Tomoyoshi Shibuya,Keiichi Haga,Michio Saeki,Mayuko Haraikawa,Hitoshi Tsuchihashi,Koki Okahara,Osamu Nomura,Hirofumi Fukushima,Takashi Murakami Dai Ishikawa,Shigaku Ikeda,Akihito Nagahara

J Clin Apher.  2020 Sep;35(5):488-492. doi: 10.1002/jca.21821. Epub 2020 Aug 7.

Pyoderma gangrenosum (PG) is an extra-intestinal skin lesion in inflammatory bowel disease (IBD) as is erythema nodosum. Vedolizumab (VED) is a monoclonal antibody that targets α4β7 integrin and has an intestinal selective mechanism. Despite good therapeutic effects on colitis, the effect on extra-intestinal manifestations (EIMs) remains unclear. Here we report a case of ulcerative colitis complicated by PG during treatment with VED, which was successfully treated with prednisolone in combination with adsorptive granulocyte and monocyte apheresis (GMA). The patient was a 50-year-old woman with a past medical history of extensive ulcerative colitis managed by golimumab (GLM). She developed flare symptoms due to loss of response to GLM, and treatment was switched to VED. Her gastrointestinal symptoms were improved with VED treatment with less frequent bowel movements. However, infiltrative erythema with pain appeared on the right lower leg and right knee, and expanded and gradually ulcerated. Her skin lesions were treated with corticosteroid, but showed poor improvement. Therefore, granulocyte and monocyte apheresis (GMA) treatment was administered in combination with prednisolone. After 3 months, the ulcer gradually improved, and at the time of this writing, the eruptions were nearly replaced by epithelial tissue. This case study showed that patients with UC and EIMS may respond well to combination therapy of VED and GMA. GMA has a very favorable safety profile. On the other hand, the causal connection between VED and PG is still unclear. We believe that a combination therapy involving VED and GMA in IBD patients with EIMs warrants consideration.

https://pubmed.ncbi.nlm.nih.gov/32767842/

Yoh Ishiguro ¹, Toshihide Ohmori ², Ken Umemura ³, Masahiro Iizuka ⁴ ,Ther Apher Dial 2020 Oct 7.

GMA was an effective treatment for corticosteroid-naïve patients and the efficacy sustained longer in those not receiving immunomodulators during GMA. GMA fulfills the notion that apheresis is to induce disease remission by removing from the body factors known to perpetuate disease. In therapeutic settings, these findings should help better decision making and avoid futile use of medical resources.

https://pubmed.ncbi.nlm.nih.gov/33029920/

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

Chie Kurihara, Toshihide Ohmori, Kenichi Inaba, Shunsuke Komoto, Kengo Tomita, Ryota Hokari Gastroenterology 2020 158 (6) Suppl.S-1046

Background: Granulocyte and monocyte adsorptive apheresis (GMA) is non-pharmacological therapy which selective depletion of activated granulocytes and monocytes/macrophages from peripheral blood, and it is used as induction therapy for IBD. However, its therapeutic mechanism has not been well characterized. Recently, it has been reported that Th17 releases chemokines which attract neutrophils, and some neutrophils produce IL17. We investigated that changes in mRNA expression levels of inflammation associated molecules such as cytokines, chemokines in colonic mucosa of ulcerative colitis (UC) patients before and after GMA treatment in order to obtain further understanding of GMA therapeutic mechanisms. 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 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 GMA therapeutic efficacy was determined based on Mayo score. Inflammation-related molecules mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. 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. Baseline characteristics such as sex, location of disease, CRP, WBC and Mayo score were not significantly different according to GMA efficacy. In the remission group, mRNA levels in mucosal tissue of IL1β, IL6, IL17, IL23 and GM-CSF which are Th17-asociated cytokines significantly decreased after the last GMA compared to the baseline levels(P<0,05) in contrast, expression of these mRNA tended to increase following GMA treatment in the non-response group. On the other hand, IL12 and IFN- γ which are associated with Th1 did not significantly decrease in the remission group. mRNA levels of leukocyte trafficking associated molecules such as MAdCAM-1, ICAM-1, integrinβ7, IL8 and MIP-1β significantly decreased following GMA treatment in the remission group(P <0.05), whereas only IL8 mRNA expression in the non-response group tended to increase. IL1 β, IL6, GM-CSF which are Th17-asociated cytokines and IL8 mRNA expressions in post-GMA treatment were significantly higher in the non-response group compared to the remission group or control group(P <0.05). Conclusion: In UC patients who achieved clinical remission by GMA, Th17- associated cytokines and leukocyte trafficking associated molecules but not Th1-asociated cytokines decreased significantly. Furthermore, Th17-asociated cytokines increased in the non-responders. These results reaffirm the involvement of neutrophil in the pathophysiology of UC and could be helpful for characterizing of GMA therapeutic mechanism.

https://www.gastrojournal.org/article/S0016-5085(20)33300-X/pdf

Keiji Matsuda ^1 2, Kohei Ohno ¹, Yuka Okada ¹, Takahiro Yagi ¹, Mitsuo Tsukamoto ¹, Yoshihisa Fukushima ¹, Atsushi Horiuchi ¹, Ryu Shimada ^1 2, Tsuyoshi Ozawa ^1 2, Tamuro Hayama ^1 2, Takeshi Tsuchiya ^1 2, Junko Tamura ¹, Hisae Iinuma ¹, Keijiro Nozawa ^1 2, Hitoshi Aoyagi ^2 3, Akari Isono ^2 3, Koichiro Abe ^2 3, Shinya Kodashima ^2 3, Takatsugu Yamamoto ^2 3, Yoshitaka Kawasaki ⁴, Yoshifuru Tamura ⁴, Yuko Sasajima ⁵, Fukuo Kondo ⁵, Yojiro Hashiguchi ^1 2 , Inflamm Intest Dis, 2020 Feb;5(1):36-41.

The effect of GMA with concomitant PSL (Prednisolone) and that of GMA without PSL were not different, and GMA was effective irrespective of PSL administration. The present study showed that GMA had efficacy and led many UC patients treated by PSL to be steroid free with no safety concern in the real world, although there is the possibility of recruitment bias due to the retrospective nature of the study.

https://pubmed.ncbi.nlm.nih.gov/32232053/

https://www.karger.com/Article/Pdf/505484

Yuki Isami,Yuriko Kawase,Akari Kondo,Wataru Akita,Koji Yasuda,Takeshi Matsutani,Hiroshi Mitsui

J Dermatol. 2020 May;47(5):e213-e215. doi: 10.1111/1346-8138.15303. Epub 2020 Mar 11.

letter.

https://pubmed.ncbi.nlm.nih.gov/32162361/

Tomoyoshi Shibuya ¹, Osamu Nomura ², Kei Nomura ², Koki Okahara ², Keiichi Haga ², Dai Ishikawa ², Naoto Sakamoto ², Tatsuo Ogihara ², Taro Osada ², Akihito Nagahara ² , Digestion, 2020;101(1):46-52. 

Unlike pharmacologicals, the efficacy of Cytapheresis appears to be time dependent. Accordingly, in the elderly, we observed a delayed response, indicating that elderly patients may respond beyond the end of Cytapheresis therapy. Therefore, patients who do not show efficacy at the end of Cytapheresis therapy should be followed up for delayed response. Further, Cytapheresis is favored by patients for its good safety profile.

https://pubmed.ncbi.nlm.nih.gov/31722366/

Rish K Pai ¹, Douglas J Hartman ², Claudia Ramos Rivers ³, Miguel Regueiro ⁴, Marc Schwartz ³, David G Binion ³, Reetesh K Pai ⁵ , Clin Gastroenterol Hepatol. 2020 Oct;18(11):2510-2517.e5.

Histologic evidence of UC activity, including small numbers of neutrophils in the colonic mucosa, is the only factor independently associated with use of systemic corticosteroids. Complete resolution of neutrophil-associated inflammation should be a target for treatment of UC.

https://pubmed.ncbi.nlm.nih.gov/31843598/

N Ueno, Y Murakami, T Iwama, T Sasaki, T Kunogi, K Takahashi, K Tanaka, K Ando, S Kashima, Y Inaba, K Moriichi, H Tanabe, M Taruishi, M Fujiya, T Okumura, Journal of Crohn’s and Colitis, Volume 13, Issue Supplement_1, March 2019

Fcal is considered to be a useful and objective predictor of the efficacy of GMA treatment in UC patients and superior to symptomatic scores and blood parameters

https://academic.oup.com/ecco-jcc/article/13/Supplement_1/S423/5300757

Nina Worel ¹, Behrouz Mansouri Taleghani ², Erwin Strasser ³ Transfus Med Hemother 2019 Dec;46(6):394-406. doi: 10.1159/000503937. Epub 2019 Nov 6.

The section „Preparative and Therapeutic Hemapheresis“ of the German Society for Transfusion Medicine and Immunohematology (DGTI) has reviewed the actual literature and updated techniques and indications for evidence-based use of therapeutic apheresis in human disease. The recommendations are mostly in line with the „Guidelines on the Use of Therapeutic Apheresis in Clinical Practice“ published by the Writing Committee of the American Society for Apheresis (ASFA) and have been conducted by experts from the DACH (Germany, Austria, Switzerland) region.

https://pubmed.ncbi.nlm.nih.gov/31933569/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944925/