Interleukin-36 Is Highly Expressed in Skin Biopsies from Two Patients with Netherton Syndrome.

Netherton syndrome (NS) is a rare autosomal recessive disorder that occurs due to a loss-of-function mutation in SPINK5; this loss results in significant inflammation, as well as perturbations of the skin barrier's integrity and functionality. While it is unclear which inflammatory pathways contribute to the development of NS, recent studies have demonstrated the expression of interleukin (IL)-17/IL-36, as well as several Th2 cytokines. Consequently, immunohistochemistry (IHC) with IL-36 may serve as a potential tool for aiding the histopathological diagnosis of this condition. In this case series, we present two cases of NS and capture their immunostaining pattern with IL-36. Both cases demonstrated robust expression of IL-36. This finding bolsters the hypothesis that NS is partially driven by Th17 activation and suggests the potential utility of IL-36 IHC as part of the workup for this rare and diagnostically elusive entity. LEKTI IHC was negative in one biopsy, revealing a limitation of this stain in diagnosing NS.

Important Roles of Interleukin-36, Interleukin-37, and Interleukin-38 Cytokines in the Pathogenesis of Rosacea.

Background: Rosacea is a chronic inflammatory skin disease. Previous studies have determined that IL-36, IL-37, and IL-38 may play a role in the pathogenesis of various inflammatory diseases. Aims and Objectives: The present study aims to evaluate the relationship of these cytokines with rosacea. Materials and Methods: A total of 100 individuals, including 50 patients with rosacea and 50 healthy controls, were included in the study. IL-36, IL-37, and IL-38 levels were measured using the ELISA method by taking serum samples from all participants. Results: The mean serum levels of IL-36, IL-37, and IL-38 in the patient group were 52.17 ± 24.07 pg/ml, 18.46 ± 8.18 pg/ml, and 25.74 ± 8.36 ng/l, respectively. The mean serum levels of IL-36, IL-37, and IL-38 in the control group were 32.99 ± 19.90 pg/ml, 44.61 ± 22.27 pg/ml, and 45.61 ± 17.32 ng/l, respectively. The difference between the serum levels of IL-36, IL-37, and IL-38 in the patient and control groups was statistically significant (P < 0.001). Conclusion: Based on these findings, an increase in IL-36 and a decrease in IL-37 and IL-38 may contribute to the pathogenesis of rosacea. Future rosacea treatments could target and/or interact with these possible steps in the pathogenesis of rosacea.

Pharmacokinetics and Safety of Spesolimab in Healthy Chinese Subjects: An Open-Label, Phase I Study.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening inflammatory skin disease. Interleukin (IL)-36 signalling may play a central role in GPP pathogenesis. Spesolimab is a humanized anti-IL-36 monoclonal antibody inhibiting the IL-36 signalling pathway. Here, we investigated the pharmacokinetics and safety of spesolimab in healthy Chinese subjects. METHODS: In this Phase 1, single-dose, parallel-group, open-label study, healthy Chinese subjects aged 18-45 years received a single spesolimab dose by intravenous infusion (IV; 450 mg, 900 mg, or 1200 mg) or subcutaneous (SC) administration (300 mg or 600 mg). Primary endpoints were spesolimab exposure (area under the plasma concentration-time curve and maximum plasma concentration); secondary endpoints were treatment-emergent adverse events (TEAEs) and drug-related adverse events (AEs). RESULTS: Fifty subjects received IV (n = 30) or SC (n = 20) spesolimab (n = 10 per dose group); 60.0% were male, mean ± standard deviation age was 31.5 ± 6.6 and 31.0 ± 6.5 years in the IV and SC groups, respectively. Spesolimab exposure increased in a dose-proportional manner in both groups. TEAEs were reported in 83.3% and 80.0% of subjects in the IV and SC groups, the most common TEAE was upper respiratory tract infection (20.0% and 25.0%, respectively). One serious AE of hand fracture was reported in the 900 mg IV group that was not considered drug-related. Drug-related AEs were reported in 53.3% and 55.0% of subjects in the IV and SC groups. All laboratory-related AEs were mild and resolved. CONCLUSION: Spesolimab exposure increased in a dose-proportional manner after a single dose by IV and SC administration. Spesolimab was well tolerated in healthy Chinese subjects. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov registration: NCT04390568.

Molecular aspects of Interleukin-36 cytokine activation and regulation.

Interleukin-36 (IL-36) cytokines are structurally similar to other Interleukin-1 superfamily members and are essential to convey inflammatory responses at epithelial barriers including the skin, lung, and gut. Due to their potent effects on immune cells, IL-36 cytokine activation is regulated on multiple levels, from expression and activation to receptor binding. Different IL-36 isoforms convey specific responses as a consequence of particular danger- or pathogen-associated molecular patterns. IL-36 expression and activation are regulated by exogenous pathogens, including fungi, viruses and bacteria but also by endogenous factors such as antimicrobial peptides or cytokines. Processing of IL-36 into potent bioactive forms is necessary for host protection but can elevate tissue damage. Indeed, exacerbated IL-36 signalling and hyperactivation are linked to the pathogenesis of diseases such as plaque and pustular psoriasis, emphasising the importance of understanding the molecular aspects regulating IL-36 activation. Here, we summarise facets of the electrochemical properties, regulation of extracellular cleavage by various proteases and receptor signalling of the pro-inflammatory and anti-inflammatory IL-36 family members. Additionally, this intriguing cytokine subfamily displays many characteristics that are unique from prototypical members of the IL-1 family and these key distinctions are outlined here.

Krüppel-like Factor-4-Mediated Macrophage Polarization and Phenotypic Transitions Drive Intestinal Fibrosis in THP-1 Monocyte Models In Vitro.

Background and Objectives: Despite the fact that biologic drugs have transformed inflammatory bowel disease (IBD) treatment, addressing fibrosis-related strictures remains a research gap. This study explored the roles of cytokines, macrophages, and Krüppel-like factors (KLFs), specifically KLF4, in intestinal fibrosis, as well as the interplay of KLF4 with various gut components. Materials and Methods: This study examined macrophage subtypes, their KLF4 expression, and the effects of KLF4 knockdown on macrophage polarization and cytokine expression using THP-1 monocyte models. Co-culture experiments with stromal myofibroblasts and a conditioned medium from macrophage subtype cultures were conducted to study the role of these cells in intestinal fibrosis. Human-induced pluripotent stem cell-derived small intestinal organoids were used to confirm inflammatory and fibrotic responses in the human small intestinal epithelium. Results: Each macrophage subtype exhibited distinct phenotypes and KLF4 expression. Knockdown of KLF4 induced inflammatory cytokine expression in M0, M2a, and M2c cells. M2b exerted anti-fibrotic effects via interleukin (IL)-10. M0 and M2b cells showed a high migratory capacity toward activated stromal myofibroblasts. M0 cells interacting with activated stromal myofibroblasts transformed into inflammatory macrophages, thereby increasing pro-inflammatory cytokine expression. The expression of IL-36α, linked to fibrosis, was upregulated. Conclusions: This study elucidated the role of KLF4 in macrophage polarization and the intricate interactions between macrophages, stromal myofibroblasts, and cytokines in experimental in vitro models of intestinal fibrosis. The obtained results may suggest the mechanism of fibrosis formation in clinical IBD.

The Clinical Significance of Serum Interleukin-36α Levels in Patients with Gout.

BACKGROUND: Gout is a chronic inflammatory diseases caused by monosodium urate crystal deposition. However, the role of interleukin (IL)-36 in gout has not dbeen elucidated. METHODS: We enrolled 75 subjects, including 20 healthy controls (HC), 30 patients with acute gout attack and 25 patients in remission. Baseline data were obtained through clinical interrogation and laboratory data were obtained through tests of blood samples. Serum levels of IL-36α were detected using enzyme-linked immunosorbent assay. Spearman correlation analysis was used to investigate the correlation of IL-36α with other parameters. The diagnostic value of IL-36α was demonstrated using a receiver operating characteristic curve. RESULTS: The serum IL-36α level of gout patients in acute attack and remission stage was significantly higher than that of HC. Serum IL-36α was positively correlated with alanine transaminase (ALT) and aspartate transaminase (AST). Serum amyloid A (SAA) levels positively correlated with C-reactive protein levels and erythrocyte sedimentation rates. Glutamyl transpeptidase levels positively correlated with AST and ALT levels. CONCLUSION: In conclusion, serum IL-36α levels were elevated in patients with gout and correlated with the clinical markers of inflammation. Our findings suggest that IL-36α may be a novel inflammatory indicator for gout.

Exploring the Clinical Presentation, Course, and Burden of Disease in Generalized Pustular Psoriasis [Podcast].

Generalized pustular psoriasis (GPP) is the most severe form of pustular psoriasis and affects large areas of the body. GPP is a rare disease, and has a variable presentation; thus, its diagnosis is challenging. The onset of symptoms is rapid, with the appearance of painful skin erythema, followed by the widespread eruption of sterile pustules. Acute GPP (called a flare) is often accompanied by systemic symptoms, including high fever, pain in skin lesions, malaise, and fatigue. Approximately half of GPP flares require hospitalization, with an average inpatient duration of 10-14 days. GPP prevalence estimates range from approximately 2-124 cases per million persons, with a female predominance. The most common age of onset of GPP is 40-60 years, although cases have been described in younger adults and children. GPP affects every aspect of patients' lives and has a high physical and psycho-social impact. Recent research on the interleukin-36 pathway associated with GPP led to the development of a GPP-specific treatment, spesolimab, which was approved by the US FDA in September 2022. This podcast explores the clinical presentation, disease course, and burden of disease in GPP, including differential diagnosis and common triggers of an acute flare.

Acquired diffuse palmoplantar erythema with keratoderma in Chinese patients with pustular psoriasis: A predictor for IL36 receptor antagonist c.115+6T>C mutation?

Several studies have suggested that mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to generalized pustular psoriasis (GPP), and the presence of IL36RN mutation may affect the clinical manifestations and treatment responses. However, genetic testing is not routinely available in clinical practice for the diagnosis of GPP. Previously, GPP patients with acrodermatitis continua of Hallopeau (ACH) were found to have a high percentage of carrying IL36RN mutation. In this study, we reported six patients with pustular psoriasis presenting as diffuse palmoplantar erythema with keratoderma among 60 patients who carried IL36RN mutation. ACH was present in five patients and five patients had acute flare of GPP. This unique presentation may serve as a predictor for IL36RN mutation in patients with pustular psoriasis, similar to ACH.

AMPK activation modulates IL-36-induced inflammatory responses by regulating IκBζ expression in the skin.

BACKGROUND AND PURPOSE: The interleukin (IL)-36 pathway is a critical player in the pathogenesis of pustular psoriasis. However, therapies targeting this pathway are limited or unaffordable (e.g. the anti-IL-36 receptor antibody). AMP-activated protein kinase (AMPK), a regulator of cellular energy and metabolism, is known to participate in inflammatory diseases. However, its role in IL-36-induced skin inflammation remains unclear. Therefore, we sought to investigate the role of AMPK signals in regulating IL-36-induced responses in the skin. EXPERIMENTAL APPROACH: IL-36-stimulated primary normal human epidermal keratinocytes (NHEKs) and IL-36-injected (intradermally) BALB/c mice served as the cell and animal models, respectively. Additionally, 5-aminoimidazole-4-carboxamide riboside (AICAR) and A769662 served as AMPK activators. KEY RESULTS: AICAR and A769662 significantly suppressed the IL-36-induced IL-8 (CXCL8) and CCL20 production from NHEKs. IL-36-induced IκBζ protein expression was prominently reduced and IKK/IκBα phosphorylation was attenuated by AICAR and A769662. Conversely, AMPKα knockdown increased IκBζ protein expression and IKK/IκBα phosphorylation in IL-36-treated NHEKs. Furthermore, AICAR and A769662 enhanced IL-36-induced-IκBζ protein degradation via the proteasome-dependent but not the lysosome-dependent pathway. Pretreatment of NHEKs with IL-36 slightly suppressed the AICAR- and A769662-triggered phosphorylation of AMPK and acetyl-CoA carboxylase. In the mouse model, topical application of AICAR significantly reduced ear swelling, redness, epidermal thickening, neutrophil infiltration and inflammatory and antimicrobial peptide gene expression. CONCLUSION AND IMPLICATIONS: AMPK activation suppresses IL-36-induced IL-8 and CCL20 release by regulating IκBζ expression in keratinocytes and reduces IL-36-induced skin inflammation in mice, suggesting that AMPK activation is a potential strategy for treating patients with IL-36-mediated inflammatory skin disorders.

Different Gene Expression Patterns of IL-1 Family Members in Parkinson's Disease: Results from Bayesian Regression Model.

Parkinson's disease, the second most prevalent neurodegenerative disorder lacking a recognized etiology, is influenced by oxidative stress and alterations in inflammatory cytokine levels. This study aimed to investigate the expression levels of Interleukin(IL)1 receptor accessory protein (IL-1RAcP), IL1ß, IL1α, IL33, and IL36 genes in blood cells and serum IL-1ß levels in Parkinson's disease patients compared to healthy controls (HCs).I n this case-control study, 44 Parkinson's disease patients and 44 age- and sex-matched HCs were included. Gene expression levels were assessed using Quantitative Real-time PCR, and serum IL-1ß levels were measured via enzyme-linked immunosorbent assay. Advanced statistical analyses using the Bayesian regression model in R software were employed. Parkinson's disease patients exhibited elevated expression levels of IL-1RAcP and IL1ß genes  but decreased levels of IL1α, IL33, and IL36 compared to HCs. Age-based differences were not significant. Regarding gender, IL33 transcript levels were significantly higher in males, and serum IL-1ß levels were increased in patients. Subgroup analysis by gender indicated alterations in IL1ß and IL-1RAcP expression in both genders, while IL1α, IL33, and IL36 showed reduced expression only in males. Remarkably, only female patients displayed significantly higher serum IL-1ß levels than female HCs. These findings suggest that dysregulation of immune-related factors plays a crucial role in Parkinson's disease.

Interleukin-36 receptor antagonist stimulation in vitro inhibits peripheral and lung-resident T cell response isolated from patients with ventilator-associated pneumonia.

Interleukin-36 (IL-36) cytokine family members play an immunomodulatory function to immune cells through IL-36 receptor signaling pathway. However, the regulatory role of IL-36 exerted on T cells is not completely elucidated in patients with ventilator-associated pneumonia (VAP). For this purpose, this study enrolled 51 VAP patients and 27 controls. IL-36 levels were measured by ELISA. The mRNA levels of IL-36 receptor subunits were determined by real-time PCR. CD4+ and CD8+ T cells were enriched, and stimulated with recombinant IL-36 receptor antagonist (IL-36RA). The influence of IL-36RA on transcription factors and cytokine secretions by CD4+ T cells was investigated. The modulatory function of IL-36RA on CD8+ T cells was assessed by measuring target cell death and cytokine secretions. There were no significant differences in serum IL-36 levels between VAP patients and controls. Only IL-36RA, but not IL-36α, IL-36ß, or IL-36γ, in bronchoalveolar lavage fluid was elevated in infection site of VAP patients. IL-36 receptor subunits in CD4+ and CD8+ T cells were comparable between VAP patients and controls. 10 ng/mL of IL-36RA stimulation dampened peripheral effector CD4+ T cell response isolated from both VAP patients and controls. Target cell death mediated by CD8+ T cells isolated from BAFL of VAP patients was suppressed by 100 ng/mL of IL-36RA stimulation in vitro. The down-regulations of perforin, granzyme B, interferon-γ, tumor necrosis factor-α, and Fas ligand following IL-36RA stimulation in vitro were responsible for reduced CD8+ T cell-mediated cytotoxicity. IL-36RA revealed an immunosuppressive property for T cell response in vitro, and may be involved in the protective mechanism in VAP patients.

Monitoring coronary blood flow by laser speckle contrast imaging after myocardial ischaemia reperfusion injury in adult and aged mice.

Introduction: Investigating coronary microvascular perfusion responses after myocardial infarction (MI) would aid in the development of flow preserving therapies. Laser speckle contrast imaging (LSCI) is a powerful tool used for real-time, non-contact, full-field imaging of blood flow in various tissues/organs. However, its use in the beating heart has been limited due to motion artifacts. Methods: In this paper, we report the novel use of LSCI, combined with custom speckle analysis software (SpAn), to visualise and quantitate changes in ventricular perfusion in adult and aged mice undergoing ischaemia-reperfusion (IR) injury. The therapeutic benefit of inhibiting the actions of the pro-inflammatory cytokine interleukin-36 (IL-36) was also investigated using an IL-36 receptor antagonist (IL-36Ra). Results: Imaging from uncovered and covered regions of the left ventricle demonstrated that whilst part of the LSCI flux signal was derived from beating motion, a significant contributor to the flux signal came from ventricular microcirculatory blood flow. We show that a biphasic flux profile corresponding to diastolic and systolic phases of the cardiac cycle can be detected without mathematically processing the total flux data to denoise motion artifacts. Furthermore, perfusion responses to ischaemia and postischaemia were strong, reproducible and could easily be detected without the need to subtract motion-related flux signals. LSCI also identified significantly poorer ventricular perfusion in injured aged mice following IR injury which markedly improved with IL-36Ra. Discussion: We therefore propose that LSCI of the heart is possible despite motion artifacts and may facilitate future investigations into the role of the coronary microcirculation in cardiovascular diseases and development of novel therapies.

Interleukin-36gamma Mediates the In Vitro Activation of CD8+ T Cells from Patients Living with Chronic Human Immunodeficiency Virus-1 Infection.

Interleukin-36 (IL-36) signaling plays an important role in promoting CD8+ T cell-mediated antitumor immune responses. The role of IL-36 signaling in CD8+ T cells that are involved in host immune responses during human immunodeficiency virus-1 (HIV-1) infection has not been characterized. Sixty-one patients living with chronic HIV-1 infection and 23 controls were enrolled in this study. The levels of IL-36 cytokine family members were measured by enzyme-linked immunosorbent assay. Purified CD8+ T cells were stimulated with recombinant IL-36gamma (1 or 10 ng/mL). The expression of inhibitory receptors, the secretion of cytotoxic molecules and interferon-gamma, and the mRNA levels of apoptosis-related ligands were assessed to evaluate the effect of IL-36gamma on CD8+ T cell function in vitro. There were no significant differences in IL-36alpha, IL-36beta, or IL-36 receptor antagonist levels between patients living with chronic HIV-1 infection and controls. Plasma IL-36gamma levels were reduced in patients living with chronic HIV-1 infection. Perforin, granzyme B, and granulysin secretion, as well as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) mRNA expression, but not programmed death-1 (PD-1) or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) expression was downregulated in CD8+ T cells from patients living with chronic HIV-1 infection. The addition of both 1 and 10 ng/mL IL-36gamma enhanced perforin, granzyme B, granulysin, and interferon-gamma secretion by CD8+ T cells without affecting PD-1/CTLA-4 or TRAIL/FasL mRNA expression in CD8+ T cells from patients living with chronic HIV-1 infection. The addition of 1 ng/mL IL-36gamma also promoted perforin and granzyme B secretion by HIV-1-specific CD8+ T cells from patients living with chronic HIV-1 infection. The reduced IL-36gamma levels in patients living with chronic HIV-1 infection might be insufficient for the activation of CD8+ T cells, leading to CD8+ T cell exhaustion.

Spesolimab, A Novel Interleukin-36 Inhibitor for Generalized Pustular Psoriasis Flares in Adult Patients.

Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations. Mutations in the interleukin-36 receptor antagonist (IL36RN) gene have been implicated in its pathogenesis. Spesolimab is a novel systemic biologic therapy that selectively inhibits interleukin-36. It was recently approved by Health Canada and the US FDA for the treatment of GPP flares in adults. Results from phase 1 and 2 studies have been promising. Herein, we review the efficacy and safety of spesolimab for the treatment of GPP flares, as demonstrated in clinical trials.

Clinical advances in biological therapy for generalized pustular psoriasis: a review.

INTRODUCTION: In 2022, U.S. Food and Drug Administration (FDA) approved the first biologics, intravenous spesolimab, for acute flare of generalized pustular psoriasis (GPP). The drug works by blocking IL-36 signaling, the key pathway of GPP. Among the known mutations causing GPP, IL36RN mutations are most common, and the presence of IL36RN mutations had been found to affect the clinical manifestations and treatment response of GPP. AREAS COVERED: Literature search was conducted in PubMed, Embase and ClinicalTrials.gov for relevant studies discussing biologic treatment for GPP with special emphasis on larger studies, pediatric group, pregnant women, and the influence of IL36RN mutation on the effectiveness of biologics. EXPERT OPINION: The approval of spesolimab for GPP flare treatment marks a new era. However, whether spesolimab will be placed as the treatment of choice remains unknown, considering its higher cost, lack of direct comparison with existing biologics, and uncertain effects on co-existing plaque-type psoriasis. However, the demonstration of numerically better efficacy for patients carrying pathogenic IL36RN mutations suggests the role of pharmacogenetics in the choices of GPP treatment. Future randomized studies are warranted to investigate the effectiveness and safety of biologics for GPP in pediatric and pregnant groups.

Emerging Role of the IL-36/IL-36R Axis in Multiple Inflammatory Skin Diseases.

IL-36 is a most recent member of the IL-1 cytokine family, primarily expressed at barrier sites of the body such as the skin, lungs, and intestine. It plays a vital role in inflammation and is implicated in the development of various cutaneous; intestinal; and pulmonary disorders, including psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. IL-36 comprises 4 isoforms: the proinflammatory IL-36α, IL-36ß, and IL-36γ and the anti-inflammatory IL-36R antagonist. An imbalance between proinflammatory and anti-inflammatory IL-36 isoforms can contribute to the inflammatory fate of cells and tissues. IL-36 cytokines signal through an IL-36R heterodimer mediating their function through canonical signaling cacade, including the NF-B pathway. Prominent for its role in psoriasis, IL-36 has recently been associated with disease mechanisms in atopic dermatitis, hidradenitis suppurativa, neutrophilic dermatoses, autoimmune blistering disease, and Netherton syndrome. The major cutaneous source of IL-36 cytokines is keratinocytes, pointing to its role in the communication between the epidermis, innate (neutrophils, dendritic cells) immune system, and adaptive (T helper [Th]1 cells, Th17) immune system. Thus, cutaneous IL-36 signaling is crucial for the immunopathological outcome of various skin diseases. Consequently, the IL-36/IL-36R axis has recently been recognized as a promising drug target for the treatment of inflammatory disorders beyond psoriasis. This review summarizes the current update on IL-36 cytokines in inflammatory skin diseases.

Staphylococcus aureus proteases trigger eosinophil-mediated skin inflammation.

Staphylococcus aureus skin colonization and eosinophil infiltration are associated with many inflammatory skin disorders, including atopic dermatitis, bullous pemphigoid, Netherton's syndrome, and prurigo nodularis. However, whether there is a relationship between S. aureus and eosinophils and how this interaction influences skin inflammation is largely undefined. We show in a preclinical mouse model that S. aureus epicutaneous exposure induced eosinophil-recruiting chemokines and eosinophil infiltration into the skin. Remarkably, we found that eosinophils had a comparable contribution to the skin inflammation as T cells, in a manner dependent on eosinophil-derived IL-17A and IL-17F production. Importantly, IL-36R signaling induced CCL7-mediated eosinophil recruitment to the inflamed skin. Last, S. aureus proteases induced IL-36α expression in keratinocytes, which promoted infiltration of IL-17-producing eosinophils. Collectively, we uncovered a mechanism for S. aureus proteases to trigger eosinophil-mediated skin inflammation, which has implications in the pathogenesis of inflammatory skin diseases.

Cutaneous findings and treatments in deficiency of interleukin-36 receptor antagonist (DITRA): A review of the literature.

Deficiency of the interleukin-36 receptor antagonist (DITRA) is a rare autoinflammatory disorder caused by mutations in the IL36RN gene. This mutation leads to a lack of functional interleukin-36 receptor antagonists (IL-36Ra), which results in an overactive immune system and chronic inflammation. Despite its rarity, numerous case series and individual reports in the literature emphasize the importance of recognizing and managing DITRA. Early identification of the cutaneous signs of DITRA is crucial for accurate diagnosis and timely administration of appropriate treatment. This review article provides a comprehensive overview of the current understanding of the cutaneous, non-cutaneous and histopathological manifestations of DITRA, with a focus on reported treatments. The disease typically presents in early childhood, although the age of onset can vary. Patients with DITRA exhibit recurrent episodes of skin inflammation, often with a pustular or pustular psoriasis-like appearance. Additionally, non-cutaneous manifestations are common, with recurrent fevers and elevated acute-phase reactants being the most prevalent. The exact prevalence of DITRA is unknown. Some cases of loss-of-function mutations in the IL36RN gene, considered a hallmark for diagnosis, have been identified in patients with familial generalized pustular psoriasis (GPP). Biological therapies with inhibition of IL-12/23 and IL-17 are promising treatment options; paediatric patients with DITRA have shown complete response with mild relapses. New and emerging biologic therapeutics targeting the IL-36 pathway are also of interest in the management of this rare autoinflammatory disorder.