Paola Contini 1, Simone Negrini 1, Giorgia Bodini 2, Cecilia Trucchi 3, Gianluca Ubezio 4, Paolo Strada 4, Vincenzo Savarino 2, Massimo Ghio 1, J Clin Apher. 2017 Feb;32(1):49-55.

 Taken together, these findings suggest that the immunosuppressive effects attributed to granulocyte and monocyte apheresis might depend, at least in part, on the sensitivity of activated leucocytes to the bioactivity of sHLA-I molecules.

https://pubmed.ncbi.nlm.nih.gov/27080173/

Shoichi Nishise ¹, Yuji Takeda ², Yasuhiko Abe ¹, Yu Sasaki ¹, Hidetoshi Nara ², Hironobu Asao ², Yoshiyuki 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.

https://pubmed.ncbi.nlm.nih.gov/28661094/

Esteban Sáez-González ¹, Inés Moret ^2 3 4, Diego Alvarez-Sotomayor ², Francia Carolina Díaz-Jaime ², Elena Cerrillo ^2 3, Marisa Iborra ^2 3 4, Pilar Nos ^2 3 4, Belén Beltrán ^2 3 4 , Dig Dis Sci. 2017 Jun;62(6):1417-1425.

The benefit of cytapheresis appears to rest upon its ability to reduce levels of certain immune cell populations; however, whether this depletion results in further changes in lymphocyte populations and cytokine production needs further clarification. In this review, we aim to summarize existing evidence on the role of cytapheresis in patients with IBD, its effect on cytokine levels and cellular populations, and to discuss its potential impact on disease activity.

https://pubmed.ncbi.nlm.nih.gov/28432476/

Tomotaka Tanaka and Abbi Saniabadi,

By the power of colonoscopy over a decade in patients with UC, we have learnt that all patients with the first UC episode and short duration of disease readily respond to GMA and can be spared from multiple drug therapy. Similarly, moststeroid naïve or dependent patients who have a fair level of intact mucosal tissue are potential responders to GMA. Additionally, it is important to bear in mind that patients who respond to GMA and avoid pharmacologics from the initial stages of their UC continue to respond well and attain a favourable future clinical course. Patients with extensive loss of the mucosal tissue together with
a long history of exposure to multiple pharmacologics are unlikely to respond to GMA. Further,GMA with the Adacolumn is very much favoured by patients for its safety profile. Serious side effects are very rare. This is in sharp contrast to multiple severe side effects associated with most conventional pharmacologics and new biologics. Our view is that in patients with UC, there is an evolving scope for therapeutic opportunity based on taking away the sources of inflammatorycytokines. However, selective depletion of activated and elevated myeloid lineage leucocytes to achieve IBD remission by applying GMA represents an intrigue, but this is yet to be achieved in all treated patients.

RII-15-01.pdf (smjournals.com)

Chiharu Tominaga ¹, Masaaki Yamamoto ¹, Yasutomo Imai ¹, Kiyofumi Yamanishi ¹ , Case Rep Dermatol. 2015 Feb 21;7(1):29-35.

 She is the oldest reported case of GPP with a deficiency of interleukin-36 receptor antagonist (DITRA), although GPP in DITRA has been suggested to usually occur in younger cases with no pre-existing psoriasis vulgaris.

https://pubmed.ncbi.nlm.nih.gov/25848350/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357681/pdf/cde-0007-0029.pdf

Keiichi Hashiguchi ¹, Fuminao Takeshima, Yuko Akazawa, Kayoko Matsushima, Hitomi Minami, Haruhisa Machida, Naoyuki Yamaguchi, Ken Shiozawa, Kazuo Ohba, Ken Ohnita, Tatsuki Ichikawa, Hajime Isomoto, Kazuhiko Nakao, Digestion. 2015;91(3):208-17.

Background: Fecal lactoferrin has been introduced as a useful tool for the diagnosis and monitoring of inflammatory bowel disease (IBD). The aim of this study was to assess if fecal lactoferrin can be employed to predict or estimate the effect of granulocyte and monocyte adsorptive apheresis (GMA) in ulcerative colitis (UC). Methods: This was a prospective study involving 21 patients with UC. Patients with moderately-to-severely active UC who were scheduled to undergo GMA were recruited. Changes in fecal lactoferrin concentration were compared between the GMA-responder and -nonresponder groups. Results: In the GMA-responder group, fecal lactoferrin significantly increased 1 week after the introduction of GMA and then significantly decreased after GMA sessions. Fecal lactoferrin concentrations were significantly higher in the GMA-responder group than in the GMA-nonresponder group at 1 and 2 weeks after the introduction of GMA. Multivariate logistic regression analysis revealed that fecal lactoferrin concentration 1 week after the introduction of GMA was the most contributing factor for the effectiveness of GMA in patients with UC. Conclusions: In the GMA-responder group, fecal lactoferrin concentration significantly increased 1 week after the introduction of GMA. Fecal lactoferrin may be beneficial for predicting clinical response of GMA in patients with UC at an early stage of GMA treatment.

https://pubmed.ncbi.nlm.nih.gov/25823500/

Koji Kamiya ¹, Yumi Aoyama ², Mariko Kawata ², Tetsuya Takiguchi ³, Seiko Mitsui ², Yoshiki Tokura ⁴, Keiji Iwatsuki ² , Eur J Dermatol. 2015 Apr;25(2):189-90.

https://pubmed.ncbi.nlm.nih.gov/26075324/

Massimo Ghio, Giorgia Bodini, Paola Contini, Vincenzo Savarino, Edoardo Savarino Gastroenterology, 2015 148(4), S-698–. doi:10.1016/S0016-5085(15)32367-2 

Background Plasmapheresis is used in immune-mediate disease in order to remove humoral factors and, in addition, to modulate cellular immunity. It has been shown that during aphaeretic centrifugation , whole and/or re-folded soluble HLA class I molecules (sHLAI) bind to the circuit surfaces. Similarly, neutrophils can bind sHLA-I molecules with immunoglobulin-like transcript (ILT) membrane receptors, becoming hereafter sensitive to
the immunomodulation of sHLA-I such as transcriptional and post-transcriptional transforming growth factor (TGF)-β1 modulation. On the other hand, TGFβ signaling plays a major role in the pathogenesis of inflammatory bowel diseases and it is known to directly induce Foxp3 expression. Besides, Foxp3 expression has been reported increased in patients who responded to granulocytes apheresis with remission of clinical symptoms. Aim The aim of this prospective study was to evaluate a possible sHLA-I mediated immunomodulation in granulocytes and monocytes apheresis in ulcerative colitis patients who responded to therapy. Methods We prospectively enrolled a total of 10 patients (4M/6F; mean age 49, range 27-73) who achieved clinical remission with GMA. The GMA sessions (5 cycle/session) were performed using Adacolumn device. Instantly before each single apheresis and immediately after each procedure, neutrophils were analyzed for a possible in vivo aftermath of sHLA-I binding with corresponding ligands Ig-like-transcripts. The concentrations of sFasL molecules were determined by double-determinant immunoassay (DDIA) and the concentrations of TGFb1 were determined by double-determinant immunoassays utilizing a commercially available kits. Results Between every GMA cycle a significant upregulation of intracytoplasmic TGFβ1 molecule or TGFβ1-mRNA was observed in neutrophils and CD8+ T lymphocytes drawn along the apheretic therapeutic treatments. In particular, the greatest mean increase was found after the first and the forth GMA cycles (from +1% to +30%). A significant up-regulation of sFasL and TGFβ1 concentrations in plasma was observed along the procedures. Similarly, the mean difference increases in comparison with previous samples were constantly found raising during scheduled blood sampling for both molecules. In CD4+ T lymphocytes, unable to bind sHLA-I, the aphaeretic procedures never induced TGFβ1 modulation Conclusion: Our findings suggest that the immunosuppressive effects following therapeutic apheresis might at least in part depend on activated leukocyte sensitivity to sHLA-I molecule bioactivity.

https://www.gastrojournal.org/article/S0016-5085(15)32367-2/pdf

Chiara De Cassan ¹, Edoardo Savarino ¹, Piero Marson ¹, Tiziana Tison ¹, Giorgia Hatem ¹, Giacomo Carlo Sturniolo ¹, Renata D’Incà ¹ , World J Gastroenterol. 2014 Dec 7;20(45):17155-62.

Patients with mild UC benefit from GMA more than patients with moderate to severe disease in the short-term period. GMA should be considered a valid therapeutic option in cases of contraindications to immunosuppressants, corticosteroids and/or biologics.

https://pubmed.ncbi.nlm.nih.gov/25493030/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258586/pdf/WJG-20-17155.pdf

Masanao Sakanoue ¹, Koichiro Takeda, Kazuhiro Kawai, Takuro Kanekura, Ther Apher Dial. 2013 Oct;17(5):477-83.

Granulocyte and monocyte adsorption apheresis (GMA), an extracorporeal apheresis instrument whose column contains cellulose acetate (CA) beads, is designed to remove activated granulocytes and monocytes. We previously demonstrated that GMA was useful for treating neutrophilic dermatoses and associated arthropathy as it adsorbs Mac-1 (CD11b/CD18)-expressing neutrophils to the CA beads by the binding of complement component (iC3b) and CD11b expressed on activated neutrophils. The objective of this study is to further assess the clinical effectiveness of GMA in the treatment of neutrophilic dermatoses and associated arthropathy. The effect of GMA for skin lesions and joint lesions was assessed in 44 and 23 patients, respectively. Mac-1 expression on peripheral neutrophils was measured by flow cytometry. Skin lesions and arthropathy improved in 39 of 44 patients (88.6%) and 22 of 23 (95.6%), respectively. Mac-1 (CD11b/CD18) expression on the peripheral neutrophils, 27.1 ± 6.66 MFI (mean fluorescence intensity) before treatment, was reduced to 17.9 ± 3.02 MFI by GMA (P < 0.05). Clinical effectiveness of GMA for the treatment of intractable neutrophilic dermatoses and associated arthropathy was further confirmed.

https://pubmed.ncbi.nlm.nih.gov/24107275/