Role of neutrophil interleukin-23 in spondyloarthropathy spectrum disorders.

Neutrophilic inflammation is a pervasive characteristic common to spondyloarthropathies and related disorders. This inflammation manifests as Munro's microabscesses of the skin and osteoarticular neutrophilic inflammation in patients with psoriatic arthritis, intestinal crypt abscesses in patients with inflammatory bowel disease, ocular hypopyon in anterior uveitis, and neutrophilic macroscopic and microscopic inflammation in patients with Behçet's disease. Strong MHC class I associations are seen in these diseases, which represent so-called MHC-I-opathies, and these associations indicate an involvement of CD8 T-cell immunopathology that is not yet well understood.

Anti-IL-5 biologics and rheumatoid arthritis: a single-centre 500 patient year exposure analysis.

Objective: The increasing use of biological therapies has led to the paradoxical finding that monoclonal antibody therapy for one inflammatory disease can sometimes induce another inflammatory disease. Recently, the use of anti-IL-5 (IL, interleukin) antibody therapies for severe asthma has been associated with the onset of rheumatoid arthritis (RA) and other inflammatory rheumatological disease. We undertook this audit to identify the prevalence of this finding across a large clinical cohort of patients receiving anti-IL-5 therapy.

Molecular and cellular regulation of psoriatic inflammation.

This review highlights the molecular and cellular mechanisms underlying psoriatic inflammation with an emphasis on recent developments which may impact on treatment approaches for this chronic disease. We consider both the skin and the musculoskeletal compartment and how different manifestations of psoriatic inflammation are linked. This review brings a focus to the importance of inflammatory feedback loops that exist in the initiation and chronic stages of the condition, and how close interaction between the epidermis and both innate and adaptive immune compartments drives psoriatic inflammation.

Perspective: The Case for Acute Large Vessel Ischemic Stroke in COVID-19 Originating Within Thrombosed Pulmonary Venules.

The main burden of SARS-CoV-2 falls on the lungs but neurological manifestations, the most disabling of which are strokes and which correlate with disease severity, are common. We proffer a novel mechanism for acute COVID-19 stroke whereby pulmonary vein clots developing within the characteristic pulmonary intravascular thrombotic lesions can embolize to the brain. Appreciation of this mechanism requires an understanding of the tricompartmental model of lung parenchyma oxygenation (the alveolus, the bronchial artery, and the pulmonary artery), all of which are compromised in COVID-19.

Sex-Based Medicine Meets Psoriatic Arthritis: Lessons Learned and to Learn.

Humorally associated autoimmune diseases generally show a female predominance whereas ankylosing spondylitis, a disease that overlaps with psoriatic arthritis (PsA), shows a male predominance. The present review ascertains the current knowledge of sex-specific differences related to psoriatic arthritis (PsA), a chronic, inflammatory condition associated with psoriasis. Sex differences may have important implications for clinical research in PsA and in terms of epidemiology (incidence, prevalence, lifetime risk, survival, and mortality), clinical, radiological, and laboratory features, and response to treatment.

COVID-19 Vasculitis and vasculopathy-Distinct immunopathology emerging from the close juxtaposition of Type II Pneumocytes and Pulmonary Endothelial Cells.

The SARS-CoV-2 virus ACE-2 receptor utilization for cellular entry and the defined ACE-2 receptor role in cardiovascular medicine hinted at dysregulated endothelial function or even direct viral endotheliitis as the key driver of severe COVID-19 vascular immunopathology including reports of vasculitis. In this article, we critically review COVID-19 immunopathology from the vasculitis perspective and highlight the non-infectious nature of vascular endothelial involvement in severe COVID-19. Whilst COVID-19 lung disease pathological changes included juxta-capillary and vascular macrophage and lymphocytic infiltration typical of vasculitis, we review the evidence reflecting that such "vasculitis" reflects an extension of pneumonic inflammatory pathology to encompass these thin-walled vessels.

T Helper 2 IL-4/IL-13 Dual Blockade with Dupilumab Is Linked to Some Emergent T Helper 17‒Type Diseases, Including Seronegative Arthritis and Enthesitis/Enthesopathy, but Not to Humoral Autoimmune Diseases.

Dupilumab, an IL-4/IL-13 receptor blocker, has been linked to emergent seronegative inflammatory arthritis and psoriasis that form part of the spondyloarthropathy spectrum. We systematically investigated patterns of immune disorders, including predominantly T helper 17‒(spondyloarthropathy pattern) and T helper 2‒mediated disorders and humoral autoimmune pattern diseases, using VigiBase, the World Health Organization's global pharmacovigilance of adverse drug reactions. Several bioinformatics databases and repositories were mined to couple dupilumab-related immunopharmacovigilance with molecular cascades relevant to reported findings.

Harnessing Big Data, Smart and Digital Technologies and Artificial Intelligence for Preventing, Early Intercepting, Managing, and Treating Psoriatic Arthritis: Insights From a Systematic Review of the Literature.

Background: Rheumatological and dermatological disorders contribute to a significant portion of the global burden of disease. Big Data are increasingly having a more and more relevant role, being highly ubiquitous and pervasive in contemporary society and paving the way for new, unprecedented perspectives in biomedicine, including dermatology and rheumatology. Rheumatology and dermatology can potentially benefit from Big Data.

Characterization of Blood Mucosal-Associated Invariant T Cells in Patients With Axial Spondyloarthritis and of Resident Mucosal-Associated Invariant T Cells From the Axial Entheses of Non-Axial Spondyloarthritis Control Patients.

Objective: The importance of interleukin-17A (IL-17A) in the pathogenesis of axial spondyloarthritis (SpA) has been demonstrated by the success of IL-17A blockade. However, the nature of the cell populations that produce this important proinflammatory cytokine remains poorly defined. We undertook this study to characterize the major IL-17A-producing blood cell populations in the peripheral blood of patients with axial SpA, with a focus on mucosal-associated invariant T (MAIT) cells, a population known to be capable of producing IL-17.

A role for neutrophils in early enthesitis in spondyloarthritis.

Background: Neutrophils are present in the early phases of spondyloarthritis-related uveitis, skin and intestinal disease, but their role in enthesitis, a cardinal musculoskeletal lesion in spondyloarthritis, remains unknown. We considered the role of neutrophils in the experimental SKG mouse model of SpA and in human axial entheses.

Methods: Early inflammatory infiltrates in the axial and peripheral entheseal sites in SKG mice were evaluated using immunohistochemistry and laser capture microdissection of entheseal tissue.

The Immunological Impact of IL-1 Family Cytokines on the Epidermal Barrier.

The skin barrier would not function without IL-1 family members, but their physiological role in the immunological aspects of skin barrier function are often overlooked. This review summarises the role of IL-1 family cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-38) in the skin. We focus on novel aspects of their interaction with commensals and pathogens, the important impact of proteases on cytokine activity, on healing responses and inflammation limiting mechanisms.

Therapeutic implications of ongoing alveolar viral replication in COVID-19.

In patients with moderate-to-severe COVID-19 pneumonia, an aberrant post-viral alveolitis with excessive inflammatory responses and immunothrombosis underpins use of immunomodulatory therapy (eg, corticosteroids and interleukin-6 receptor antagonism). By contrast, immunosuppression in individuals with mild COVID-19 who do not require oxygen therapy or in those with critical disease undergoing prolonged ventilation is of no proven benefit. Furthermore, a window of opportunity is thought to exist for timely immunosuppression in patients with moderate-to-severe COVID-19 pneumonia shortly after clinical presentation.

Unexpected connections of the IL-23/IL-17 and IL-4/IL-13 cytokine axes in inflammatory arthritis and enthesitis.

The IL-23/IL-17 cytokine axis is related to spondyloarthropathy (SpA) pattern diseases that target the skin, eye, gut and joints. These share overlapping target tissues with Th2 type or allergic diseases, including the skin, eye and gut but SpA diseases exhibit distinct microanatomical topography, molecular characteristics, and clinical features including uveitis, psoriasis, apical pulmonary involvement, lower gastrointestinal involvement with colitis, and related arthritides including psoriatic arthritis and ankylosing spondylitis. Inflammatory arthritis is conspicuously absent from the Th2 diseases which are characterised IL-4/IL-13 dependent pathway activation including allergic rhino-conjunctivitis, atopic eczema, allergic asthma and food allergies.

Higher rates of COVID-19 but less severe infections reported for patients on Dupilumab: a Big Data analysis of the World Health Organization VigiBase.

Objective: Dupilumab (Dupixent®) is a monoclonal antibody that inhibits IL-4 and IL-13 signaling used for the treatment of allergic diseases. Whilst biologic therapy is traditionally regarded as immunosuppressive and capable to increase the infectious risk, Dupilumab does not display these characteristics and may be even protective in certain cases. We investigated the link between Dupilumab therapy and SARS-CoV-2 infection.

Dupilumab: An Opportunity to Unravel In Vivo Actions of IL-4 and IL-13 in Humans.

The application of biologics in clinical practice allows immunological observations under real-life conditions. In a new article in the Journal of Investigative Dermatology, Bakker et al. (2021) use deep immune cell phenotyping to demonstrate how dupilumab acts in a targeted fashion on skin-homing T cells, the driver cells of atopic dermatitis.

Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection.

Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin-Induced Thrombocytopenia (HIT).

A tricompartmental model of lung oxygenation disruption to explain pulmonary and systemic pathology in severe COVID-19.

The emergent 21st century betacoronaviruses, including SARS-CoV-2, lead to clinicopathological manifestations with unusual features, such as early-onset chest pain, pulmonary infarction, and pulmonary and systemic thromboembolism that is pathologically linked to extensive capillary, arteriolar, and venular thrombosis. Early ground glass opacities detected by CT, which are reminiscent of lung infarcts associated with pulmonary embolism, point to a novel vascular pathology in COVID-19. Under physiological conditions, normal parenchymal oxygenation is maintained by three sources: the alveolus itself and dual oxygen supply from the pulmonary and bronchial artery circulations.

SARS-CoV-2 Infection Induces Psoriatic Arthritis Flares and Enthesis Resident Plasmacytoid Dendritic Cell Type-1 Interferon Inhibition by JAK Antagonism Offer Novel Spondyloarthritis Pathogenesis Insights.

Objective: Bacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares.

Why Inhibition of IL-23 Lacked Efficacy in Ankylosing Spondylitis.

The term spondyloarthritis pertains to both axial and peripheral arthritis including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which is strongly linked to psoriasis and also the arthritis associated with inflammatory bowel disease. The argument supporting the role for IL-23 across the spectrum of SpA comes from 4 sources. First, genome wide associated studies (GWAS) have shown that all the aforementioned disorders exhibit IL-23R pathway SNPs, whereas HLA-B27 is not linked to all of these diseases-hence the IL-23 pathway represents the common genetic denominator.