Biju Vasudevan ¹, Pankaj Das ¹, Siddharth Bhatt ¹ Indian J Dermatol Venereol Leprol. 2023 May 28:1-11.

Pustular psoriasis is a distinct subset of psoriasis that presents with involvement of the skin in the form of sterile pustules along with systemic manifestations. Though it has been conventionally grouped under the umbrella of psoriasis, recent research has shed light on its pathogenetic mechanisms associated with the IL-36 pathway, which is distinct from conventional psoriasis. Pustular psoriasis in itself is a heterogeneous entity consisting of various subtypes, including generalized, localized, acute, and chronic forms. There is confusion regarding its current classification as entities like deficiency of IL-36 antagonist (DITRA) which are closely related to pustular psoriasis both in their pathogenetic mechanism and its clinical manifestations, are not included under pustular psoriasis. Entities like palmoplantar pustulosis, which presents with similar clinical features but is pathogenetically distinct from other forms of pustular psoriasis, are included under this condition. Management of pustular psoriasis depends upon its severity; while some of the localized variants can be managed with topical therapy alone, the generalized variants like Von Zumbusch disease and impetigo herpetiformis may need intensive care unit admission and tailor-made treatment protocols. The advent of newer biologics and better insight into the pathogenesis of pustular psoriasis has opened the way for newer therapies, including tumor necrosis factor-alpha inhibitors, interleukin-1 inhibitors, interleukin-17 inhibitors, and granulocyte monocyte apheresis. It continues to be an enigma whether pustular psoriasis is actually a variant of psoriasis or an entirely different disease entity, though we feel that it is an entirely different disease process.

Pustular psoriasis: A distinct aetiopathogenic and clinical entity – PubMed (nih.gov)

Pustular psoriasis: A distinct aetiopathogenic and clinical entity – Indian Journal of Dermatology, Venereology and Leprology (ijdvl.com)

Keiki Shimada, Daisuke Katagiri, Aika Kato, Naoto Nunose, Motohiko Sato, Yuri Katayama, Kanako Terakawa, Takahito Niikura, Emi Sakamoto, Yuki Yoshizaki, Minami Suzuki, Takashi Fukaya, Takeshi Tamaki & Hideki Takano Ren Replace Ther 8, 50 (2022). https://doi.org/10.1186/s41100-022-00439-y

Background Generalized pustular psoriasis (GPP) usually presents with fever, generalized flushing, and multiple sterile pustules on the skin, which histopathologically form subcorneal pustules characterized by Kogoj spongiform pustules. Granulocyte/monocyte adsorption apheresis (GMA) was approved in Japan in 2012. The use of biologics for psoriasis treatment is increasing. Several case reports have evaluated the combination of GMA and cyclosporine (CyA) for GPP. However, very few English reports on combining biologics and GMA in treating GPP exist. Case presentation A 79-year-old man with a history of hypertension, diabetes mellitus, chronic kidney disease, and atrial fibrillation was admitted. He had been consulting a dermatologist for psoriasis vulgaris (PV) since the age of 44. The patient was diagnosed with severe GPP and treated with 300 mg secukinumab (SEC) on day 3. SEC is a fully human monoclonal IgG1 antibody that targets IL-17A. Five doses were administered. In addition, GMA was administered once a week, three times from day 4. After the first administration of GMA, the inflammatory response and skin condition improved markedly. The patient was discharged from the hospital on day 34. Conclusions The present study is the first English-written report on the combined administration of SEC and GMA both instituted since admission for severe GPP, with immediate patient response to treatment. Notably, IL-17A plays a vital role in the pathogenesis of GPP. GMA can eliminate activated leukocytes, and the early introduction of combined IL-17 monoclonal antibody and GMA may allow disease suppression in patients with severe GPP, thus avoiding progression to multiorgan failure. Further studies may verify the effects of IL-17 monoclonal antibodies and GMA on severe GPP.

https://rrtjournal.biomedcentral.com/articles/10.1186/s41100-022-00439-y#citeas

Laura Gnesotto ¹, Guido Mioso ¹, Mauro Alaibac ¹

Exp Ther Med 2022 Jun 24;24(2):536. doi: 10.3892/etm.2022.11463. eCollection 2022 Aug. DOI: 10.3892/etm.2022.11463

Adsorptive granulocyte and monocyte apheresis (GMA) is an extracorporeal treatment that selectively removes activated myeloid lineage leukocytes from peripheral blood. This technique consists of a column with cellulose acetate beads as absorptive leukocytapheresis carriers, and was initially used to treat ulcerative colitis. A literature search was conducted to extract recently published studies about the clinical efficacy of GMA in patients with different skin disorders, reporting information on demographics, clinical symptoms, treatment and clinical course. Dermatological diseases, in which GMA has been performed, include generalized pustular psoriasis, pyoderma gangrenosum, palmoplantar pustular psoriasis, Behcet’s disease, Sweet’s syndrome, adult-onset Still’s disease, impetigo herpetiformis, reactive arthritis, acne and hidradenitis suppurativa syndrome, cutaneous allergic vasculitis and systemic lupus erythematosus. In most patients, GMA was started after the failure of conventional therapeutic options and it was helpful in the majority of cases. Based on the information summarized, GMA could be considered a valid non-pharmacological treatment option for patients with several dermatological conditions, which are difficult to treat with other pharmacological preparations.

 PASH syndrome; cutaneous allergic vasculitis; granulocyte and monocyte apheresis; neutrophilic dermatoses; reactive arthritis; systemic lupus erythematosus.

https://pubmed.ncbi.nlm.nih.gov/35837066/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257973/

Mariko Seishima ^1 2, Kento Fujii ³, Yoko Mizutani ³ Am J Clin Dermatol 2022 Jun 15. doi: 10.1007/s40257-022-00698-9.

Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disease characterized by sudden widespread eruption of sterile pustules with or without systemic symptoms. GPP may be life threatening in cases with severe complications such as cardiovascular failure, acute respiratory distress syndrome, and serious infections. Impetigo herpetiformis (IH) is a GPP that is induced and exacerbated by pregnancy and occurs most frequently during the last trimester. IH may result in poor or fatal neonatal outcomes, including placental insufficiency, fetal abnormalities, stillbirth, and early neonatal death. Most patients have prompt remission in the postpartum period; however, earlier appearance and more severe symptoms are observed during subsequent pregnancies. Appropriate treatment and close monitoring of the mother and fetus are vital for the management of patients with IH. Particular attention is required for the management of patients with IH to avoid an influence on the fetus. However, data regarding treatments for GPP in pregnant women are sparse. Over the last decade, many patients with IH have been treated with cyclosporine, corticosteroids, tumor necrosis factor-α inhibitors, interleukin (IL)-17 and IL-12/23 inhibitors, and granulocyte and monocyte adsorption apheresis (GMA). GMA may be an important option for patients with IH as it is presently one of the safest available therapeutic options, but there have been no reports to fully confirm its safety in pregnant patients with GPP. Alternatively, based on recent advances in the understanding of the role of the IL-36 axis in the pathogenesis of GPP, biologic agents that target the IL-36 pathway may demonstrate promising efficacy in IH.

Generalized Pustular Psoriasis in Pregnancy: Current and Future Treatments – PubMed (nih.gov)

Masashi Akiyama 

J Dermatol Sci 2022 Jan;105(1):11-17. doi: 10.1016/j.jdermsci.2021.11.009. 

Pustular psoriasis is a chronic inflammatory skin disease characterized by erythematous plaques with sterile pustules. It includes the distinct clinical entities generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau (ACH) and palmoplantar pustular psoriasis (PPPP). Recently clarified pathomechanisms of pustular psoriasis indicate that hyperactivation of the skin innate immunity, including of the IL-1/IL-36 axis, plays an important role in the pathogenesis of pustular psoriasis. Autoinflammatory keratinization disease (AiKD) is the umbrella clinical entity for inflammatory keratinization disorders with genetic autoinflammatory pathomechanisms, and pustular psoriasis is a representative AiKD. To date, mutations/variants in five genes-IL36RN, CARD14, AP1S3, MPO and SERPINA3-have been reported to be genetic causative or predisposing factors for pustular psoriasis. The pathogenic mechanisms induced by the mutations/variants in these genes are all closely related to the excessive activation of skin innate immunity and autoinflammation. A number of biologics (e.g., tumor necrosis factor inhibitors, IL-17/IL-17 receptor inhibitors and IL-23 inhibitors) and granulocyte and monocyte adsorption apheresis are used to treat pustular psoriasis. Recently, based on novel information on the pathomechanisms of pustular psoriasis, which are mainly associated with autoinflammation, inhibitors of several pathogenic pathways, including of the IL-1, IL-36, IL-8 and granulocyte colony-stimulating factor signaling pathways, have been studied as emerging treatments.

Pustular psoriasis as an autoinflammatory keratinization disease (AiKD): Genetic predisposing factors and promising therapeutic targets – PubMed (nih.gov)

Pustular psoriasis as an autoinflammatory keratinization disease (AiKD): Genetic predisposing factors and promising therapeutic targets – Journal of Dermatological Science (jdsjournal.com)

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

https://pubmed.ncbi.nlm.nih.gov/34567002/

Asumi Fujii, Yuki Hattori, Miho Kawamura, Yoko Mizutani, En Shu, Mariko Seishima

poster at ISFA 2019 pag 141-142

A 31-year-old woman with the IL36RN gene mutation developed psoriasis at 3 years old. As she had pustular psoriasis at 16 years old, she was treated with cyclosporine (Cys), resulting in remission at 20 years old. Afterwards, she had been maintained by topical treatment for long years.During the first pregnancy at the age of 29, she developed pustular psoriasis at 29 weeks
of gestation. She received one course of granulocyte / monocyte adsorption apheresis (GMA) with Cys and prednisolone (PSL), and gave birth to a girl at 33 weeks of gestation. The baby was a low birth weight child, but is healthy and has no problems in growth and development until now. However, the patient did not sufficiently improve symptoms after delivery. We thus started the treatment with infliximab (IFX) BS at 2 months postpartum. During the second pregnancy at the age of 30, we continued the IFX-BS administration. She had erythema and pustules rapidly enlarged from 23 weeks of pregnancy. Oral administration of PSL and GMA were started. However, we switched the therapy to intensive GMA (twice in a week), because the effect was insufficient. Initially, administration of IFX-BS was scheduled to end at 30 weeks of gestation, but due to unstable symptoms, we considered it was necessary to use another biologics even after 30 weeks of gestation. We switched to non-placental certolizumab pegol (CTZ) from 26 weeks of gestation and continued the administration until delivery, and she gave birth to a girl at 35 weeks of gestation. Although the baby was a low birth weight child, there was no physical abnormality and the baby was discharged after gaining weight. After delivery, administration of CTZ was discontinued and the PSL dose was gradually reduced. However,reintroduction of biologics is under consideration, because erythema and pustules still remain.

http://www.atalacia.com/isfa/data/abstract.pdf

Yuko Higashi, Munekazu Yamakuchi, Takuro Kanekura

poster at ISFA 2019 pag 126

Neutrophilic skin diseases are a group of disorders characterized by intense dermal infiltration of neutrophils without infection. They include a variety of diseases, such as pyoderma gangrenosum, pustular psoriasis, and palmoplantar pustulosis. We demonstrated that granulocyte and monocyte adsorption apheresis (GMA) is a useful treatment modality for such refractory skin diseases. Microarray analysis of microRNAs (miRNAs) was performed using sera of patients with neutrophilic skin diseases before and after GMA. Several miRNAs significantly increased in patients compared to control subjects. The expression of three
miRNAs decreased after apheresis, suggesting that these miRNAs might be involved in the pathogenesis of neutrophilic skin decreases. To prove the function of these miRNAs, HL-60, a human acute promyelocytic leukemia cell line, was differentiated by the treatment of alltrans retinoic acid (ATRA). When HL-60 was differentiated to neutrophilic cells, the HEstaining shows an increased cytoplasm to nucleus ratio, condensated chromatin, and nuclear segmentation. The expression of three miRNAs increased during the neutrophilic differentiation. Stimulation of ATRA-treated HL-60 by some cytokines altered miRNA expressions. Moreover, manipulation of these miRNAs changed proliferation of cultured keratinocytes. These data
suggest that miRNAs play an important role in regulating neutrophilic differentiation and proliferation of keratinocytes in case of neutrophilic disorders such as psoriasis. These miRNAs could be markers of disease severity and response of GMA.

http://www.atalacia.com/isfa/data/abstract.pdf

Miho Hatanaka, Yuko Higashi, Takuro Kanekura

poster at ISFA 2019 pag 104

Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and
systemic flushing accompanied by extensive sterile pustules. Treatments of GPP are usually
topical corticosteroids, activated vitamin D3 ointment, ultraviolet light (UV) therapy, and
oral administration of etretinate, cyclosporine, or methotrexate. Recently, biologics such as
TNF- α; inhibitors, anti-IL-17- and anti-IL-23 antibodies are used. Pustulosis palmoplantaris
(PPP) is a chronic recurrent disorder of the palms and soles characterized by sterile intradermal
pustules. PPP often accompanies joint symptoms. In some instances, PPP is associated with
a focus of infection somewhere in the body; elimination of the infection sometimes improve
symptom. Some treatments of GPP are used for PPP. Psoriatic arthritis (PsA) is a disease
characterized by skin and nail psoriasis together with widespread musculoskeletal inflammation
such as peripheral joint disease, axial joint disease, enthesitis, and dactylitis. Treatment of
PsA is oral administration of NSAID’s, cyclosporine, methotrexate and phosphodiesterase 4
inhibitors for mild to moderate cases. Biologics; TNF- αinhibitors, anti-IL-17- and anti-IL-23
antibodies; have been approved for severe or advanced cases. Granulocyte/monocyte adsorption
apheresis (GMA) is an extracorporeal therapy designed to remove and suppress the functions
of neutrophils, macrophages and monocytes that accumulate in the inflamed tissue and are
involved in the pahogenesis. GMA may be considered as a safe treatment modality with few
side-effects for GPP, PPP and PsA. The effect and safety of GMA have been reported mostly in
case reports. Although the effect and safety of GMA were demonstrated in a multicenter study.
GMA’s utility is expected based on the mechanism of action.

http://www.atalacia.com/isfa/data/abstract.pdf

Mariko Seishima

poster at ISFA 2019 pag 57

Generalized pustular psoriasis (GPP) is a rare inflammatory skin disorder characterized by a fever, edema, and generalized erythema with neutrophilic pustules. It sometimes occurs in the course of psoriasis vulgaris, or develops suddenly without any history of psoriasis. Mutations of the IL36RN (deficiency of interleukin thirty-six receptor antagonist: DITRA), CARD14 and AP1S3 genes underlie monogenic auto-inflammatory disorders causing GPP. GPP patients are usually treated with oral administration of etretinate, cyclosporine, and metrexate, biologics including TNF α inhibitors, antibodies to IL-17, IL-17 receptor, and IL-23 p19, and granulocyte and monocyte adsorption apheresis (GMA). Cyclosporine, TNF α inhibitors, and GMA are used for GPP in pediatric, pregnant, or lactating patients. GMA is an extracorporeal apheresis that removes activated granulocytes and monocytes using a column packed with cellulose acetate beads. Multicenter study was performed to access efficacy of selectively depleting the myeloid lineage leukocytes in GPP patients. Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Based on the GPP severity scores relative to entry, the overall scores improved, and the area of erythroderma, pustules, and edema decreased. Likewise, Dermatology Life Quality Index (DLQI) improved, reflecting better daily function and quality of life. Twelve out of 14 patients were judged as responders (85.7%), and 10 out of 12 patients maintained the clinical response for10 weeks after the last GMA session without any change in medication. Thus, GMA is estimated to be safe and effective, suggesting a major role of granulocytes/ monocytes in the immunepathogenesis of GPP. Recent study showed that GMA was effective for 100% of DITRA patients and for 64.7% of the patients with IL36RN mutation-negative GPP. Thus, GMA is effective therapy for both DITRA and non-DITRA GPP patients. GMA may be a useful therapy for all GPP patients

http://www.atalacia.com/isfa/data/abstract.pdf