Tomoyoshi Shibuya,Osamu Nomura,Kei Nomura,Mayuko Haraikawa,Keiichi Haga,Dai Ishikawa,Taro Osada,Ken Yamaji,Shigaku Ikeda,Akihito Nagahara

Ther Apher Dial 2022 Mar 5. doi: 10.1111/1744-9987.13823. Online ahead of print.

Introduction: In recent years, the prevalence of inflammatory bowel diseases has been increasing in Japan due to the westernization of lifestyles. Many patients have been reported to have extra-intestinal manifestations (EIMs) at least once. Skin lesions occur with a high degree of frequency among EIMs, with erythema nodosum (EN) and pyoderma gangrenosum (PG) the main complications. Cytapheresis is again attracting attention as a treatment with few side effects. Methods: We investigated the therapeutic effect of cytapheresis on ulcerative colitis (UC) and cutaneous EIMs. Between 2008 and 2021, 240 patients with active UC had induction therapy by cytapheresis at our hospital. Results: Remission and response rates were 50.0% and 67.5%, respectively. Apheresis was performed on seven patients with PG and five patients with EN with a good response. Serious adverse events were not observed. Conclusion: This retrospective assessment of efficacy showed that EN and PG responded favorably to cytapheresis.

https://pubmed.ncbi.nlm.nih.gov/35247233/

Víctor López Baez, Pedro Arango Sancho, Yolanda Calzada Baños, Elena Codina Sampera, Ana Vinuesa Jaca, Lina Hernández Zúñiga, Álvaro Madrid Aris, Nephrology Dialysis Transplantation, Volume 35, Issue Supplement_3

The apheresis techniques in pediatrics had been presented with few complications in our center, none derived from vascular access, anticoagulation, infections or adverse effects due to use of replacement fluid. The training of medical and nursing staff is essential to identify risk situations. The use of protocols and international guidelines ensure safety in pediatrics.

https://academic.oup.com/ndt/article/35/Supplement_3/gfaa140.MO079/5853667

OP-NDTJ_Perlims 1..15 (silverchair.com)

Kazuki Kakimoto ¹, Minoru Matsuura ², Takumi Fukuchi ³, Hitoshi Hongo ⁴, Tsuguhiro Kimura ⁴, Nobuo Aoyama ⁵, Yorihide Okuda ⁶, Kazuki Aomatsu ⁷, Noriko Kamata ⁸, Yoko Yokoyama ⁹, Chiemi Mizuno ¹⁰, Takuya Inoue ¹, Takako Miyazaki ¹, Shiro Nakamura ¹, Kazuhide Higuchi ¹, Hiroshi Nakase ¹¹ , Crohns Colitis 360. 2020 Sep 23;2(4):otaa073.

GMA shows effectiveness in inducing remission in UC patients not receiving steroid.

https://pubmed.ncbi.nlm.nih.gov/34192247/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797742/pdf/otaa073.pdf

Shoichi Nishise ^1 2, Yuji Takeda ³, Yasuhiko Abe ¹, Yu Sasaki ¹, Shinichi Saitoh ³, Hidetoshi Nara ³, Hironobu Asao ³, Yoshiyuki Ueno, Ther Apher Dial 2020 Oct 17.

These results indicated that physiological heating of the apheresis carrier augmented the anti-inflammatory reaction in vitro. Thus, heating during GMA may be a new approach for augmenting clinical efficacy.

https://pubmed.ncbi.nlm.nih.gov/33067913/

Tetsurou Imai ¹, Hiroshi Yamasaki ^2 3 4, Keiichi Mitsuyama ³, Osamu Yamaga ¹, Gaku Sugihara ¹, Yusuke Kaida ⁵, Ryo Shibata ⁵, Takuma Hazama ⁵, Shinichiro Yoshioka ^2 3, Takuji Torimura ², Kei Fukami ⁵, Norio Yamashita ⁶

Kurume Med J. 2020 Jul 1;66(1):1-7. doi: 10.2739/kurumemedj.MS661002. Epub 2020 Jan 15.

Introduction: Granulocyte and monocyte apheresis (GMA) is an effective treatment strategy for active ulcerative colitis (UC) in Japan. Single needle (SN) apheresis reduces needle puncture pain in patients because it requires only one puncture site. We evaluated whether single-needle apheresis could be a safe and effective means of reducing patient burden. Method: We performed a retrospective study of active UC patients who were treated with either SN apheresis or conventional double-needle (DN) apheresis at the Kurume university hospital from April 2014 to March 2018. All the patients treated with GMA after September 2016 underwent SN apheresis. Thus, the two groups predominantly belonged to different time periods. We assessed the safety of SN apheresis. Result: Six patients underwent SN apheresis, and 6 underwent DN apheresis. The average time to the start of apheresis was significantly reduced from 23.1 minutes in the case of DN apheresis to 12.6 minutes for SN apheresis. In addition, the number of difficult punctures was significantly reduced with SN apheresis. There were no differences in adverse events between SN and DN apheresis. Treatment benefits, remission rate and disease activity were similar between SN and DN apheresis.Conclusion: SN apheresis reduced both the time to treatment initiation and pain during puncture, and there was no difference in the number of blood clotting episodes as compared with DN. Although further comparative studies are needed, SN apheresis may be a safe alternative for patients to reduce the strain of treatment.

https://pubmed.ncbi.nlm.nih.gov/31941846/

https://www.jstage.jst.go.jp/article/kurumemedj/66/1/66_MS661002/_article

N Toita, H Tanaka, K Arai, H Shimizu, D Abukawa, T Kobayashi, N Yoshimura, S Tanida, E Hosoi, Journal of Crohn’s and Colitis, Volume 13, Issue Supplement_1, March 2019

Background: The usefulness of granulocyte and monocyte adsorptive apheresis (GMA) in paediatric patients with inflammatory bowel disease (IBD) has not been studied in depth. We investigated the safety and effectiveness of GMA in paediatric patients with IBD who participated in a post-marketing surveillance study referred to as the PARTICULAR study.

Methods: The PARTICULAR study was a retrospective, multi-centre cohort study that included patients with ulcerative colitis (UC) or Crohn’s disease (CD) who received GMA between November 2013 and March 2017. The study enrolled patients with at least one special situation, including paediatric, being elderly, with anaemia and concomitant treatment with multiple immunosuppressants. Patients aged >18 years were excluded from this study. The GMA was performed using Adacolumn® (JIMRO, Takasaki, Japan). Each patient underwent up to 11 GMA sessions. All adverse events (AEs) were recorded during the observation time interval. Any AE, for which the causality of the GMA could not be ruled out was classified as an adverse device effect (ADE). In addition, feasibility problems (FPs) during the operation of the GMA column were recorded. The effectiveness of GMA was assessed in UC patients with a partial Mayo (pMayo) score of ≥3. Remission was defined as a pMayo score of ≤2. Patients receiving concomitant treatment with infliximab, adalimumab or calcineurin inhibitors were excluded from the effectiveness assessment.

Results: A total of 53 paediatric patients (40 UC, 13 CD) from 27 institutions, with a mean age of 15.0 years, were included. The incidence of AEs, ADEs and FPs were 18.9%, 5.7% and 20.8%, respectively. The ADEs included abdominal discomfort in 2 (3.8%) patients and one patient each with fever, nausea/vomiting and headache (1.9% each). The FPs included blood access failure in 10 patients (18.9%), venous pressure elevation in 4 (7.5%), clot formation in the apheresis lines in 2 (3.8%) and venous access difficulty in 1 patient (1.9%). A total of 17 patients (32.1%) discontinued GMA therapy ahead of the planned treatment schedule. Among these patients, the GMA therapy was discontinued for the following reasons: (1) decision by the physician (n = 12), (2) withdrawal due to AE (n = 4) and (3) withdrawal by own wish (n = 1); none were discontinued due to ADE and FP. The effectiveness of the GMA was assessed in 29 UC patients. The remission rate of the paediatric UC patients was 43.5%. Conclusions: There were AEs and FPs in approximately 20% of paediatric patients with IBD treated by GMA, but none of these discontinued the GMA treatment due to ADE or FP. Remission was achieved by GMA in 44% of the paediatric UC patients. This study showed that GMA was well tolerated treatment option for the paediatric IBD patients.

https://academic.oup.com/ecco-jcc/article/13/Supplement_1/S281/5301146?login=true

Miho Hatanaka, Yuko Higashi, Takuro Kanekura

poster at ISFA 2019 pag 104

Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and
systemic flushing accompanied by extensive sterile pustules. Treatments of GPP are usually
topical corticosteroids, activated vitamin D3 ointment, ultraviolet light (UV) therapy, and
oral administration of etretinate, cyclosporine, or methotrexate. Recently, biologics such as
TNF- α; inhibitors, anti-IL-17- and anti-IL-23 antibodies are used. Pustulosis palmoplantaris
(PPP) is a chronic recurrent disorder of the palms and soles characterized by sterile intradermal
pustules. PPP often accompanies joint symptoms. In some instances, PPP is associated with
a focus of infection somewhere in the body; elimination of the infection sometimes improve
symptom. Some treatments of GPP are used for PPP. Psoriatic arthritis (PsA) is a disease
characterized by skin and nail psoriasis together with widespread musculoskeletal inflammation
such as peripheral joint disease, axial joint disease, enthesitis, and dactylitis. Treatment of
PsA is oral administration of NSAID’s, cyclosporine, methotrexate and phosphodiesterase 4
inhibitors for mild to moderate cases. Biologics; TNF- αinhibitors, anti-IL-17- and anti-IL-23
antibodies; have been approved for severe or advanced cases. Granulocyte/monocyte adsorption
apheresis (GMA) is an extracorporeal therapy designed to remove and suppress the functions
of neutrophils, macrophages and monocytes that accumulate in the inflamed tissue and are
involved in the pahogenesis. GMA may be considered as a safe treatment modality with few
side-effects for GPP, PPP and PsA. The effect and safety of GMA have been reported mostly in
case reports. Although the effect and safety of GMA were demonstrated in a multicenter study.
GMA’s utility is expected based on the mechanism of action.

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

Takuro Kanekura

poster at ISFA 2019 pag 58

Adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn is an extracorporeal treatment, which uses cellulose acetate (CA) beads as adsorptive leucocytapheresis carriers designed to remove elevated and potentially activated myeloid lineage leucocytes. Case series studies on the clinical effectiveness of GMA on skin diseases and associated arthropathy attributable to activated myeloid lineage leucocytes returned remarkable outcome without any serious adverse events. Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis. PsA is an intractable immune disorder and refractory to pharmacological intervention. Efficacy of selective depletion of myeloid lineage leucocytes in patients with PsA was assessed.in a multicenter setting. A total of 20 patients with moderate to severe PsA refractory to conventional and biological disease-modifying antirheumatic drugs were enrolled. Each patient received 5 sessions of GMA once a week. The primary efficacy outcome was 20% or more decrease in the American College of Rheumatology score 20 (ACR20). Partial responders received an additional 5 GMA sessions. Of 20 patients, 2 did not complete the study, 9 responded to 5 GMA sessions and 9 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 7 of 10 (70%) and 5 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 multicenter study demonstrated that GMA was effective with good safety profile in patients with PsA refractory to pharmacologicals, We present the results of this study and mode of action of GMA.

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

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