCAP. Among these patients, all of them achieved 20% improvement in the core set of the American College of Rheumatology (ACR20), and thus, they were confirmed as LCAP responders. Gene expression analysis was done with a high‐resolution DNA microarray. The results of each of the two groups' gene expression values (immediately before and after LCAP) were calculated using Welch's t‐test. Calculations were performed with a statistical software R.basic package: if the P‐value was less than 0.05, this was seen as a significant change. In a comparison of 25 370 gene expressions, the number of genes showing a P‐value < 0.05 in the upregulating group was 2110, and in the downregulating group it was 1864. The results of pathway analysis using the MetaCore program indicate that gene groups work for cytoskeletal remodeling are upregulated, and genes related to immune responses, such as antigens presenting via major histocompatibility complex class I and II, are downregulated just after LCAP. These findings may relate to LCAP efficacy for RA patients, but this needs further investigation.     

Basic Clinical Study of an Easy and Effective Leukocytapheresis by the Use of Nonwoven Polyester Filter

Abstract: Leukocytapheresis (LCAP) is widely used for the treatment of immunological diseases. We studied a new treatment of LCAP using a nonwoven polyester filter. In a basic study, 30–70% of the lymphocytes were adsorbed. Also, 30–68% of the lymphocyte subsets were removed. This method was applied to 2 patients with corti-costeroid-resistant active ulerative colitis. Erosion, edema, bleeding, ulcer formation, and stenosis of the colon were almost completely repaired after 6 LCAP treatments. LCAP using a nonwoven polyester filter will be a very useful treatment for immunological diseases and extracorporeal immunomodulation.     

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

Apheresis has been recognized both economically and therapeutically as a novel approach for the treatment of inflammatory diseases, and certain others, which respond poorly to drug therapy. This report is about Adacolumn, an adsorptive carrier based granulocyte and monocyte apheresis device with a volume of 335 mL, filled with about 220 g of cellulose acetate beads of 2 mm diameter as the column adsorptive carriers. Pre- and post-column leukocyte counts have shown that the carriers adsorb about 65% of granulocytes, 55% of monocytes and 2% of lymphocytes from the blood in the column. Additionally, after apheresis, there is a marked decrease in inflammatory cytokines (TNF-alpha, IL-1beta, IL-6 and IL-8) produced by blood leukocytes, together with down-modulation of L-selectin and the chemokine receptor CXCR3. Adacolumn has been used to treat patients with rheumatoid arthritis, ulcerative colitis and HIV infection. Typical apheresis sessions have been 4-10, at a frequency of one or two sessions per week. Treatment of patients with Adacolumn has been associated with very promising efficacy and safety data. Accordingly, in Japan, Adacolumn has been approved by the Ministry of Health for the treatment of ulcerative colitia. Furthermore, Adacolumn met the required quality and safety standards for medical devices and received an EC certification (CE-mark) from TUV in 1999. However, although Adacolumn carriers are very efficient in depleting excess and activated granulocytes and monocytes/macrophages, the clinical efficacy associated with Adacolumn apheresis cannot be fully explained on the basis of reducing granulocytes and monocytes per se. Hence, a long lasting effect on inflammatory cytokine generation, chemokine activities or immunomodulation is likely, but the precise mechanisms involved are not fully understood yet.     

Improved response to infliximab after leukocytapheresis in a patent with rheumatoid arthritis

This is the first report on effective leukocytapheresis (LCAP) in an acquired infliximab (IFM) resistant patient with rheumatoid arthritis (RA). A 44-year-old Japanese woman with RA was treated with prednisolone, cyclosporine A, and methotrexate, which failed to stabilize the disease. Infliximab was then administered and the disease activity was controlled on December 2003. However, RA became active again on June 2004 so that LCAP was administered weekly for 5 weeks. After the LCAP treatment, the ACR20% response was obtained again and IFM has regained its efficacy.     

A Case Report: First Case of Filtration Leukocytapheresis for a Patient of Aortitis Syndrome Associated with Ulcerative Colitis

Abstract: An 18‐year‐old woman was treated with leukocytapheresis (LCAP) for her combined ulcerative colitis (UC) and aortitis syndrome (AS). Because a close relationship between these two diseases has been suspected based on their etiological and/or pathological findings, we had hypothesized that LCAP, which has satisfactory effects on inflammatory bowel disease such as UC and Crohn's disease might be effective for both her UC and her AS. After informed consent, LCAP therapy was performed once a week for a total of 7 times. Endoscopic remission of the UC was observed. Even though there were no significant improvements in her subjective symptoms of AS such as side‐neck pain and dizziness, objective evidence of improvement was obtained when the patient's condition was compared before and after LCAP by angiography, angio‐magnetic resonance imaging, and the plethysmogram of her fingertips. These results suggest that LCAP may be valuable as a new adjunct therapy for AS.     

Efficacy of granulocytapheresis and leukocytapheresis for the treatment of microscopic polyangiitis

We evaluated the efficacy of granulocytaperesis and leukocytapheresis for the treatment of rapidly progressive glomerulonephritis (RPGN) and lung hemorrhage caused by microscopic polyangiitis. Three patients with RPGN were treated by granulocytapheresis (GCAP) and five patients with RPGN were treated by leukocytapheresis (LCAP). The prednisolone dose was 0.4 +/- 0.2 g/kg/day (mean +/- SD; range 0.2-0.8 g/kg/day). Pre-treatment serum creatinine was 3.2 +/- 1.4 mg/dL (1.4-5.1 mg/dL). The patients were followed for a mean period of 15 +/- 6 months (6-23 months). Renal function improved in five of the eight RPGN patients. Three lung hemorrhage episodes in two different patients were treated with GCAP and one lung hemorrhage episode was treated with LCAP combined with various doses of corticosteroids. All four lung hemorrhage episodes were ameliorated. We concluded that combined therapy of GCAP or LCAP and corticosteroids is effective for the treatment of RPGN and lung hemorrhage due to microscopic polyangiitis.     

Safety and clinical efficacy of granulocyte and monocyte adsorptive apheresis therapy for ulcerative colitis

Active ulcerative colitis(UC)is frequently associated withinfiltration of a large number of leukocytes into the bowelmucosa.Therefore,removal of activated circulatingleukocytes by apheresis has the potential for improvingUC.In Japan,since April 2000,leukocytapheresis usingAdacolumn has been approved as the treatment foractive UC by the Ministry of Health and Welfare.TheAdacolumn is an extracorporeal leukocyte apheresisdevice filled with cellulose acetate beads,and selectivelyadsorbs granulocytes and monocytes/macrophages.Toassess the safety and clinical efficacy of granulocyteand monocyte adsorptive apheresis(GMCAP)for UC,wereviewed 10 open trials of the use of GMCAP to treatUC.One apheresis session(session time,60 min)perweek for five consecutive weeks(a total of five apheresissessions)has been a standard protocol.Several studiesused modified protocols with two sessions per week,with90-min session,or with a total of 10 apheresis sessions.Typical adverse reactions were dizziness,nausea,headache,flushing,and fever.No serious adverse effectswere reported during and after GMCAP therapy,andalmost all the patients could complete the treatmentcourse.GMCAP is safe and well-tolerated.In the majorityof patients,GMCAP therapy achieved clinical remissionor improvement.GMCAP is a useful alternative therapyfor patients with steroid-refractory or-dependent UC.GMCAP should have the potential to allow tapering thedose of steroids,and is useful for shortening the timeto remission and avoiding re-administration of steroidsat the time of relapse.Furthermore,GMCAP may haveefficacy as the first-line therapy for steroid-naive patientsor patients who have the first attack of UC.However,most of the previous studies were uncontrolled trials.Toassess a definite efficacy of GMCAP,randomized,double-blind,sham-controlled trials are necessary.A seriousproblem with GMCAP is cost;a single session costs145 000($1 300).However,if this treatment preventshospital admission,re-administration of steroids and surgery,and improves a quality of life of the patients,GMCAP may prove to be cost-effective.     

Leukocytapheresis for the treatment of refractory Henoch–Schönlein purpura resistant to both prednisolone and intravenous immunoglobulin therapy

Henoch–Schönlein purpura (HSP) is a childhood disorder, which is the vasculitis of systemic small vessels of unknown etiology. We encountered the dramatic efficacy of leukocytapheresis in a Japanese girl with refractory HSP resistant to combined prednisolone plus intravenous immunoglobulin therapy administration.     

New Technique of Leukocytapheresis by the Use of Nonwoven Polyester Fiber Filter for Inflammatory Bowel Disease

Abstract: Leukocytapheresis (LCAP) is widely used for the treatment of immunological diseases. We studied a new treatment of LCAP using a nonwoven polyester fiber filter. In a basic study, 30–70% of leukocytes were removed. Also, 30–68% of the leukocyte subsets were removed. Sixteen inflammatory bowel disease (IBD) patients, mainly with ulcerative colitis (UC), were treated by this method. Their cytokine activity was normalized in the filter and in the peripheral blood. Eleven of 12 patients with UC were induced to remission. Four patients with Crohn's disease (CD) exhibited improvement. The LCAP using a nonwoven polyester fiber filter was very efficient for treating the patients with IBD. Also, it will be a very useful treatment for immunological diseases and extracorporeal immunomodulation.     

Granulocyte‐Monocyte Apheresis as an Adjuvant Therapy to Anti‐Tumor Necrosis Factor Drugs for Ulcerative Colitis

Biologic anti‐tumor necrosis factor (TNF) drugs have demonstrated their efficacy for the treatment of ulcerative colitis. Nevertheless, some patients will not respond to this therapy or will develop loss of response. Leukapheresis is the main non‐pharmacological therapy for some immune‐mediated diseases. The aim of our study was to describe our experience with this therapy in ulcerative colitis patients after loss of response to anti‐TNF treatment. Leukapheresis was indicated in four patients with left‐sided or extensive colitis because of partial response to biological therapy or secondary loss of response to it. All patients received 8 to 10 sessions in an intensive regimen. Globally, a decrease in the Mayo score was observed. The overall response rate was 50% with one patient who displayed sustained response. No patients have required colectomy during follow‐up. Adjuvant treatment with leukapheresis in patients with inadequate response to anti‐TNF treatment showed some beneficial effect, although of limited duration, in patients with ulcerative colitis.