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SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.

IntroductionImmunotherapy with biologics targeting programmed cell death protein-1 (PD-1) is highly effective in the treatment of various malignancies. Nevertheless, it is frequently responsible for unexpected cutaneous manifestations, including psoriasis-like dermatitis. The pathogenesis of anti-PD-1-induced psoriasis has yet to be clarified, even though it is plausible that some innate and adaptive immunity processes are in common with canonical psoriasis. The genetic predisposition to psoriasis of patients could also be a contributing factor. Here, we investigated the immunological and genetic profiles of two patients with metastatic melanoma and one patient affected by lung cancer, who developed severe psoriasis after receiving anti-PD-1 nivolumab therapy.MethodsThe immune patterns of the three patients were compared with those detectable in classical, chronic plaque-type psoriasis or paradoxical psoriasis induced by anti-TNF-α therapy, mostly sustained by adaptive and innate immunity processes, respectively. Therefore, immunohistochemistry and mRNA analyses of innate and adaptive immunity molecules were conducted on skin biopsy of patients. Genetic analysis of polymorphisms predisposing to psoriasis was carried out by NGS technology.ResultsWe found that anti-PD-1-induced psoriasis showed immunological features similar to chronic psoriasis, characterized by the presence of cellular players of adaptive immunity, with abundant CD3+, CD8+ T cells and CD11c+ dendritic cells infiltrating skin lesions, and producing IL-23, IL-6, TNF-α, IFN-γ and IL-17. On the contrary, a lower number of innate immunity cells (BDCA2+ plasmacytoid dendritic cells, CD15+ neutrophils, CD117+ mast cells) and reduced IFN-α/β, lymphotoxin (LT)-α/β, were observed in anti-PD-1-induced psoriasis lesions, as compared with anti-TNF-α-induced paradoxical psoriasis. Importantly, the disintegrin and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) psoriasis autoantigen was significantly upregulated in psoriasis lesions of anti-PD-1-treated patients, at levels comparable with chronic plaque-type psoriasis. Finally, NGS analysis revealed that all patients carried several allelic variants in psoriasis susceptibility genes, such as HLA-C, ERAP1 and other genes of the major psoriasis susceptibility PSORS1 locus.DiscussionOur study showed that adaptive immunity predominates over innate immunity in anti-PD-1-induced psoriasis lesions, consistently with the local ADAMTSL5 overexpression. The presence of numerous SNPs in psoriasis susceptibility genes of the three patients also suggested their strong predisposition to the disease.

In the past decade, our understanding of psoriasis pathogenesis has made significant steps forward, leading to the development of multiple game-changing therapies. While psoriasis primarily affects the skin, it is increasingly recognized as a systemic disease that can have effects beyond the skin. Obesity is associated with more severe forms of psoriasis and can potentially worsen the systemic inflammation and metabolic dysfunction seen in psoriatic patients. The exact mechanisms underlying the link between these two conditions are not fully understood, but it is believed that chronic inflammation and immune dysregulation play a role. In this review, we examine the existing body of knowledge regarding the intersection of pathogenic processes responsible for psoriasis and obesity. The ability of biological therapies to reduce systemic and obesity-related inflammation in patients with psoriasis will be also discussed.

Introduction: Health care-associated infections (HAIs) contribute to morbidity and mortality and to the dissemination of multidrug-resistant organisms. Children admitted to the intensive care unit undergo invasive procedures that increase their risk of developing HAIs and sepsis. The aim of the study was to analyse factors associated with mortality due to sepsis arising from HAIs. Patients and methods: We conducted a case-control study in a 7-bed multipurpose paediatric intensive care unit in a tertiary care teaching hospital. The sample consisted of 90 children admitted between January 2014 and December 2018. The case group consisted of patients who died from sepsis associated with the main health care-associated infections; the control group consisted of patients who survived sepsis associated with the same infections. Results: Death was associated with age less than or equal to 12 months, presence of comorbidity, congenital disease, recurrent ventilator-associated pneumonia and septic shock. In the multiple regression analysis, heart disease (OR, 12.48; CI 2.55–60.93; P = .002), infection by carbapenem-resistant bacteria (OR, 31.51; CI 4.01–247.25; P = .001), cancer (OR, 58.23; CI 4.54–746.27; P = .002), and treatment with adrenaline (OR, 13.14; CI 1.35–128.02; P = .003) continued to be significantly associated with death. Conclusions: Hospital sepsis secondary to carbapenem-resistant bacteria contributed to a high mortality rate in this cohort. Children with heart disease or neoplasia or who needed vasopressor drugs had poorer outcomes. Resumen: Introducción: Las infecciones relacionadas con la asistencia sanitaria (IRAS) contribuyen a la morbimortalidad y a la diseminación de organismos multirresistentes. Los niños ingresados en la unidad de cuidados intensivos son sometidos a procedimientos invasivos que aumentan su riesgo de desarrollar IRAS y sepsis. El objetivo de este estudio fue analizar los factores asociados a la letalidad por sepsis derivada de IRAS. Pacientes y métodos: Estudio de casos y controles, en una unidad de cuidados intensivos pediátricos polivalente de 7 camas de un hospital universitario de tercer nivel. La muestra consistió en 90 niños ingresados entre enero de 2014 y diciembre de 2018. Los casos se definieron como fallecimientos por sepsis asociada a infecciones asistenciales principales; los controles fueron los pacientes supervivientes que presentaron sepsis asociada a las mismas infecciones. Resultados: La muerte se asoció a edad menor o igual a 12 meses, presencia de comorbilidad, enfermedad congénita, neumonía recurrente asociada a ventilación mecánica y shock séptico. En el análisis múltiple, la cardiopatía (OR 12,48; IC 2,55–60,93; p = 0,002), la infección por bacterias resistentes a carbapenémicos (OR 31,51; IC 4,01–247,25; p = 0,001), el cáncer (OR 58,23; IC 4,54–746,27; p = 0,002) y el uso de adrenalina (OR 13,14; IC 1,35–128,02; p = 0,003) siguieron asociados a la muerte. Conclusiones: La sepsis hospitalaria secundaria a bacterias resistentes a carbapenémicos contribuyó a una elevada tasa de mortalidad. Los niños con cardiopatía o neoplasia o que necesitaron fármacos vasopresores tuvieron peores desenlaces.