Psoriasis is a common inflammatory skin disease characterized by the appearance of red scaly plaques that can affect any part of the body. High prevalence, chronicity, disfiguration, disability, and ...associated comorbidity make it a challenge for clinicians of multiple specialties. Likewise, its complex pathogenesis, comprising inflammation, hyperproliferation, and angioneogenesis, intrigues numerous scientific disciplines, namely, immunology. From a clinical perspective, the severity of psoriasis is highlighted by its increased mortality, with cardiovascular diseases contributing the highest excess risk. From a scientific point of view, psoriasis has to be considered a systemic inflammatory condition, as blood biomarkers of inflammation are elevated and imaging techniques document sites of inflammation beyond the skin. While the association of psoriasis with cardiovascular diseases is now widely accepted, causes and consequences of this association are controversially discussed. This review comments on epidemiologic, genetic, and mechanistic studies that analyzed the relation between psoriasis and cardiovascular comorbidity. The hypothesis of psoriasis potentially being an independent cardiovascular risk factor, driving atherosclerosis
inflammation-induced endothelial dysfunction, will be discussed. Finally, consequences for the management of psoriasis with the objective to reduce the patients' excess cardiovascular risk will be pointed out.
Psoriasis is a frequent chronic inflammatory skin disease, nowadays considered a major global health problem. Several new drugs, targeting the IL-23/IL-17A pathway, have been recently licensed or are ...in clinical development. These therapies represent a major improvement of the way in which psoriasis is managed, since they show an unprecedented efficacy on skin symptoms of psoriasis. This has been made possible, thanks to an increasingly more accurate pathogenic view of psoriasis. Today, the belief that Th17 cells mediate psoriasis is moving to the concept of psoriasis as an IL-17A-driven disease. New questions arise at the horizon, given that IL-17A is part of a newly described family of cytokines, which has five distinct homologous: IL-17B, IL-17C, IL-17D, IL-17E, also known as IL-25 and IL-17F. IL-17 family cytokines elicit similar effects in target cells, but simultaneously trigger different and sometimes opposite functions in a tissue-specific manner. This is complicated by the fact that IL-17 cytokines show a high capacity of synergisms with other inflammatory stimuli. In this review, we will summarize the current knowledge around the cytokines belonging to the IL-17 family in relation to skin inflammation in general and psoriasis in particular, and discuss possible clinical implications. A comprehensive understanding of the different roles played by the IL-17 cytokines is crucial to appreciate current and developing therapies and to allow an effective pathogenesis- and mechanisms-driven drug design.
Psoriasis Boehncke, Wolf-Henning, Prof; Schön, Michael P, Prof
The Lancet (British edition),
09/2015, Letnik:
386, Številka:
9997
Journal Article
Recenzirano
Summary Psoriasis is an immune-mediated, genetic disease manifesting in the skin or joints or both. A diverse team of clinicians with a range of expertise is often needed to treat the disease. ...Psoriasis provides many challenges including high prevalence, chronicity, disfiguration, disability, and associated comorbidity. Understanding the role of immune function in psoriasis and the interplay between the innate and adaptive immune system has helped to manage this complex disease, which affects patients far beyond the skin. In this Seminar, we highlight the clinical diversity of psoriasis and associated comorbid diseases. We describe recent developments in psoriasis epidemiology, pathogenesis, and genetics to better understand present trends in psoriasis management. Our key objective is to raise awareness of the complexity of this multifaceted disease, the potential of state-of-the-art therapeutic approaches, and the need for early diagnosis and comprehensive management of patients with psoriasis.
: There is increasing awareness that psoriasis is more than ‘skin deep’. Several recent reviews focussed on biomarkers indicating the systemic dimension of psoriasis and the aspect of comorbidity ...psoriasis shares with other chronic inflammatory diseases, such as Crohn’s disease and rheumatoid arthritis. Of emerging significance is the relationship to cardiovascular disease, as this contributes substantially to the patients’ increased mortality. In this viewpoint, we examine currently available evidence favouring the concept of a causal link between psoriasis and cardiovascular disease: systemic inflammation may cause insulin resistance, which in turn triggers endothelial cell dysfunction, leading to atherosclerosis and finally myocardial infarction or stroke. While this ‘psoriatic march’ is not yet formally proven, it raises clinically and academically relevant questions, and gains support by recent observations of numerous investigators.
IL-25, also known as IL-17E, is a unique cytokine of the IL-17 family. Indeed, IL-25 exclusively was shown to strongly induce expression of the cytokines associated with type 2 immunity. Although ...produced by several types of immune cells, such as T cells, dendritic cells, or group 2 innate lymphoid cells, a vast amount of IL-25 derives from epithelial cells. The functions of IL-25 have been actively studied in the context of physiology and pathology of various organs including skin, airways and lungs, gastrointestinal tract, and thymus. Accumulating evidence suggests that IL-25 is a “barrier surface” cytokine whose expression depends on extrinsic environmental factors and when upregulated may lead to inflammatory disorders such as atopic dermatitis, psoriasis, or asthma. This review summarizes the progress of the recent years regarding the effects of IL-25 on the regulation of immune response and the balance between its homeostatic and pathogenic role in various epithelia. We revisit IL-25’s general and tissue-specific mechanisms of action, mediated signaling pathways, and transcription factors activated in immune and resident cells. Finally, we discuss perspectives of the IL-25–based therapies for inflammatory disorders and compare them with the mainstream ones that target IL-17A.
Etiology and Pathogenesis of Psoriasis Boehncke, Wolf-Henning
Rheumatic diseases clinics of North America,
11/2015, Letnik:
41, Številka:
4
Journal Article
Recenzirano
Psoriasis is a common, chronic inflammatory skin disease most often appearing in the form of well-demarcated, scaly plaques. These lesions highlight the fundamental processes underlying its ...pathogenesis, namely, inflammation and epidermal hyperproliferation. Both phenomena are considered consequences of an intimate interplay between the innate and the adaptive immune system. This concept is supported by results of genetic studies, pointing toward the signaling pathways of nuclear factor-κB, interferon-γ, and interleukin (IL)-23 as well as antigen presentation as central axes of the psoriatic inflammation. Efficacy of biologics targeting tumor necrosis factor-α, IL-23, or IL-17 provides further evidence in favor of this model.
Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, ...significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial.
This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting).
From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 59% of 128 95% CI 50–68) and every 8 weeks group (66 52% of 127 43–61) than in the placebo group (28 22% of 126 15–30), with percentage differences versus placebo of 37% (95% CI 26–48) for the every 4 weeks group and 30% (19–41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections.
Guselkumab demonstrated a favourable benefit–risk profile and might be an effective treatment option for patients with active psoriatic arthritis.
Janssen Research and Development.
Psoriasis is a common chronic inflammatory skin disease, associated with substantial comorbidity. TH17 lymphocytes, differentiating under the influence of dendritic cell-derived IL-23, and mediating ...their effects
IL-17A, are believed to be central effector cells in psoriasis. This concept is underlined by the unprecedented efficacy of therapeutics targeting this pathogenetic axis. In recent years, numerous observations made it necessary to revisit and refine this simple "linear" pathogenetic model. It became evident that IL-23 independent cells exist that produce IL-17A, that IL-17 homologues may exhibit synergistic biological effects, and that the blockade of IL-17A alone is clinically less effective compared to the inhibition of several IL-17 homologues. In this review, we will summarize the current knowledge around IL-17A and its five currently known homologues, namely IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F, in relation to skin inflammation in general and psoriasis in particular. We will also re-visit the above-mentioned observations and integrate them into a more comprehensive pathogenetic model. This may help to appreciate current as well as developing anti-psoriatic therapies and to prioritize the selection of future drugs' mode(s) of action.
Objective
To update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with ...psoriatic arthritis (PsA).
Methods
GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA, based on consensus achieved at face‐to‐face meetings and via online surveys. We conducted literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin disease, and nail disease) and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, using an online questionnaire.
Results
Six overarching principles had ≥80% agreement among both health care professionals (n = 135) and patient research partners (n = 10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin disease, nail disease, and comorbidities in the setting of PsA, using the Grading of Recommendations, Assessment, Development and Evaluation process. Agreement of >80% was reached for approval of the individual recommendations and the overall schema.
Conclusion
We present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other health care providers, and patient research partners). Further updates are anticipated as the therapeutic landscape in PsA evolves.
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