Mariko Seishima

poster at ISFA 2019 pag 57

Generalized pustular psoriasis (GPP) is a rare inflammatory skin disorder characterized by a fever, edema, and generalized erythema with neutrophilic pustules. It sometimes occurs in the course of psoriasis vulgaris, or develops suddenly without any history of psoriasis. Mutations of the IL36RN (deficiency of interleukin thirty-six receptor antagonist: DITRA), CARD14 and AP1S3 genes underlie monogenic auto-inflammatory disorders causing GPP. GPP patients are usually treated with oral administration of etretinate, cyclosporine, and metrexate, biologics including TNF α inhibitors, antibodies to IL-17, IL-17 receptor, and IL-23 p19, and granulocyte and monocyte adsorption apheresis (GMA). Cyclosporine, TNF α inhibitors, and GMA are used for GPP in pediatric, pregnant, or lactating patients. GMA is an extracorporeal apheresis that removes activated granulocytes and monocytes using a column packed with cellulose acetate beads. Multicenter study was performed to access efficacy of selectively depleting the myeloid lineage leukocytes in GPP patients. Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Based on the GPP severity scores relative to entry, the overall scores improved, and the area of erythroderma, pustules, and edema decreased. Likewise, Dermatology Life Quality Index (DLQI) improved, reflecting better daily function and quality of life. Twelve out of 14 patients were judged as responders (85.7%), and 10 out of 12 patients maintained the clinical response for10 weeks after the last GMA session without any change in medication. Thus, GMA is estimated to be safe and effective, suggesting a major role of granulocytes/ monocytes in the immunepathogenesis of GPP. Recent study showed that GMA was effective for 100% of DITRA patients and for 64.7% of the patients with IL36RN mutation-negative GPP. Thus, GMA is effective therapy for both DITRA and non-DITRA GPP patients. GMA may be a useful therapy for all GPP patients

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

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

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

Takayuki Yamamoto ¹, Takayuki Iida ², Kentaro Ikeya ², Masaichi Kato ², Ai Matsuura ², Satoshi Tamura ³, Ryosuke Takano ³, Shinya Tani ⁴, Satoshi Osawa ⁴, Ken Sugimoto ³, Takahiro Shimoyama ⁵, Hiroyuki Hanai ² , Clin Transl Gastroenterol 2018 Jul 6;9(7):170.

Objectives: Adsorptive granulomonocytapheresis (GMA) with the Adacolumn has been introduced as a non-pharmacologic treatment for ulcerative colitis (UC). However, a subset of patients who might respond well to GMA needs to be targeted. This study was conducted at three IBD centers to determine factors affecting the efficacy of GMA in patients with moderately-to-severely active UC. 1234567890(); 1234567890(),; 1234567890(); 1234567890(); Methods: From January 2008 to December 2017, a total of 894 active episodes (first attack or relapse) in 593 patients were treated with GMA. Clinical remission was defined as normal stool frequency and no rectal bleeding. Multiple clinical and laboratory parameters at entry were considered for efficacy assessment. Results: Clinical remission was achieved during 422 (47%) of the 894 treatment cases. In the multivariate analysis, predictors for favorable response to GMA were age ≤60 years, UC duration <1 year, Mayo endoscopic subscore 2 (vs. 3), steroid naïve UC, and biologic naïve UC. Clinical remission rate was 70% in patients with four of the five factors, 52% in patients with three factors, 46% in patients with two factors, 39% in patients with one factor, and 18% in patients with none of these factors. Overall, the clinical remission rate was significantly higher in patients with a greater number of the five predictors (P < 0.0001). Conclusions: GMA appeared to be effective in steroid naïve and biologic naïve patients with short duration of UC. Elderly patients (>60 years) and those with severe endoscopic activity did not respond well to GMA. Additional, well designed, prospective, controlled trials should strengthen our findings.

https://pubmed.ncbi.nlm.nih.gov/29977035/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033883/pdf/41424_2018_Article_37.pdf

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

Gianni Imperiali ¹, Arnaldo Amato ¹, Maria Maddalena Terpin ², Ivo Beverina ³, Aurora Bortoli ⁴, Massimo Devani ⁴, Chiara Viganò ⁵,Gastroenterol Res Pract2017;2017:9728324.

Our study shows that a standard course of granulocyte-monocyte apheresis is associated with a 36% steroid-free clinical remission in patients with steroid-dependent, azathioprine-intolerant or resistant moderate ulcerative colitis. Apheresis might represent an alternative to biologic therapy or surgery in this specific subgroup of patients

https://pubmed.ncbi.nlm.nih.gov/29403531/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748298/pdf/GRP2017-9728324.pdf

Ya-Min Lai ¹, Wei-Yan Yao ², Yao He ³, Xuan Jiang ⁴, Yu-Bei Gu ², Min-Hu Chen ³, Yu-Lan Liu ⁴, Yao-Zong Yuan ², Jia-Ming Qian ¹ , Gut Liver. 2017 Mar 15;11(2):216-225.

The overall efficacy of GMA in patients with active UC who were taking first-line medications or were corticosteroid refractory was encouraging. Additionally, GMA was well tolerated and had a good safety profile.

https://pubmed.ncbi.nlm.nih.gov/27843131/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347645/pdf/gnl-11-216.pdf

Yusuke Okuyama,Akira Andoh,Masakazu Nishishita,Ken Fukunaga,Koji Kamikozuru,Yoko Yokoyama,Yoshitaka Ueno,Shinji Tanaka,Hiroyuki Kuge,Syusaku Yoshikawa,Atsushi Sugahara,Emi Anami,Yoshinori Munetomo,Chiyuki Watanabe,Yoshihide Fujiyama &Takayuki Matsumoto Scand. J. Gastro. 2013, 48 (4), 412-418. https://doi.org/10.3109/00365521.2012.763175

Objective. This study aimed to assess the efficacy and tolerability of leukocytapheresis (LCAP) and to investigate predictive factors for mucosal healing and a sustained clinical response in steroid-free and steroid-refractory patients with ulcerative colitis (UC). Material and methods. Thirty-one steroid-free or steroid-refractory patients with active UC were enrolled. Five or ten consecutive sessions of LCAP were performed in each patient. The efficacy and tolerability was then evaluated at weeks 3 and 6. Endoscopic examination was performed at week 6 to evaluate the mucosal healing, and the sustained cumulative response rate was evaluated at 12 months. Results. At week 6, the mean Mayo clinical activity score had decreased significantly from 8.0 to 4.6 in the steroid-free patients and from 8.3 to 3.9 in the steroid-refractory patients. Rachmilewitz’s endoscopic index had also decreased significantly from 9.1 to 6.1 in the steroid-free patients and from 10.0 to 5.7 in the steroid-refractory patients. Forty-seven percent of the steroid-free patients and 33% of the steroid-refractory patients achieved mucosal healing. The peripheral platelet counts had decreased significantly at weeks 3 and 6 in the mucosal healing group, compared with the non-mucosal healing group. The patients with a more than 15% platelet reduction had a significantly higher cumulative response rate, compared with the patients without a platelet reduction (p = 0.015). Conclusions. LCAP is beneficial for the induction of mucosal healing in steroid-free and steroid-refractory patients with UC. The degree of platelet reduction during LCAP might be a predictive marker for mucosal healing and a sustained clinical response.

Multicenter prospective study for clinical and endoscopic efficacies of leukocytapheresis therapy in patients with ulcerative colitis – PubMed (nih.gov)

Multicenter prospective study for clinical and endoscopic efficacies of leukocytapheresis therapy in patients with ulcerative colitis: Scandinavian Journal of Gastroenterology: Vol 48, No 4 (tandfonline.com)

Takeshi Tomomasa ¹, Hitoshi Tajiri, Seiichi Kagimoto, Toshiaki Shimizu, Atsushi Yoden, Kosuke Ushijima, Keiichi Uchida, Hiroaki Kaneko, Daiki Abukawa, Mutsuko Konno, Shun-ichi Maisawa, Takao Kohsaka, Akio Kobayashi, Japanese Study Group for Pediatric Ulcerative Colitis. J Pediatr Gastroenterol Nutr. 2011 Jul;53(1):34-9. doi: 10.1097/MPG.0b013e31821058bc.

Objective: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. Patients and methods: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. Results: The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. Conclusions: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.

https://pubmed.ncbi.nlm.nih.gov/21694533/

Leukocytapheresis in Pediatric Patients With Ulcerative Coli… : Journal of Pediatric Gastroenterology and Nutrition (lww.com)

Toshifumi Ashida ¹, Yutaka Kohgo, Akihiro Munakata, Mitsunori Noguchi, Bunei Iizuka, Yutaka Endo, Hiroyuki Hanai, Toshikazu Yoshikawa, Takayuki Matsumoto, Nobuo Aoyama, Toshiyuki Matsui, Keiichi Mitsuyama, Toshifumi Hibi

Transfus Apher Sci 2011 Apr;44(2):113-7. doi: 10.1016/j.transci.2011.01.001.

We conducted a multicenter study to investigate the efficacy of leukocytapheresis (LCAP) without concomitant steroid therapy in active ulcerative colitis (UC) patients. Twenty patients were enrolled. LCAP was performed twice a week for 3 weeks. The results revealed a significant decrease of the Lichtiger’s clinical activity index (CAI) from 11.7±2.6 at baseline to 6.6±4.1 after the therapy. The endoscopic index and serum C-reactive protein levels also decreased significantly after the therapy. Of the 20 patients, 15 (75%) were assessed as responders (CAI≤4 or ΔCAI≥3), and 7 (35%) achieved complete remission (CAI≤4). No serious adverse reactions were encountered. The results suggest that LCAP is an effective and safe option for patients with active UC who had not received systemic steroid treatment.

https://pubmed.ncbi.nlm.nih.gov/21402309/