Positions of selective leukocytapheresis in the medical therapy of ulcerative colitis

Ulcerative colitis （UC） and Crohn＇s disease （CD） are the major forms of idiopathic inflammatory bowel disease （IBD）. Both UC and CD are debilitating chronic disorders that afflict millions of individuals throughout the world with symptoms which impair function and quality of life. The etiology of IBD is inadequately understood and therefore, drug therapy has been empirical instead of being based on sound understanding of IBD pathogenesis. This is a major factor for poor drug efficacy and drug related side effects that often add to the disease complexity. The development of biologicals notably infliximab to intercept tumor necrosis factor （TNF）-α reflects some progress, albeit major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD seems to be perpetuated by inflammatory cytokines like TNF-α, interleukin （IL）-Iβ, IL-6 and IL-8 for which activated peripheral granulocytes and monocytes/macrophages （GH） are major sources. Further, in IBD, peripheral GHs are elevated with activation behavior, increased survival time and are found in vast numbers within the inflamed intestinal mucosa; they are suspected to be major factors in the immunopathogenesis of IBD. Hence, peripheral blood GMs should be appropriate targets of therapy. The Adacolumn is a medical device developed for selective depletion of GH by receptor-mediated adsorption （GHA）. Clinical data show GMA, in patients with steroid dependent or steroid refractory UC, is associated with up to 85% efficacy and tapering or discontinuation of steroids, while in steroid nai＇ve patients （the best responders）, GHA spares patients from exposure to steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse suppresses relapse thus sparing the patients from the morbidity associated with IBD relapse. Further, GHA appears to reduce the number of patients being submitted to colectomy or exposure to unsafe immunosupressants. First UC episode, steroid naivety and short disease duration appear good predictors of response to GMA and based on the available data, GMA seems to have an excellent safety profile.

Steroid-sparing strategies in the management of ulcerative colitis:Efficacy of leukocytapheresis

Active ulcerative colitis （UC） is frequently associated with infiltration of a large number of leukocytes into the bowel mucosa. Leukocytapheresis is a novel nonphar- macologic approach for active UC, in which leukocytes are mechanically removed from the circulatory system. Current data indicate that leukocytapheresis is effica- cious in improving response and remission rates with excellent tolerability and safety in patients with UC. Corticosteroid therapy remains a mainstay in the treat- ment of active UC, however, long-term, high doses of corticosteroids usually produce predictable and po- tentially serious side effects. If leukocytapheresis can spare patients from exposure to corticosteroids, the risk of steroid-induced adverse events should be mini- mized. This may be of great benefit to patients because severe side effects of steroids seriously impair health- related quality of life. In this article, we reviewed cur- rent evidence on whether leukocytapheresis can avoid or reduce the use of corticosteroids in the manage- ment of patients with UC. Several studies have shown that leukocytapheresis was effective for steroid-nafve patients with active UC. Furthermore, both short-term and long-term studies have demonstrated the steroid- sparing effects of leukocytapheresis therapy in patients with UC. Although the evidence level is not striking, theavailable data suggest that leukocytapheresis can avoid or reduce the use of corticosteroids in the management of UC. Large, well-designed clinical trials are necessary to more accurately evaluate the steroid-sparing effects of leukocytapheresis in the management of UC.

Endoscopic findings can predict the efficacy of leukocytapheresis for steroid-naive patients with moderately active ulcerative colitis

AIM:To investigate the therapeutic usefulness of leukocytapheresis (LCAP; Cellsoba) in steroid-naive patients with moderately active ulcerative colitis (UC). METHODS: Eighteen steroid-naive patients with moderately active UC received one LCAP session every week for fi ve consecutive weeks. RESULTS: The remission rate 8 weeks after the last LCAP session was 61.1% (11/18). All three patients with deep ulcers showed worsening after LCAP. For the remaining 15 patients, who had erosions or geographic ulcers, the average clinical activity index (CAI) score dropped significantly from 9.4 to 3.8 eight weeks after the last LCAP session (t = 4.89, P = 0.001). The average C-reactive protein (CRP) levels before and after LCAP were 1.2 mg/dL and 1.0 mg/dL, respectively. Of the patients with erosions, geographic ulcers, and deep ulcers, 100% (9/9), 33.3% (2/6), and 0% (0/3) were in remission 8 weeks after the last LCAP session, respectively (χ2 = 7.65, P < 0.005). Forty- eight weeks after the last LCAP session, the remission rates for patients with erosions and geographic ulcers were 44.4% (4/9) and 16.7% (1/6), respectively. Only one patient suffered a mild adverse event after LCAP (nausea). CONCLUSION: LCAP is a useful and safe therapyfor steroid-naive UC patients with moderate disease activity. Moreover, the effi cacy of the treatment can be predicted on the basis of endoscopic fi ndings.

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

Active ulcerative colitis （UC） is frequently associated with infiltration of a large number of leukocytes into the bowel mucosa. Therefore, removal of activated circulating leukocytes by apheresis has the potential for improving UC. In Japan, since April 2000, leukocytapheresis using Adacolumn has been approved as the treatment for active UC by the Ministry of Health and Welfare. The Adacolumn is an extracorporeal leukocyte apheresis device filled with cellulose acetate beads, and selectively adsorbs granulocytes and monocytes/macrophages. To assess the safety and clinical efficacy of granulocyte and monocyte adsorptive apheresis （GMCAP） for UC, we reviewed 10 open trials of the use of GMCAP to treat UC. One apheresis session （session time, 60 min） per week for five consecutive weeks （a total of five apheresis sessions） has been a standard protocol. Several studies used modified protocols with two sessions per week, with 90-min session, or with a total of 10 apheresis sessions. Typical adverse reactions were dizziness, nausea, headache, flushing, and fever. No serious adverse effects were reported during and after GMCAP therapy, and almost all the patients could complete the treatment course. GMCAP is safe and well-tolerated. In the majority of patients, GMCAP therapy achieved clinical remission or improvement. GMCAP is a useful alternative therapy for patients with steroid-refractory or -dependent UC. GMCAP should have the potential to allow tapering the dose of steroids, and is useful for shortening the time to remission and avoiding re-administration of steroids at the time of relapse. Furthermore, GMCAP may have efficacy as the first-line therapy for steroid-naive patients or patients who have the first attack of UC. However, most of the previous studies were uncontrolled trials. To assess a definite efficacy of GMCAP, randomized, doubleblind, sham-controlled trials are necessary. A serious problem with GMCAP is cost; a single session costs ￥145 000 （$1 300）. However, if this treatment prevents hospital admission, re-administration of steroids and surgery, and improves a quality of life of the patients, GMCAP may prove to be cost-effective.

Regulatory T cells in patients with inflammatory bowel diseases treated with adacolumn granulocytapheresis

AIM: To investigate if the clinical efficacy of granulocytes and monocytes by adsorption (GMA) is associated with an increased frequency of peripheral regulatory T cells (Tregs), as these cells have proven to be successful in suppressing inflammatory bowel disease (IBD) in animal models. METHODS: We report four cases of corticosteroid- dependent ulcerative colitis (UC) and two Crohn’s disease (CD) cases with severe cutaneous lesions who received GMA therapy. The frequency of CD4+ CD25high (Tregs) in peripheral blood was analyzed by flow cytometry and the expression of FoxP3 and TGF beta in purified CD4+ T cells was determined by real time PCR prior to and one month after the last apheresis session, and at the time of endoscopic and clinical assessing. RESULTS: Increased expression of Fox P3 mRNA was found in all five patients who responded to cytapheresis with remission of clinical symptoms, mucosal inflammation and cutaneous lesions, and an increased frequency of circulating Tregs was found in four patients. These changes were not observed in the patient with UC who did no respond to GMA. Variations in TGF-β (mRNA) did not parallel that of FoxP3 mRNA. CONCLUSION: The clinical efficacy of GMA on IBD and related extra intestinal manifestations was associated with an expansion of circulating CD4+ CD25+ Tregs and higher expression of FoxP3 in CD4+ T cells. Accordingly, an elevated CD4+ CD25+ FoxP3 may be a valuable index of remission in patients with IBD and other chronic relapsing-remitting inflammatory conditions during treatment with GMA.

Apheresis:A cell-based therapeutic tool for the inflammatory bowel disease

Inflammatory Bowel Disease(IBD)is a hallmark of leukocyte infiltration,followed by the release of cytokines and interleukins.Disease progression to Ulcerative Colitis(UC)or Crohn’s Disease(CD)remained largely incurable.The genetic and environmental factors disrupt enteral bacteria in the gut,which hampers the intestinal repairing capability of damaged mucosa.Commonly practiced pharmacological therapies include 5-aminosalicylic acid with corticosteroids and tumor necrosis factor(TNF)-α.New interventions such as CDP571 and TNF-blocking RDP58 report the loss of patient response.This review discusses the non-pharmacologic selective granulocyte–monocyte-apheresis(GMA)and leukocytapheresis(LCAP)that have been proposed as treatment modalities that reduce mortality.GMA,an extracorporeal vein-to-vein technique,presents a strong safety profile case for its use as a viable therapeutic option compared to GMA's conventional medication safety profile.GMA reported minimal to no side effects in the pediatric population and pregnant women.Numerous studies report the efficacious nature of GMA in UC patients,whereas data on CD patients is insufficient.Its benefits outweigh the risks and are emerging as a favored nonpharmacological treatment option.On the contrary,LCAP uses a general extracorporeal treatment that entraps leukocytes and suppresses cytokine release.It has been deemed more efficacious than conventional drug treatments,the former causing better disease remission,and maintenance.Patients with UC/CD secondary to complications have responded well to the treatment.Side effects of the procedure have remained mild to moderate,and there is little evidence of any severe adverse event occurring in most age groups.LCAP decreases the dependence on steroids and immunosuppressive therapies for IBD.The review will discuss the role of GMA and LCAP.