Iizuka M, Etou T, Sagara S.  World J Gastroenterol 2022; 28(34): 4959-4972 DOI: 10.3748/wjg.v28.i34.4959

For the optimal management of refractory ulcerative colitis (UC), secondary loss of response (LOR) and primary non-response to biologics is a critical issue. This article aimed to summarize the current literature on the use of cytapheresis (CAP) in patients with UC showing a poor response or LOR to biologics and discuss its advantages and limitations. Further, we summarized the efficacy of CAP in patients with UC showing insufficient response to thiopurines or immunomodulators (IM). Eight studies evaluated the efficacy of CAP in patients with UC with inadequate responses to thiopurines or IM. There were no significant differences in the rate of remission and steroid-free remission between patients exposed or not exposed to thiopurines or IM. Three studies evaluated the efficacy of CAP in patients with UC showing an insufficient response to biologic therapies. Mean remission rates of biologics exposed or unexposed patients were 29.4 % and 44.2%, respectively. Fourteen studies evaluated the efficacy of CAP in combination with biologics in patients with inflammatory bowel disease showing a poor response or LOR to biologics. The rates of remission/response and steroid-free remission in patients with UC ranged 32%-69% (mean: 48.0%, median: 42.9%) and 9%-75% (mean: 40.7%, median: 38%), respectively. CAP had the same effectiveness for remission induction with or without prior failure on thiopurines or IM but showed little benefit in patients with UC refractory to biologics. Although heterogeneity existed in the efficacy of the combination therapy with CAP and biologics, these combination therapies induced clinical remission/response and steroid-free remission in more than 40% of patients with UC refractory to biologics on average. Given the excellent safety profile of CAP, this combination therapy can be an alternative therapeutic strategy for UC refractory to biologics. Extensive prospective studies are needed to understand the efficacy of combination therapy with CAP and biologics.

https://pubmed.ncbi.nlm.nih.gov/36160647/

https://www.wjgnet.com/1007-9327/full/v28/i34/4959.htm

Masahiro Iizuka, Takeshi Etou , Yosuke Shimodaira , Takashi Hatakeyama , Shiho Sagara,World J Gastroenterol 2021 Mar 28;27(12):1194-1212. 

Our results suggest that CAP effectively induces and maintains steroid-free remission in refractory UC and re-induces steroid-free remission in patients achieving steroid-free remission after the first course of CAP.

https://pubmed.ncbi.nlm.nih.gov/33828394/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006096/pdf/WJG-27-1194.pdf

ISFA-EIFA-2021

Remission induction was more challenging in elderly UC patients. However, CAP was safe and effective for remission induction as a non-pharmacological treatment, even in elderly UC patients, after the incorporation of practical measures. Optimized and contrived CAP is still useful as the sole or concomitant treatment.

https://www.eventclass.org/contxt_eisfa2021/online-program/session?s=S-05

Kentaro Tominaga, Kenya Kamimura, Hiroki Sato, Masayoshi Ko, Yuzo Kawata, Takeshi Mizusawa, Junji Yokoyama, and Shuji Terai, World J Clin Cases. 2020 Jun 6; 8(11): 2092–2101.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis clinically characterized by the presence of painful skin ulcerations with erythematous. As it is frequently associated with inflammatory bowel diseases, including ulcerative colitis, gastroenterologists should be familiar with the disease including therapeutic options. Pyoderma gangrenosum is one of the neutrophilic dermatoses often complicated with ulcerative colitis. The corticosteroid and other immune modulator have been used for the treatment, however, as its disease mechanism has not been clarified, there is no additional option for those who showed poor response and refractory to the conventional therapies. Therefore, we have conducted a review focusing on the cytapheresis for PG in cases of inflammatory bowel diseases. A literature search was conducted to extract studies published in the last 20 years, with information on demographics, clinical symptoms, treatment, and the clinical course from a total of 22 cases reported and our recent case. In most patients, cytapheresis was associated with improvement or resolution of PG after failure of conventional therapeutic options such as corticosteroids, antibiotics, immunosuppressive agents and immunoglobulin. Based on the recent reports, we have summarized the clinical course of 23 cases and efficacy of cytapheresis..Cytapheresis is helpful in the majority of patients with PG refractory to medical treatment associated with inflammatory bowel diseases and could be further studied in a multicenter, randomized trial.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281039/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281039/pdf/WJCC-8-2092.pdf

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/

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

S Takahashi, M Colvin, J Toyosawa, M Ishida, T Kagawa, S Kuraoka, Y Aoyama, K Okamoto, I Sakakihara, K Izumikawa, K Yamamoto, S Tanaka, M Matsuura, S Ishikawa, M Wato, T Hasui, T Inaba, Journal of Crohn’s and Colitis, Volume 12, Issue supplement_1, February 2018

Cytapheresis therapy as an additional therapy to oral tacrolimus is effective in patients with severe ulcerative colitis.

)https://academic.oup.com/ecco-jcc/article/12/supplement_1/S328/4808317

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

TARO OSADA＊, SUMIO WATANABE＊, Juntendo Medical Journal61 (6), 588-596

In recent years, landmark progress has been made in the treatment of patients with inflammatory bowel
diseases (IBD). The anti-tumour necrosis factor (TNF)-α antibody era has shown that mucosal healing is a key
therapeutic goal, and may predict the sustainability of remission or resection-free survival in IBD patients.
Further, the anti-TNF-α antibody infliximab (IFX) became an alternative medication for refractory UC in 2010
under the Japan national health reimbursement scheme. However, to induce remission in steroid-refractory UC,
currently several therapeutic options are available in Japan including cytapheresis, tacrolimus, and anti-TNF-α
biologics, but as yet, there are no guidelines for the sequence and timing of these therapeutic interventions.
Additionally, there are many patients who do not respond, or are intolerant, to anti-TNF-α biologics. Recently,
new strategies like faecal microbiota transplantation and anti-leucocyte infiltration have been tested for induction
and maintenance of remission in IBD patients. This paper provides an overview of the latest treatment options and
future perspectives in IBD therapy

https://www.jstage.jst.go.jp/article/jmj/61/6/61_588/_pdf/-char/en

Tetsuro Takayama ¹, Takanaori Kanai, Katsuyoshi Matsuoka, Susumu Okamoto, Tomohisa Sujino, Yohei Mikami, Tadakazu Hisamatsu, Tomoharu Yajima, Yasushi Iwao, Haruhiko Ogata, Toshifumi Hibi, J Crohns Colitis. 2013 Mar;7(2):e49-54.

Background: Although accumulating studies in Japan show that cytapheresis (CAP) therapy is safe and effective for the induction of remission of moderate or severe ulcerative colitis (UC), the long-term prognosis of UC patients treated with CAP is unknown. The aim of this study was to determine the long-term prognosis of UC patients treated with CAP. Methods: Ninety patients treated previously with CAP and followed for more than 3 years were evaluated. The rates of operation, readmission, and use or dose-up of corticosteroid were analyzed as long-term prognosis. Results: Following the first course of CAP treatment, 64% of patients showed clinical improvement (> 4-point decrease in the clinical activity index (CAI)), and 49% of patients achieved clinical remission (CAI ≤ 4). Longer disease duration and lower age at the first CAP treatment correlated significantly with the therapeutic effects of CAP (p = 0.003 and 0.035, respectively). The rates of operation and readmission were significantly lower in patients who showed previous clinical effects of CAP than in those who did not respond to CAP. The rates of operation and readmission were also significantly lower in patients whose treatment was combined with immunomodulators after the initiation of CAP than in patients who did not use immunomodulators. Importantly, the second course of CAP was also effective in most of the patients who showed a clinical response to the first CAP. Conclusions: Patients who achieve remission after the first CAP therapy may have a good long-term prognosis and a good response to a second CAP therapy even after relapse.

https://pubmed.ncbi.nlm.nih.gov/22633997/

https://academic.oup.com/ecco-jcc/article/7/2/e49/484944?login=false