Masashi Akiyama ¹

J Dermatol. 2025 Mar;52(3):400-407. doi: 10.1111/1346-8138.17585. Epub 2024 Dec 19.

Generalized pustular psoriasis (GPP) is a severe autoinflammatory keratinization disease (AiKD) characterized by acute flares of widespread sterile pustules and high fever. GPP is potentially life-threatening. Recently clarified genetic predisposing factors for GPP suggest that the excessive activation of innate immune pathways in the skin, including of interleukin (IL)-1 and IL-36 signaling, plays a significant role in the GPP pathogenesis. IL36RN, CARD14, AP1S3, MPO, SERPINA3, BTN3A3, and MEFV have been identified as GPP-related genes. The pathogenesis of GPP provoked by variants in these seven genes is tightly associated with the excessive activation of innate immune pathways and the resulting autoinflammation in the skin. Various biologics, including inhibitors for the tumor necrosis factor, IL-17, and IL-23 pathways, are used as treatments for GPP. The new understanding of the genetic background of GPP, mentioned above, indicates that the genetic predisposing factors are predominantly related to the excessive activation of innate immunity and autoinflammation. In this context, inhibitors of inflammatory signaling, including of the IL-1 and IL-36 pathways, have been used in clinical practice and investigated as potential future therapies.

Ryo Hisamune ¹, Kazuma Yamakawa ¹, Katsuhide Kayano ¹, Noritaka Ushio ¹, Takeshi Wada ², Kohei Taniguchi ³, Akira Takasu ¹ Acute Med Surg. . 2024 Aug 29;11(1):e70003. doi: 10.1002/ams2.70003. eCollection 2024 Jan-Dec.

Aims: SARS-CoV-2 causes systemic immune dysfunction, leading to severe respiratory dysfunction and multiorgan dysfunction. Granulocyte and monocyte adsorptive apheresis (GMA) therapy is designed to regulate an excessive inflammatory response and has been proposed as a potential therapeutic strategy for coronavirus disease 2019 (COVID-19). We aimed to investigate a targeted subset of granulocytes and monocytes to be removed after GMA therapy in patients with severe COVID-19 infection.

Methods: We established an ex vivo experimental system to study the effects of GMA. Blood samples were collected into EDTA-treated tubes and a mixture of blood samples and cellulose acetate beads was used in GMA. After GMA, blood samples were removed, and the granulocyte and monocyte subtypes before and after GMA were determined by CyTOF mass cytometry. To analyze mass cytometry data with a self-organizing map, hierarchical clustering was used to determine the appropriate number of metaclusters from t-distributed stochastic neighbor embedding.

Results: We included seven patients with severe COVID-19 and four age- and sex-matched volunteers. Granulocyte subsets removed by GMA strongly expressed CD11b, CD16, and CD66b, and weakly expressed CD11c, consistent with mature and activated neutrophils. Monocyte subsets strongly expressed CD14, weakly expressed CD33 and CD45RO, and did not express CD16. These subsets were indicated to promote the release of inflammatory cytokines and activate T cells.

Conclusions: The identification of the granulocyte and monocyte subsets removed after GMA in patients with severe COVID-19 may help explain the potential mechanism underlying the effectiveness of GMA in COVID-19 and other inflammatory diseases.

A Yoshifuku ¹, K Oyama, A Ibusuki, M Kawasaki, M Sakanoue, S Matsushita, K Kawai, K Kawahara, I Maruyama, T Kanekura

Clin Exp Dermatol 2012 Apr;37(3):241-4. doi: 10.1111/j.1365-2230.2011.04181.x. Epub 2011 Oct 18.

Reiter disease (RD) is characterized by a triad of sterile arthritis, urethritis and conjunctivitis. The conditions occur concomitantly or sequentially, and are associated with mucocutaneous features such as circinate balanitis and stomatitis. Arthritis usually occurs in attacks followed by recovery, but it sometimes progresses to permanent damage of the affected joints. Because the symptoms of this disorder are attributable to activated neutrophils, we assessed the efficacy of granulocyte and monocyte adsorption apheresis (GCAP) in a 73-year-old man with RD who had skin rashes on his penis, scrotum and right hand, with severe arthralgia. The patient’s skin rash and joint pain responded dramatically to five sessions of GCAP delivered at intervals of 5 days. We present a detailed description of the patient and discuss the mechanisms of GCAP, and suggest that GCAP may be useful for treating RD.

https://pubmed.ncbi.nlm.nih.gov/22007878/

Tomomi Fujisawa ¹, Kana Murase, Yoko Okumura, Hiroyuki Kanoh, Tomoaki Doi, Shouzo Yoshida, Shinji Ogura, Mariko Seishima

Ther Apher Dial 2011 Aug;15(4):374-8. doi: 10.1111/j.1744-9987.2011.00961.x. Epub 2011 Jun 7.

Generalized pustular psoriasis (GPP) is one of the neutrophilic dermatoses mainly caused by activated neutrophils and monocytes. Granulocyte and monocyte adsorption apheresis (GCAP) is a useful extracorporeal circulation therapy for removal of activated granulocytes and monocytes. In this study, GCAP was used to treat three patients with different types of GPP; the diagnoses indicated patient 1 had GPP, patient 2 had GPP developed from psoriasis vulgaris and patient 3 had GPP based on psoriatic erythroderma. We performed GCAP on each of these patients once a week, for a total of five times. We found that the patients’ pustules and edema disappeared and their erythema was reduced by GCAP therapy. Moreover, no adverse effects were observed. Thus, we conclude GCAP could be effective for treating various types of GPP.

https://pubmed.ncbi.nlm.nih.gov/21884472/

Toshimi Chibaa, Mikiya Endob, Shoko Matsushitab, Mika Sasakib, Shoichi Chidab, Yosuke Toyaa, Satoshi Kasugaia, Nozomi atsudaa, Shunsuke Orikasaa, Yukito Abikoa, Norihiko Kudaraa, Shuhei Oanaa, Masaki Endoa, Kazuyuki Suzukia© 2011 S. Karger AG, BaselISSN 1662–0631

Granulocyte and monocyte adsorptive apheresis (GMA) is reportedly useful as induction therapy for Crohn’s disease (CD). However, the effects of GMA on CD64 have not been well characterized. We report here our assessment of CD64 expression on neutrophils before and after treatment with GMA in two patients with CD. The severity of CD was assessed with the CD activity index (CDAI). The duration of each GMA session was 60 min at a flow rate of 30 ml/min as per protocol. CD64 expression on neutrophils was measured by analyzing whole blood with a FACScan flow cytometer. In case 1, CD64 levels after each session of GMA tended to decrease compared to pretreatment levels, whereas in case 2, CD64 levels dropped significantly after treatment. The CDAI decreased after GMA in both cases 1 and 2. A significant correlation was noted between CDAI scores and CD64 levels in both cases. In conclusion, GMA reduced blood CD64 levels, which would be an important factor for the decrease of CDAI scores.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250654/pdf/crg0005-0667.pdf

Takuro Kanekura ¹, Noriko Yoshii, Koichi Kawahara, Ikuro Maruyama, Tamotsu Kanzaki

Ther Apher Dial 2006 Jun;10(3):287-90. doi: 10.1111/j.1744-9987.2006.00335.x.

Cutaneous allergic vasculitis (CAV) is characterized clinically by purpuric patches with secondary ulcerations, and histologically by leukocytoclastic vasculitis with neutrophil infiltrates. Granulocyte and monocyte adsorption apheresis (GCAP) is an extracorporeal apheresis instrument using a column containing cellulose acetate beads designed to remove pathogenic granulocytes. Here we report our assessment of the efficacy of GCAP for recurrent leg ulcers in a 49-year-old woman with CAV. She underwent five GCAP treatments at one-week intervals. In each treatment session, 1800 mL of blood was processed. Her leg ulcers responded well and her white blood cell and neutrophil counts and the expression level of CD11b/CD18, a marker for activated neutrophils, on her peripheral neutrophils were reduced from 7500/microL to 6500/microL, 4350/microL to 3315/microL, and 64.9 MFI (mean fluorescence intensity) to 27.0 MFI (normal controls: 10.5 +/- 1.2 MFI) by GCAP, respectively. These results suggest that GCAP is useful for skin disorders with leucocytoclastic vasculitis.

https://pubmed.ncbi.nlm.nih.gov/16817796/

Takuro Kanekura ¹, Hisashi Kawabata, Ikuro Maruyama, Tamotsu Kanzaki

J Am Acad Dermatol  2004 Feb;50(2):242-6. doi: 10.1016/s0190-9622(03)02474-5.

Granulocyte and monocyte adsorption apheresis (GCAP) is a new extracorporeal apheresis treatment modality that removes pathogenic granulocytes. Recently, we found that GCAP is useful for treating pyoderma gangrenosum and pustular psoriasis. We thought that this treatment may also be effective for treating other disorders attributable to activated granulocytes and studied the efficacy of GCAP in 4 patients with psoriatic arthritis. Treatment with GCAP resulted in remarkable clearing of joint pain, suggesting that GCAP is valuable for treating arthritis as well as skin disorders. We present a detailed description of these patients and this novel therapy.

https://pubmed.ncbi.nlm.nih.gov/14726879/