I Rodríguez-Lago, D Ginard, R J Díaz Molina, M Vicuña, E Domenech, M Abanades, O Moralejo Lozano, G Bastida, A D Sánchez Capilla, E Iglesias, F Rancel-Medina, M D M Blasco, M Bosca-Watts, M Calvo Iñiguez, C Herrera deGuisé, E Leo, A Viejo Almanzor, V Hernández Ramirez, C Suárez Ferrer, L Quilez Pérez, M Muñoz, F Fernández Pérez, J M Huguet, P Fradejas, C López Ramos, A M Fuentes Coronel, C Reygosa Castro, N Rull Murillo, P Zapico, J L Cabriada
Journal of Crohn’s and Colitis, Volume 18, Issue Supplement_1, January 2024, Page i1011, doi.org=10.1093/ecco-jcc/jjad212.0641

Background
The clinical efficacy of granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn in patients (pts) with inflammatory bowel disease (IBD) has been reported in several clinical trials (CT), with significant clinical remission rates. However, evidence on real-world effectiveness of GMA with Adacolumn in ulcerative colitis (UC) or Crohn’s disease (CD) patients who were underrepresented in CT is still limited.

Methods
GRACE is a multicentric, prospective observational study conducted at 31 centres in Spain. The study included adults (≥18 years) diagnosed with UC or CD who had been scheduled to receive GMA with Adacolumn in clinical practice. The study consisted of a baseline (GMA initiation) and 3 follow-up visits at 4, 24, and 48 weeks after the last GMA session. The primary endpoint is the steroid-free remission rate at 24 weeks. This interim analysis is focused on clinical characterization of patients and their management and outcome 4 weeks after GMA treatment.

Results
A total of 95 evaluable patients were included at data cut-off date (25 Sept 2023) (median age: 54 years; 50% men: 81% outpatients). Overall, 89.4% (n=84) of patients had UC, being moderate-to-severe in 85.5%; 57,8% had pancolitis, and the median Mayo score was 5 (interquartile range [IQR], 3-6). Out of the 10 patients (10.6%) with CD, all had B1, and 3 patients had L1, 4 L2 and 3 L3. Overall, 17% had extraintestinal manifestations. Regarding IBD-related therapy, 52.6% of patients had previously received anti-TNF agents, 37.9% thiopurines, and 17.8% JAK inhibitors. Overall, 85.3% of patients received concomitant treatment with GMA, most commonly 5-ASA (60%), corticosteroids (51,6%), ustekinumab (20%), vedolizumab (17.9%), and anti-TNF therapy (11.6%). A total of 71 patients reached the 4-week visit after receiving a median of 10 (IQR, 8-10) GMA sessions (weekly: 26.3%, biweekly: 36.8%, and weekly/biweekly: 31.6%). At week 4, clinical remission was achieved by 50.7% of patients (UC: 49.2%; CD: 66.7%), being 50% and 53.3% in patients concomitantly treated with ustekinumab and vedolizumab. Steroid-free remission rate was 26.1% (UC: 22.2%; CD: 66.7%) at week 4. Overall, 11,2% of patients experienced AEs related to GMA, most of them being mild (73%) or moderate (22.4%). Most common AEs were headache and asthenia. No SAEs were observed.

Conclusion
Preliminary data at 4 weeks show that Adacolumn is a safe and effective treatment in a cohort of IBD refractory patients with previous failure to multiple therapies including thiopurines, biologics and JAK inhibitors. Half of patients were concomitantly treated with biologics, and their clinical remission rate was similar to the overall population. Long-term results of this study (48 weeks) are required to confirm these findings.

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

Takumi Fukuchi , Kousaku Kawashima , Hideaki Koga , Ran Utsunomiya, Kohei Sugiyama , Keiji Shimazu , Takaaki Eguchi , Shunji Ishihara J Clin Biochem Nutr. 2022 Mar;70(2):197-204. doi: 10.3164/jcbn.21-112. Epub 2021 Dec 25.

This study examined the long-term maintenance rate after inducing remission by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids (CS) and GMA re-treatment efficacy in the same patients upon relapse with ulcerative colitis. Patients who achieved clinical remission and mucosal healing (MH) by first-time intensive GMA (first GMA) without CS were enrolled. The cumulative non-relapse survival rate up to week 156 was calculated. Patients with relapse during the maintenance period underwent second-time intensive GMA (second GMA) without CS. Clinical remission and MH rates following second GMA were compared to those following first GMA in the same patients. Of the 84 patients enrolled, 78 were followed until week 156 and 34 demonstrated relapse. The cumulative non-relapse survival rate by week 156 was 56.4%. Clinical remission and MH rates after second GMA did not differ from those after first GMA in the same patients (week 6: clinical remission, 100% vs 88.4%, p = 0.134; MH, 100% vs 84.8%, p = 0.074). In conclusion, MH induction by intensive GMA without use of CS in ulcerative colitis patients contributes to subsequent long-term clinical remission maintenance. GMA re-treatment efficacy was comparable to that of first GMA in the same patients who had relapse.

https://pubmed.ncbi.nlm.nih.gov/35400813/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921725/

Gerardo Prieto Bozano an. pedatr. contin.2012;10(5):286-9

• Existen 2 dispositivos de granulocitoféresis: Cellsorba^® (fibras de poliéster no tejidas), que fija granulocitos y linfocitos, y Adacolumn^® (acetato de celulosa) que fija selectivamente granulocitos y monocitos.
• Además de retirar leucocitos activados, la aféresis produce incremento del número de granulocitos CD10-negativos (inmaduros), disminución de citocinas proinflamatorias (factor de necrosis tumoral alfa [TNF-α], interleucina [IL-6],IL-8 e IL-1β) e incremento de citocinas inhibitorias (IL-1, IL-10)
• La granulocitoféresis es un método razonablemente eficaz y seguro para obtener la remisión en niños con colitis ulcerosa corticodependiente o resistente, sobre todo en pacientes en el primer episodio, en enfermedad de corta evolución y en aquellos que no han recibido esteroides
• El procedimiento requiere 2 accesos venosos de buen flujo. La pauta más habitual de tratamiento consiste en 1–2 sesiones semanales de 60min a un flujo de 30ml/min, hasta un total de 5–10 sesiones

https://www.elsevier.es/es-revista-anales-pediatria-continuada-51-articulo-granulocitoferesis-colitis-ulcerosa-S1696281812701002

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

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

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

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

J L Cabriada ¹, E Domènech, N Ibargoyen, V Hernández, J Clofent, D Ginard, I Gutiérrez-Ibarluzea, J Hinojosa, J Gastroenterol. 2012 Apr;47(4):359-65.

 

Background: Several small, prospective, open studies suggest that leukocytapheresis might be efficient in patients with steroid-dependent ulcerative colitis (UC). Aim: To evaluate the short- and long-term effectiveness of leukocytapheresis for the management of steroid-dependent UC in clinical practice. Methods: A Web-based, nationwide database specifically designed to record the efficacy and safety data of leukocytapheresis therapy in UC was available from September 2007 in Spain. Clinical data were collected at treatment baseline, 1 month after the last apheresis session (initial efficacy), and 6 and 12 months thereafter (long-term efficacy). Remission was defined as a Mayo Clinic index ≤2 together with complete steroid withdrawal and response as a decrease of ≥3 from the baseline score. Results: A total of 142 steroid-dependent UC patients were included in the registry, most of them treated with the Adacolumn™ system. In 69% of patients thiopurine therapy failed to achieve steroid-free clinical remission. Initial clinical remission was obtained in 37% of cases. The initial corticosteroid dose, the number and frequency of apheresis sessions, or the previous failure of thiopurines and/or infliximab did not influence the initial remission rate, but a greater decrease in CRP levels was associated with a higher probability to obtain initial remission. At 6 and 12 months, 41 and 36% of patients were in clinical remission, respectively. Only one serious adverse effect was recorded. Conclusions: In clinical practice, apheresis allows long-term steroid-free clinical remission in up to one third of steroid-dependent UC patients, even in those with prior failure of thiopurines.

https://pubmed.ncbi.nlm.nih.gov/22105230/

Tarja Ruuska, Marja-Leena Lähdeaho, Yelda Sutas, Merja Ashorn, Juhani Grönlund Scand J Gastroenterol 2007 Nov; 42(11):1390-1. doi: 10.1080/00365520701231116.

Recent studies show corticosteroid dependency in 45% of paediatric ulcerative colitis (UC) patients despite using other medicaments, including immunomodulators This patient group is problematic as corticosteroids have numerous side effects when used long term. New biological approaches have proved effective in the treatment of inflammatory bowel disease (IBD), but as the side effects can be severe, especially in young patients, their use is restricted in UC.

In UC, circulating activated granulocytes and macrophages/monocytes are increased and can infiltrate the bowel and cause tissue injury by producing inflammatory cytokines, being thus involved in the initiation and perpetuation of an inflammatory disorder. Periodic removal of activated granulocytes and monocytes/ macrophages with selective leucocyte apheresis (Adacolumn; JIMRO, Japan) is expected to reduce leucocyte-dependent tissue injury. Preliminary reports show promising results in the treatment of IBD, in children with corticosteroid-dependent or -resistant UC.

We design a  pilot study where 11 children (7 corticosteroid-dependent, 3 corticosteroid-resistant and 1 refusing corticosteroids) were treated with apheresis and their data analysed. Treatment was given once a week, a total of 5-9 sessions. 8 out of the remaining 11 patients responded well to the treatment. Corticosteroids could be tapered-off either totally or to minimal doses in all cases. Treatment was well tolerated.

https://pubmed.ncbi.nlm.nih.gov/17918012/

https://www.tandfonline.com/doi/full/10.1080/00365520701231116?scroll=top&needAccess=true