Taku Kobayashi

poster at ISFA 2019 pag 53

There are two types of extracorporeal therapy for treating active ulcerative colitis (UC), granulocyte and monocyte adsorption (GMA) and leukocytapheresis (LCAP). Although Sawada et al reported the efficacy of LCAP by the randomized controlled trial (Sawada K et al. Am J Gastroenterol 2005), the larger sham-controlled multicenter trial of GMA failed to prove its efficacy (Sands BE et al. Gastroenterol 2008). Therefore, evidence to show their efficacy relies more on the real-world data, including the post-marketing surveillance (PMS). The large-scale PMS for LCAP was named as REFINE study, involving 847 patients from 116 medical facilities in Japan (Yokoyama Y, Kobayashi T et al. J Crohn Colitis 2014). Adverse events were seen only in 10.3% and the vast majority were mild. The overall clinical remission rate was 68.9%, and the mucosal healing rate was 62.5%. These results were very consistent with the results from PMS of 697 patients treated with GMA, which also demonstrated its real-world effectiveness and safety (Hibi T et al. Dig Liver Dis 2008). In addition, a retrospective observational study aimed to evaluate the clinical outcome at 1 year and identify risk factors for relapse after LCAP was recently conducted among patients who had achieved remission in the PMS (Kobayashi T et al. J Gastroenterol 2018). The 1-year cumulative relapse free rate was 63.6%. Following LCAP, a high clinical activity and a high leukocyte count were associated with a greater risk of relapse. Intensive LCAP was associated with favorable long-term outcomes in corticosteroidrefractory patients. The response rate of re-treatment upon relapse was as high as 85%. These results on the risks of relapse as well as effectiveness of re-treatment may help to overcome the weakness of cytapheresis therapy in maintaining remission. Results from the clinical trial evaluating the clinical efficacy of intermittent maintenance cytapheresis therapy are also warranted.

http://www.atalacia.com/isfa/data/abstract.pdf

Mariko Sawada

poster at ISFA 2019 pag 164-165

Ensuring reliable vascular access (VA) and maintaining stable extracorporeal circulation are the most basic aspects of blood purification therapy (BPT). In children and neonates, specific tips could be helpful for BPT.
VA guidelines were published in 2011 and management methods have been unified. To ensure VA, it is necessary to determine a suitable placement site and catheter size (diameter and length), adjust the catheter tip position, and manage the catheters appropriately. It is common to use dialysis catheters for BPT, placing them in the central and peripheral veins. In neonates, the umbilical vein could also be one of the options, and central venous catheters and peripheral vein catheters could be used for BPT. In order to maintain stable extracorporeal circulation, it is necessary to maintain sufficient intravascular volume and blood pressure, set appropriate blood flow rates, and adjust the type and amount of anticoagulant. In children who cannot cooperate,
sedation management and catheter fixation should be performed to stabilize extracorporeal circulation.
There are also tips specialized for each disease state. In neonates, there is a high risk of intracranial hemorrhage and nafamostat mesylate is often used as an anticoagulant. In addition, it is necessary to increase the dose of anticoagulant or administer it from two places in the circuits. In patients with severe inflammatory bowel diseases, intestinal bleeding continues despite increased clotting function and hypovolemia is common. Heparin and nafamostat mesylate are chosen as anticoagulants. During BPT, monitoring activated clotting time, administering minimal anticoagulants, and administering transfusion and fluid load are useful methods to maintain stable extracorporeal circulation. BPT might be a powerful therapeutic tool for children as well as adults, ensuring reliable VA and maintaining stable extracorporeal circulation.

http://www.atalacia.com/isfa/data/abstract.pdf

Hisashi Matono1), Akiyoshi Okada2), Junya Imada1), Tetsushi Nakahara1),
Atsushi Ono1), Takuma Usuda1), Atsuo Kitano

poster at ISFA 2019 pag 164

Introduction
We can provide the GMA treatment by venepuncture without VAC detaining you like other blood purification therapy. The puncture by the peripheral vein puncture is easy, but, on the other hand, it often becomes difficult to secure blood flow necessary for extracorporeal circulation enough and is one of the trouble factors of the GMA treatment We use an echo to
evade a puncture trouble in our institution. We introduce the approach this time.
Approach method The site of puncture uses brachial veins basically. There is little valve of vein as a reason and chooses the blood stream because securing of blood flow with a little meandering is relatively easy. However, the depth from skin may be deepened as compared with the erasion blood vessel such as radius cutaneous veins, and the like, too, and attention is necessary. We often perform GMA in outpatient department at this hospital, and order enters the new induction when a chief physician judged induction from an encounter. Therefore it is difficult to obtain the patients information beforehand and a blood vessel echo uses site of puncture after the patients admission and is determined and performs the puncture in echo guides, if necessary. Also, the judgments such as the dehydration, and the like are possible by using an echo, and there is the
merit that they receive instructions such as the transfusion load, and the like in what we report to a chief physician, and can dissolve puncture difficulty.
Conclusion One of the troubles of the GMA treatment has securing of access. If extracorporeal circulation is possible without poor blood removal, we can provide GMA treatment more effectively. We regard the echo inflection of that purpose as a required device on providing GMA treatment.

http://www.atalacia.com/isfa/data/abstract.pdf

Chie Kurihara, Toshihide Ohmori, Hirotaka Furuhashi, Kenichi Inaba, Nao Sugihara, Yoshinori Hanawa, Gastroenterology 2019 156 (6) Suppl. S-1146

Background: Granulocyte and monocyte adsorptive apheresis (GMA) is non-pharmacological therapy which selective depletion of activated granulocytes and monocytes/macrophages from peripheral blood. GMA is effective and safe as induction therapy in ulcerative colitis (UC) of moderate to severe patients, and commonly used in Asia and north Europe. However, therapeutic mechanism of GMA, especially its effect on mucosal healing, has not been well characterized. Since moderate to severe patients with UC sometimes become fulminant, it is important to select an appropriate induction therapy. GMA treatment efficacy is reported about 60% patients respond, whereas, there is not useful parameter that predicts GMA therapeutic efficacy before treatment. In this study, we attempted to identify predictive factors of clinical response to GMA treatment in UC patients. Methods: Thirty-two active UC patients (Mayo score ^ 5 and Mayo endoscopic score ^ 2) and 10 non-IBD control subjects were enrolled in this study. All UC patients received 10 or 11 times of GMA, and colonoscopies were applied before the first GMA and after the last GMA. Control subjects underwent colonoscopies for screening of colon cancer. Assessment of disease activity and colonic mucosal healing were determined based on Mayo score. Inflammation-related molecules mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. ROC curves analysis was used to assess sensitivity and specificity in prediction of GMA therapeutic efficacy. Results: GMA treatment efficacy is 11 patients (34.4%) achieved clinical remission, 17 patients (53.1%) were response and 4 patients (12.5%) were non-response. Mucosal healing was observed in 18 patients (56.3%) and it was not observed in 14 patients (43.7%). Baseline characteristics were not significantly different according to GMA efficacy. Before the first GMA session, the clinical remission group showed significantly higher expressions of TNFα, MAdCAM-1 and MIP-1β mRNA than those of the non-response group (P <0.05). Patients in the response group who highly expressed these mRNA achieved mucosal healing. In the mucosal healing group, the mRNA levels of TNFα, IL-1β, IL-8, MIP-1β, TGFβ and IL-10 were significantly higher than those in the non-mucosal healing group (P <0.05). TNFα and MIP-1β had 0.83 and 0.79 of area under the curve with 83.3% and 66.7% sensitivity, 71.4% and 100% specificity, 78.9% and 100%positive predictive value, and 76.9% and 70.0% negative predictive value, respectively, for prediction of mucosal healing. Conclusion: Mucosal expression of TNFα and MIP-1β mRNA before treatment in the remission group and the mucosal healing group was significantly higher than non-responder to GMA treatment. We propose that measuring of these molecules’ expression is useful to expect GMA therapeutic efficacy in patients with UC.

https://www.gastrojournal.org/action/doSearch?text1=granulocyte+and+monocyte+apheresis+&field1=AllField&AfterYear=2018&BeforeYear=2021&pageSize=50&startPage=&SeriesKey=ygast

Maki Miyakawa, Hiroki Tanaka, Tomoyoshi Shibuya,Taro Osada, Eiji Hosoi Gastroenterol. 2019 156 (6) Suppl.S-666–S-667

Background: Few studies have assessed the safety of granulocyte and monocyte adsorptive apheresis (GMA) in patients with inflammatory bowel disease (IBD) undergoing concomitant treatment with multiple immunosuppressant medications. To address this research gap, we investigated adverse effects associated with GMA in patients with IBD treated with multiple immunosuppressants  who  participated  in  the  “Post-marketing  surveillance  study  on  the safety and response of GMA treatment in patients with Crohn’s disease or ulcerative colitis with at least one special situation who received Adacolumn® (PARTICULAR).” Methods: The PARTICULAR study was a retrospective, multicenter cohort study of patients with ulcerative colitis (UC) or Crohn’s disease (CD) who received GMA between November 2013 and March 2017. Patients meeting at least one of the following special situation were enrolled: elderly (<=65 years) or pediatric/adolescent (>=18 years) patients, patients with anemia, or patients undergoing concomitant treatment with multiple immunosuppressants. GMA was performed using Adacolumn® (JIMRO, Takasaki, Japan). Each patient received up to 11 GMA sessions, and all adverse events (AEs) during the study period were recorded. The incidence of AEs was investigated relative to the number and type of immunosuppressants using univariate and multivariate logistic regression analyses. Results: A total of 437 patients (368 UC, 69 CD) from 93 institutions were included. Of these, 140, 169, 101, and 27 patients received none, 1, 2, and >=3 immunosuppressants, respectively. In total, 125 patients received multiple immunosuppressants. Concomitant prednisolone, immunomodulators, anti-tumor necrosis factor agents, and calcineurin inhibitors were administered in 189, 151, 89, and 24 patients, respectively. The incidence of AEs was 11% in all 437 patients and 8%, 12%, 12%, and 26% in patients receiving none, 1, 2, and >=3 immunosuppressants, respectively. In multivariate logistic regression analysis, anemia and concomitant immunosuppressants were independently associated with the incidence of AEs. Particularly, a higher number of concomitant immunosuppressants showed an increasing trend with odds ratios related to AEs. In contrast, concomitant corticosteroids were associated with a reduced risk of AEs. Nausea/vomiting and headache were the most common AEs in patients on multiple immunosuppressant medications (5.6% and 3.2%, respectively). Conclusions: Concomitant treatment with immunosuppressants was independently associated with the incidence of AEs such as nausea/vomiting and headache in patients with IBD receiving GMA. As the number of concomitant immunosuppressants increased, the incidence of AEs also increased. However, our data also suggest that GMA is safe in patients with IBD receiving prednisolone.

https://www.gastrojournal.org/action/doSearch?text1=granulocyte+and+monocyte+apheresis+&field1=AllField&AfterYear=2018&BeforeYear=2021&pageSize=50&startPage=&SeriesKey=ygast

Nicolò Mezzina ¹, Sophia Elizabeth Campbell Davies ², Sandro Ardizzone ¹ Expert Opin Pharmacother 2018 Nov;19(16):1747-1757. doi: 10.1080/14656566.2018.1525361. Epub 2018 Sep 27.

Introduction: Treatment of ulcerative colitis (UC) is constantly evolving. In the last two decades, new therapeutic strategies have been implemented by addressing specific disease mechanisms: biological agents against tumor necrosis factor-α and integrins are now widely used, and more agents targeting different pathological pathways are being marketed. Despite these novel therapies, nonbiological drugs are still the mainstay of treatment, especially in mild-to-moderate disease, since a proven safety and tolerability profile is observed. Excellent efficacy both in induction and maintenance of remission is obtained, with a lower cost compared to biological agents. Areas covered: The purpose of this review is to summarize the current knowledge and the latest clinical evidence regarding nonbiological therapies for UC. Expert opinion: Concomitant administration of oral and rectal 5-aminosalicylates acid is more effective in the treatment of UC in remission. Corticosteroids are the treatment of choice in patients with moderately severe or severe UC. The association of azathioprine with biological treatments is more effective than monotherapy. Cyclosporine is an effective drug in severe UC, but its poor management must be considered. Probiotics are very popular; however, evidence on their actual role in UC still must be demonstrated; cytapheresis plays only a niche role at this time.

https://pubmed.ncbi.nlm.nih.gov/30220228/

https://www.tandfonline.com/doi/abs/10.1080/14656566.2018.1525361?journalCode=ieop20

Kengo Furuichi, Takashi Wada Contrib Nephrol  2018;196:188-193. doi: 10.1159/000485721. Epub 2018 Jul 24

Plasma exchange or double filtration plasmapheresis for rapidly progressive glomerulonephritis, and low-density lipoprotein (LDL) apheresis or leukocytapheresis for nephritic syndrome are two major apheresis therapies for kidney diseases. In addition to these apheresis therapies, plasma exchange for lupus nephritis or LDL apheresis for refractory focal segmental glomerulonephritis is clinically valuable and established. Although several possibilities of apheresis for kidney diseases were speculated in animal experiments or human studies, clinical applications have thus far been limited. In addition to clinical benefits of apheresis, reports revealed suggestive mechanisms of apheresis for the diseases. Moreover, these therapies would have a great potential for kidney diseases. Further studies are needed to establish the effectiveness of apheresis in kidney diseases in more depth.

Apheresis for Kidney Disease – PubMed (nih.gov)

Hiroki Tanaka, Satoshi Motoya, Tomoyoshi Shibuya, Satoshi Tanida, Seiichiro Kokuma, Eiji Hosoi Gastroenterology 2018 154 (6) Suppl.S-996–S-997

Background: There are few studies on the usefulness of granulocyte and monocyte adsorptive apheresis (GMA) in elderly patients with inflammatory bowel disease (IBD). We investigated the safety and effectiveness of GMA in elderly patients who participated in the Post-marketing Surveillance Study of GMA Using Adacolumn® for Patients with Inflammatory Bowel Disease Who Have Special Situations (PARTICULAR). Methods: The PARTICULAR study is a retrospective, multicenter cohort study that included patients with ulcerative colitis (UC) or Crohn’s disease (CD) who received GMA between November 2013 and March 2017. Patients with at least one special situation, including elderly patients, patients with anemia, and patients undergoing concomitant treatment with multiple immunosuppressants (IMs) were enrolled. Patients aged # 64 years were excluded from this study. GMA was performed using Adacolumn® (JIMRO, Takasaki, Japan). Each patient received up to a maximum of 11 GMA sessions. The safety of GMA was assessed in all patients. The effectiveness of GMA was assessed in patients with UC with a partial UC disease activity index (pUC-DAI) score of $ 3. Remission was defined as a pUC-DAI score of # 2. Patients receiving concomitant treatment with infliximab, adalimumab, or calcineurin inhibitors were excluded from the effectiveness assessment. The incidence of adverse events (AEs) and remission rates were compared between elderly patients with and without any special situation using univariate and multivariate logistic regression analysis. Results: A total of 125 elderly patients (118 UC, 7 CD) from 93 institutions were included. The median age was 73.2 years. Fifty-six patients did not have any special situation, and 69 had at least one or more special situations. The incidence of AEs was 11.2% in all patients. The incidence of AEs was significantly lower in elderly patients without any special situation (3.6%) than in those with at least one or more special situations (17.4%) (Figure 1A). AEs significantly occurred in elderly patients with anemia (21.9%) and on multiple concomitant IMs (23.8%) compared to those without any special situation (3.6%). Anemia and multiple concomitant IMs were identified as independent predictors for a higher incidence of AEs (Table 1). The effectiveness of GMA was assessed in 92 patients with UC. The remission rate was 48.9%. No difference was observed in the remission rate between elderly patients without any special situation (52.2%) and those with at least one or more special situations (45.7%) (Figure 1B). Conclusions: A low incidence of AEs (3.6%) was found in elderly IBD patients receiving GMA without any special situation. Remission was achieved by GMA in 48.6% of the elderly UC patients. Care should be taken when using GMA in elderly IBD patients with anemia or on multiple concomitant IMs

Katsuyoshi Matsuoka ¹, Taku Kobayashi ¹, Fumiaki Ueno ^2 3, Toshiyuki Matsui ¹, Fumihito Hirai ¹, Nagamu Inoue ¹, Jun Kato ¹, Kenji Kobayashi ¹, Kiyonori Kobayashi ¹, Kazutaka Koganei ¹, Reiko Kunisaki ¹, Satoshi Motoya ¹, Masakazu Nagahori ¹, Hiroshi Nakase ¹, Fumio Omata ¹, Masayuki Saruta ¹, Toshiaki Watanabe ¹, Toshiaki Tanaka ¹, Takanori Kanai ¹, Yoshinori Noguchi ¹, Ken-Ichi Takahashi ¹, Kenji Watanabe ¹, Toshifumi Hibi ¹, Yasuo Suzuki ¹, Mamoru Watanabe ¹, Kentaro Sugano ¹, Tooru Shimosegawa ¹ , J Gastroenterol. 2018 Mar;53(3):305-353.

Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn’s disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese.

https://pubmed.ncbi.nlm.nih.gov/29429045/

Evidence-based clinical practice guidelines for inflammatory bowel disease – PMC (nih.gov)

Takuro Kanekura ¹, Mariko Seishima ², Masaru Honma ³, Takafumi Etou ⁴, Hikaru Eto ⁵, Keiko Okuma ⁶, Yukari Okubo ⁷, Yukie Yamaguchi ⁸, Takeshi Kambara ⁹, Tomotaka Mabuchi ¹⁰, Yasushi Suga ¹¹, Akimichi Morita ¹², Kiyofumi Yamanishi ¹³, Daisuke Tsuruta ¹⁴, Kei Itoh ¹⁵, Ken Yamaji ¹⁶, Shigaku Ikeda ⁶

J Dermatol 2017 Dec;44(12):1353-1359. doi: 10.1111/1346-8138.13975. Epub 2017 Aug 3.

Psoriatic arthritis (PsA), a chronic inflammatory arthropathy associated with psoriasis, is an intractable immune disorder and refractory to pharmacological intervention. We assessed efficacy of selective depletion of myeloid lineage leukocytes in patients with PsA in a multicenter setting. A total of 20 patients with moderate to severe PsA refractory to conventional and biological disease-modifying antirheumatic drugs were included. Eligible patients had 3 points or more in the classification criteria for PsA. Each patient received five sessions, once a week, of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn^® . The primary efficacy outcome was 20% or more decrease in the American College of Rheumatology score 20 (ACR20). Partial responders could receive an additional five GMA sessions. Of 20 patients, two did not complete the study, nine responded to five GMA sessions and nine received 10 sessions. At the first evaluation 2 weeks after the last GMA session, 13 of the 20 (65.0%) patients achieved ACR20. ACR20 was maintained in seven of 10 (70%) and five of 10 (50%) patients at the follow-up evaluation points 8 and 20 weeks after the last GMA session, respectively. GMA was well tolerated without any safety concern. This study demonstrates that GMA with the Adacolumn was effective with good safety profile in patients with PsA refractory to pharmacologicals. The results indicate a major role for myeloid leukocytes in the immunopathogenesis of PsA. A large controlled study is warranted to fully evaluate the efficacy of Adacolumn GMA in patients with PsA.

https://pubmed.ncbi.nlm.nih.gov/28771892/