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Machine learning using clinical data at baseline predicts the medium-term efficacy of ustekinumab in patients with ulcerative colitis

Hiromu Morikubo, Ryuta Tojima, Tsubasa Maeda, Katsuyoshi Matsuoka, Minoru Matsuura, Jun Miyoshi, Satoshi Tamura & Tadakazu Hisamatsu Sci Rep 14, 4386 (2024).

Predicting the therapeutic response to biologics before administration is a key clinical challenge in ulcerative colitis (UC). We previously reported a model for predicting the efficacy of vedolizumab (VDZ) for UC using a machine-learning approach. Ustekinumab (UST) is now available for treating UC, but no model for predicting its efficacy has been developed. When applied to patients with UC treated with UST, our VDZ prediction model showed positive predictive value (PPV) of 56.3% and negative predictive value (NPV) of 62.5%. Given this limited predictive ability, we aimed to develop a UST-specific prediction model with clinical features at baseline including background factors, clinical and endoscopic activity, and blood test results, as we did for the VDZ prediction model. The top 10 features (Alb, monocytes, height, MCV, TP, Lichtiger index, white blood cell count, MCHC, partial Mayo score, and CRP) associated with steroid-free clinical remission at 6 months after starting UST were selected using random forest. The predictive ability of a model using these predictors was evaluated by fivefold cross-validation. Validation of the prediction model with an external cohort showed PPV of 68.8% and NPV of 71.4%. Our study suggested the importance of establishing a drug-specific prediction model.

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Circulating Metabolomic Signature in Generalized Pustular Psoriasis Blunts Monocyte Hyperinflammation by Triggering Amino Acid Response

Ning Yu 1Chen Peng 1Wenjuan Chen 1Ziwen Sun 1Jianfeng Zheng 1Shujie Zhang 2Yangfeng Ding 1Yuling Shi 1 ,

Front Immunol. 2021 Sep 8;12:739514. doi: 10.3389

Generalized pustular psoriasis (GPP), the most grievous variant of psoriasis, is featured by dysregulated systemic inflammatory response. The cellular and molecular basis of GPP is poorly understood. Blood monocytes are key players of host defense and producers of inflammatory cytokines including IL-1β. How the immune response of monocytes is affected by metabolic internal environment in GPP remains unclear. Here, we performed a metabolomic and functional investigation of GPP serum and monocytes. We demonstrated a significant increase in IL-1β production from GPP monocytes. In GPP circulation, serum amyloid A (SAA), an acute-phase reactant, was dramatically increased, which induced the release of IL-1β from monocytes in a NLRP3-dependent manner. Using metabolomic analysis, we showed that GPP serum exhibited an amino acid starvation signature, with glycine, histidine, asparagine, methionine, threonine, lysine, valine, isoleucine, tryptophan, tyrosine, alanine, proline, taurine and cystathionine being markedly downregulated. In functional assay, under amino acid starvation condition, SAA-stimulated mature IL-1β secretion was suppressed. Mechanistically, at post-transcriptional level, amino acid starvation inhibited the SAA-mediated reactive oxygen species (ROS) formation and NLRP3 inflammasome activation. Moreover, the immune-modulatory effect of amino acid starvation was blocked by silencing general control nonderepressible 2 kinase (GCN2), suggesting the involvement of amino acid response (AAR) pathway. Collectively, our results suggested that decreased serum amino acids in GPP blunted the innate immune response in blood monocytes through AAR pathway, serving as a feedback mechanism preventing excessive inflammation in GPP.

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Granulocyte and monocyte/macrophage apheresis for the treatment of immune-mediated inflammatory arthropathies: case reports

Carro Martínez AV, Montolio Chiva L, Robustillo Villarino M. Drugs Context. 2021;10:2021-8-5.

Drug therapy of immune-mediated inflammatory arthropathies is not always satisfactory, and there is a risk of adverse events. Granulocyte and monocyte/macrophage apheresis (GMA) is a non-pharmacological therapeutic option that is beneficial and very well tolerated. GMA involves passing blood through a column with cellulose acetate beads to remove increased and activated myeloid lineage cells and improve the cytokine profile. The technique reduces pain and inflammation. We present four clinical reports that illustrate the clinical uses of GMA with the medical device Adacolumn® in patients with different backgrounds and immune-mediated inflammatory arthritis. The results were positive, and no adverse events were reported..

dic.2021-8-5.pdf (

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Cellular immune response triggered by granulocytoapheresis in ulcerative colitis patients under biological treatment


GMA induces specific immunoregulatory changes in leukocyte’s subpopulations. We confirm the depletion of the
monocytes with proinflammatory phenotype after GMA. Treg and B effector cells shift to a more immunotolerant phenotype. The emergence of subpopulations with the atypical immunofluorescence staining (CXCR3+CRTH2+) related to immature T cells support the immunomodulatory effects of GMA. These findings could help to understand the pathology of UC and to identify targeted immune subpopulations for treatment

P0246 UEG.pdf

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Selective granulocyte and monocyte apheresis in inflammatory bowel disease: Its past, present and future

Xiu-Li ChenJing-Wei Mao, and Ying-De Wang, World J Gastrointest Pathophysiol. 2020 May 12; 11(3): 43–56.

The etiology and pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, are not fully understood so far. Therefore, IBD still remains incurable despite the fact that significant progress has been achieved in recent years in its treatment with innovative medicine. About 20 years ago, selective granulocyte and monocyte apheresis (GMA) was invented in Japan and later approved by the Japanese health authority for IBD treatment. From then on this technique was extensively used for IBD patients in Japan and later in Europe. Clinical trials from Japan and European countries have verified the effectiveness and safety of GMA therapy in patients with IBD. In 2013, GMA therapy was approved by China State Food and Drug Administration for therapeutic use for the Chinese IBD patients. However, GMA therapy has not been extensively used in China, although a few clinical studies also showed that it was effective in clinical and endoscopic induction of remission in Chinese IBD patients with a high safety profile. This article reviews past history, present clinical application as well as the future prospective of GMA therapy for patients with IBD.

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P356 Safety and effectiveness of granulocyte and monocyte adsorptive apheresis in paediatric patients with inflammatory bowel disease: a multi-centre cohort study

N ToitaH TanakaK AraiH ShimizuD AbukawaT KobayashiN YoshimuraS TanidaE 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.

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P614 The utility as a biomarker of faecal calprotectin for predicting the clinical outcome of granulocyte and monocyte adsorptive apheresis treatment in patients with ulcerative colitis

N UenoY MurakamiT IwamaT SasakiT KunogiK TakahashiK TanakaK AndoS KashimaY InabaK MoriichiH TanabeM TaruishiM FujiyaT 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

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Granulocyte and monocyte adsorptive apheresis ameliorates sepsis in rats.

Shuai Ma 1Qingqing Xu 1Bo Deng 1Yin Zheng 2Hongyan Tian 1Li Wang 3Feng Ding 4 , Intensive Care Med Exp. 2017 Dec;5(1):18.

This study showed that selective granulocyte and monocyte adsorption with cellulose acetate beads might ameliorate cecal ligation and puncture (CLP)-induced sepsis and improve survival and organ function.

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Inhibition of Inflammatory Cytokines and Induction of Myeloid-Derived Suppressor Cells by the Effects of Granulocyte and Monocyte Adsorption Apheresis.

Masanao Sakanoue 1Yuko Higashi 1Takuro Kanekura 1 ,Ther Apher Dial. 2017 Dec;21(6):628-634.

The clinical effectiveness of GMA may be attributable to the inhibition of pro-inflammatory cytokines and the induction of anti-inflammatory MDSCs by iC3b activation via the CA beads in the GMA column.

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Effect of Temperature on Granulocyte and Monocyte Adsorption to Cellulose Acetate Beads.

Shoichi Nishise 1Yuji Takeda 2Yasuhiko Abe 1Yu Sasaki 1Hidetoshi Nara 2Hironobu Asao 2Yoshiyuki Ueno 1 , Ther Apher Dial. 2017 Jun;21(3):248-254.

These results suggest that warming the column during GMA might increase GM adsorption to CA beads, thereby enhancing the clinical efficacy of GMA.

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