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.

Teagan S Edwards ¹, Andrew S Day ¹

Expert Rev Mol Diagn.. 2024 Jun;24(6):497-508. doi: 10.1080/14737159.2024.2375224. Epub 2024 Jul 12.

Introduction: Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and Ulcerative Colitis (UC), is a relapsing and remitting condition. Noninvasive biomarkers have an increasingly important role in the diagnosis of IBD and in the prediction of future disease course in individuals with IBD. Strategies for the management of IBD increasingly rely upon close monitoring of gastrointestinal inflammation.

Areas covered: This review provides an update on the current understanding of established and novel stool-based biomarkers in the diagnosis and management of IBD. It also highlights key gaps, identifies limitations, and advantages of current markers, and examines aspects that require further study and analysis.

Expert opinion: Current noninvasive inflammatory markers play an important role in the diagnosis and management of IBD; however, limitations exist. Future work is required to further characterize and validate current and novel markers of inflammation. In addition, it is essential to better understand the roles and characteristics of noninvasive markers to enable the appropriate selection to accurately determine the condition of the intestinal mucosa.

• Noninvasive inflammatory markers play an important role in diagnosis and management of IBD.
• Fecal inflammatory markers can reflect gut inflammation in IBD; however, they are not specific and various limitations must be considered.
• Although FCal is the most well-established and routinely used marker in IBD, it may have reduced sensitivity and specificity in some settings.
• Several emerging biomarkers including MPO have been assessed and show promise.
• Identification of effective and accurate noninvasive markers of inflammation may limit the need for repeat invasive endoscopic examinations in the future.

Takuya Takeichi ¹, Takenori Yoshikawa ¹, Muhammad Nasir Iqbal ², Muhammad Farooq ³, Tomoki Taki ¹, Yoshinao Muro ¹, Yutaka Shimomura ⁴, Mariko Seishima ⁵, Masashi Akiyama ¹ Exp Dermatol. 2023 Sep;32(9):1557-1562. doi: 10.1111/exd.14846.

Pathogenic variants in MPO, which encodes the myeloperoxidase, were reported as causative genetic defects in several cases of generalised pustular psoriasis (GPP) in addition to patients with myeloperoxidase deficiency in 2020. However, which clinical subtypes of GPP patients have pathogenic variants in MPO remains largely undetermined, and elucidating this is clinically important. The present report outlines a mild case of GPP with a rare missense heterozygous variant, c.1810C>T p.(Arg604Cys), in MPO. Our structural analysis and functional assays to measure myeloperoxidase activity suggest that the present MPO substitution is a hypomorphic variant in MPO. Thus, the mild phenotype of the present GPP patient might be associated with an incomplete hypomorphic loss-of-function variant in MPO. Additionally, the severe intractable edematous pustules and erythema improved dramatically after five rounds of granulocyte and monocyte adsorption apheresis (GMA) therapy. This is the first report of GMA treatment for GPP associated with a pathogenic variant in MPO, as far as we know. Our findings suggest that GMA might be a useful and powerful tool for controlling GPP in patients with myeloperoxidase deficiency.

Mild generalised pustular psoriasis patient with a heterozygous hypomorphic MPO variant successfully treated with granulocyte and monocyte adsorption apheresis – PubMed (nih.gov)

Mild generalised pustular psoriasis patient with a heterozygous hypomorphic MPO variant successfully treated with granulocyte and monocyte adsorption apheresis – Takeichi – 2023 – Experimental Dermatology – Wiley Online Library

Nobuhito Kashiwagi , Fumio Saito , Hidetaka Maegawa , Kenta Kaneda, Cytokine 2021 Mar;139:155410.

Objective: Apoptotic cells participate in maintenance of homeostasis of the adaptive immune system. Granulocyte/monocyte adsorptive apheresis (GMA) performed with an Adacolumn has been shown to have clinical efficacy together with immunomodulatory effects for immune-mediated disorder cases, such as inflammatory bowel disease (IBD) or psoriatic arthritis. Although induction of apoptosis in neutrophils by GMA has been observed, the detailed mechanism remains unclear. Methods: To focus on phagocytosis-induced cell death (PICD) that induces apoptotic neutrophils, a comparative study utilizing a GMA-carrier (leukocyte adsorbing carrier for Adacolumn) and yeast particles was performed with in vitro and in vivo examinations. Results: L-selectin was significantly (P = 0.0133) shed, reactive oxygen species (ROS) production was promoted (P = 0.0019), and apoptosis induction was enhanced (P = 0.0087) by peripheral blood co-cultured with the GMA-carrier or yeast particles as compared to incubated blood alone. Furthermore, degranulation of myeloperoxidase, elastase, and lactoferrin was increased by both treatments, while the highest level of interleukin-1 receptor antagonist release was found with GMA-carrier treatment (P = 0.0087) as compared to the yeast particles. Plasma from blood treated with the GMA-carrier showed chemotactic activity, and suppressed neutrophil migration to IL-8 and LTB₄. In vivo results demonstrated that neutrophil chemotaxis to IL-8 was desensitized (P = 0.0078) in rabbits following GMA apheresis, while CXCR1 and CXCR2 expressions in neutrophils were reduced by exposing peripheral blood to the GMA-carrier. Conclusions: GMA may regulate the immune system in patients with an immune-mediated disorder by inducing a biological response of neutrophils with a PICD-like reaction.

https://pubmed.ncbi.nlm.nih.gov/33395614/

Yuji Naito ¹, Tomohisa Takagi, Toshikazu Yoshikawa

J Gastroenterol  2007 Oct;42(10):787-98. doi: 10.1007/s00535-007-2096-y. Epub 2007 Oct 15.

Neutrophil accumulation within epithelial crypts and in the intestinal mucosa directly correlates with clinical disease activity and epithelial injury in inflammatory bowel disease (IBD). Current advances have defined the mechanisms by which neutrophils are activated or migrate across endothelial and mucosal epithelial cells. A better understanding of this process will likely provide new insights into novel treatment strategies for IBD. Especially, activated neutrophils produce reactive oxygen and nitrogen species and myeloperoxidase within intestinal mucosa, which induce oxidative stress. Posttranslational modification of proteins generated by these reactive species serves as a “molecular fingerprint” of protein modification by lipid peroxidation-, nitric oxide-, and myeloperoxidase-derived oxidants. Measurement of these modified proteins may serve both as a quantitative index of oxidative stress and an important new biological marker of clinical relevance to IBD. We have succeeded in the clinical development of a novel granulocyte adsorptive apheresis therapy for IBD. In this review, we discuss current advances in defining the role of neutrophil-dependent oxidative stress in IBD.

https://pubmed.ncbi.nlm.nih.gov/17940831/