Choon Jin Ooi ¹, Kwong Ming Fock, Govind K Makharia, Khean Lee Goh, Khoon Lin Ling, Ida Hilmi, Wee Chian Lim, Thia Kelvin, Peter R Gibson, Richard B Gearry, Qin Ouyang, Jose Sollano, Sathaporn Manatsathit, Rungsun Rerknimitr, Shu-Chen Wei, Wai Keung Leung, H Janaka de Silva, Rupert Wl Leong, Asia Pacific Association of Gastroenterology Working Group on Inflammatory Bowel Disease

J Gastroenterol Hepatol 2010 Mar;25(3):453-68. doi: 10.1111/j.1440-1746.2010.06241.x.

Inflammatory bowel disease (IBD) is increasing in many parts of the Asia-Pacific region. There is a need to improve the awareness of IBD and develop diagnostic and management recommendations relevant to the region. This evidence-based consensus focuses on the definition, epidemiology and management of ulcerative colitis (UC) in Asia. A multi-disciplinary group developed the consensus statements, reviewed the relevant literature, and voted on them anonymously using the Delphi method. The finalized statements were reviewed to determine the level of consensus, evidence quality and strength of recommendation. Infectious colitis must be excluded prior to diagnosing UC. Typical histology and macroscopic extent of the disease seen in the West is found in the Asia-Pacific region. Ulcerative colitis is increasing in many parts of Asia with gender distribution and age of diagnosis similar to the West. Extra-intestinal manifestations including primary sclerosing cholangitis are rarer than in the West. Clinical stratification of disease severity guides management. In Japan, leukocytapheresis is a treatment option. Access to biologic agents remains limited due to high cost and concern over opportunistic infections. The high endemic rates of hepatitis B virus infection require stringent screening before initiating immune-suppressive agents. Vaccination and prophylactic therapies should be initiated on a case-by-case basis and in accordance with local practice. Colorectal cancer complicates chronic colitis. A recent increase in UC is reported in the Asia-Pacific region. These consensus statements aim to improve the recognition of UC and assist clinicians in its management with particular relevance to the region.

https://pubmed.ncbi.nlm.nih.gov/20370724/

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1440-1746.2010.06241.x

Shin-ichiro Takeda, Toru Sato, Tatsuro Katsuno, Tomoo Nakagawa, Yoshiko Noguchi, Osamu Yokosuka & Yasushi Saito

Dig Dis Sci 55, 1886–1895 (2010). https://doi.org/10.1007/s10620-009-0974-2

Background:  Two main functionally distinct monocytes phenotypes are known: the CD14hiCD16− “classical” and the CD14+CD16+ “proinflammatory” phenotypes. The latter phenotype is elevated in patients with ulcerative colitis (UC) and is suspected to have a major role in the immunopathogenesis of UC. Aim: To selectively deplete circulating proinflammatory CD14+CD16+ monocyte phenotype. Methods: Seven corticosteroid-naïve patients with UC (clinical activity index = 8.7 ± 1.3) and seven healthy subjects were included. In patients with UC, granulocyte/monocyte adsorption (GMA) was done with an Adacolumn that selectively adsorbs leucocytes of the myeloid lineage. Blood from all subjects at baseline and from the patients immediately after the first GMA session was processed. Isolated monocytes were subjected to fluorescence-activated cell sorter analyses. Results: The seven UC patients achieved remission (CAI ≤4) after 5–10 GMA sessions. GMA induced a strong fall in the ratio (%) of CD14+CD16+ to CD14hiCD16− monocytes, from 10.0 ± 1.4 to 3.0 ± 0.9. Further, expressions of α4 integrin (374.8 ± 26.1 mean fluorescence intensity, MFI) and CX3CR1 (49.5 ± 4.6 MFI) were significantly high on CD14+CD16+monocytes as compared with on CD14hiCD16− monocytes (169.2 ± 17.2 and 33.2 ± 3.6 MFI, respectively). Additionally, GMA significantly increased the ratio of the CD14hiCD16−CCR2low “immature” monocytes from 3.74 ± 0.62 to 8.11 ± 0.56 MFI. Conclusions: We found high expressions of α4 integrin and CX₃CR1 on monocytes in patients with active UC, known to promote the extravasation of CD14⁺CD16⁺ monocytes into the mucosa. GMA effectively depletes CD14⁺CD16⁺ monocytes and concomitantly increases D14^hiCD16⁻CCR2^low “immature” monocytes; thus, GMA was associated with the emergence of less inflammatory monocyte phenotype in circulation.

https://link.springer.com/article/10.1007%2Fs10620-009-0974-2#citeas

Silvio Danese ¹, Erika Angelucci, Tommaso Stefanelli, Paolo Omodei, Carmelo Luigiano, Silvia Finazzi, Nico Pagano, Alessandro Repici, Maurizio Vecchi, Alberto Malesci, Digestion. 2008;77(2):96-107.

Ulcerative colitis and Crohn’s disease are inflammatory bowel diseases with a chronic relapsing course. Management of both conditions is far from being fully satisfactory. For this reason in the last decade a large number of biological therapies, targeting cytokines involved in intestinal inflammation, has been developed with various results in terms of efficacy, safety and costs. Activated granulocytes and monocytes represent the major sources of pro-inflammatory cytokines in the intestinal mucosa, playing a pivotal role in inducing and maintaining intestinal inflammation. Leukocytapheresis using an adsorptive carrier-based system (Adacolumn) or a removal filter column (Cellsorba) has been proposed as a feasible, safe and effective therapy for ulcerative colitis and Crohn’s disease. The objective of this paper is to provide an overview on the current knowledge about mechanisms of action, available clinical data and the possible future perspectives for the use of Adacolumn and Cellsorba in the management of inflammatory bowel diseases.

https://pubmed.ncbi.nlm.nih.gov/18382085/

T Tanaka ¹, H Okanobu, S Yoshimi, E Murakami, A Kogame, H Imagawa, Y Numata, Y Kuga, T Moriya, T Ohya, G Kajiyama

Dig Liver Dis. 2008 Sep;40(9):731-6. doi: 10.1016/j.dld.2008.02.012. Epub 2008 Apr 2.

Background: The aetiology of ulcerative colitis is inadequately understood, and drug therapy has been empirical rather than based on sound understanding of disease aetiology. This has been a major factor for refractoriness and adverse drug effects as additional complications. However, ulcerative colitis by its very nature is exacerbated and perpetuated by inflammatory cytokines, which are released by peripheral granulocytes and monocytes as well. Additionally, active ulcerative colitis is often associated with elevated peripheral granulocytes and monocytes with activation behaviour and are found in vast numbers within the colonic mucosa. Hence, from the clinicopathologic viewpoint, granulocytes and monocytes are appropriate targets for therapy in ulcerative colitis. Based on this thinking, an Adacolumn has been developed for depleting excess granulocytes and monocytes by adsorption. Methods: By colonoscopy, biopsy and histology, we investigated the impact of granulocyte and monocyte adsorption (GMA) on the mucosal level of granulocytes and monocytes in patients with active ulcerative colitis. Forty-five patients (26 steroid naïve and 19 steroid-dependent), mean age 44.7 yr, were included. Twenty patients had total colitis and 25 had left-sided colitis. Each patient was given up to 11 GMA sessions over 12 weeks. No patient received additional medications within 4 weeks (steroid) to 8 weeks (other immunosuppressants) prior to entry or during the GMA course. Colonoscopy together with biopsy was done at entry and within 2 weeks after the last GMA session. Results: At entry, the mean clinical activity index was 12.6; range 10-16. A total of 400 colonic biopsies were examined, which revealed massive infiltration of the colonic mucosa by granulocytes, and GMA was associated with striking reduction of granulocytes in the mucosa. At week 12, 33 of 45 patients (73.3%, P<0.01) had achieved clinical remission (the mean clinical activity index <or= 4). Colonoscopy revealed that most non-responders had deep colonic ulcers and extensive loss of the mucosal tissue. The response rate in steroid naïve subgroup was 22 of 26 patients (84.6%, P<0.005) and in steroid-dependent was 11 of 19 (57.9%, P<0.05 and P=0.02154 for steroid naïve vs. steroid-dependent). Patients who achieved remission could continue with their salicylates. On average, remission was sustained for 7.8 months in all 33 responders. Conclusions: This is the first report showing a striking difference in clinical response to GMA between steroid naïve and steroid-dependent patients. Further, patients with deep colonic ulcers together with extensive loss of the mucosal tissue are not like to respond to GMA.

https://pubmed.ncbi.nlm.nih.gov/18387860/

https://www.dldjournalonline.com/article/S1590-8658(08)00070-4/fulltext

Takayuki Yamamoto, Satoru Umegae, Koichi Matsumoto February 2006 World Journal of Gastroenterology 12(4):520-5 DOI:10.3748/wjg.v12.i4.520

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, double blind, 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.

https://www.researchgate.net/publication/7286897_Safety_and_clinical_efficacy_of_granulocyte_and_monocyte_adsorptive_apheresis_therapy_for_ulcerative_colitis

Russell D. Cohen

Gastroenterology2005 Vol. 128; Iss. 1 DOI:10.1053/j.gastro.2004.11.024

Clinical response rates in uncontrolled inflammatory bowel disease studies have commonly run in the 30%–50% range; as a result, early uncontrolled trials need validation from adequately blinded randomized trials before widespread application of such novel therapies. Although the long-term maintenance data from this study (60% at 8 months) is encouraging, further studies of the optimal interval for repeating apheresis for reinduction of remission or maintenance arealso in order. The potential for apheresis-based therapies as either a stand-alone strategy or in combination with other proven therapies in
the treatment of inflammatory bowel diseases also needs to be further elucidated. The promise of “no medications” for effective therapy in the treatment of ulcerative colitis is enticing, and perhaps a step closer, but clearly needs to be substantiated by larger controlled trials.

https://booksc.eu/book/20696837/914ad3

Kazuo Kusugami ¹, Kenji Ina, Takafumi Ando, Kenji Hibi, Yuji Nishio, Hidemi Goto, J Gastroenterol. 2004 Dec;39(12):1129-37.

Patients with inflammatory bowel disease (IBD) have intestinal and extraintestinal symptoms that can greatly impair their quality of life. They must rely on multiple medications with aminosalicylates, corticosteroids, and purine analogues to control these symptoms. Although decades of clinical experience in IBD management has led to optimized approaches for achieving the induction and maintenance of remission, the disease in some patients is still refractory to conventional medical treatment, or the effectiveness of these drugs can be limited by treatment-related side effects. Significant progress in our understanding of the pathogenesis of IBD has yielded several immunomodulatory approaches with novel biological agents or apparatus, such as cyclosporine, cytoprotective agents, infliximab, and leukocytapheresis. Further immunomodulatoy therapy, aiming at the inhibition of molecular and cellular mediators, is anticipated, in parallel with the clarification of immunoinflammatory pathways in IBD. An additional goal will be to identify factors predictive of response to treatment with each novel immunomodulatory agent or apparatus. This will help provide each patient with optimized and individualized therapy, thereby increasing therapeutic efficacy and reducing possible side effects.

https://pubmed.ncbi.nlm.nih.gov/15622475/

Yasuo Suzuki ¹, Naoki Yoshimura, Abby R Saniabadi, Yasushi Saito

Dig Dis Sci. 2004 Apr;49(4):565-71. doi: 10.1023/b:ddas.0000026299.43792.ae.

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 (FcgammaR 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-alpha 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.

https://pubmed.ncbi.nlm.nih.gov/15185858/