Littérature scientifique sur le sujet « Psoriasis, T helper 17 cells, biologic therapy »

Psoriasis is a common, chronic, systemic immune-mediated inflammatory disease that affects the skin, joints, and other organs and systems. Despite the fact that psoriasis is one of the most studied dermatoses, its pathogenesis has not yet been fully clarified. In recent years, the pathogenetic model leading to the formation of psoriatic papules and plaques has undergone significant changes. This article presents a retrospective analysis of the study of the disease over the past 60 years from the generally accepted concept of epidermal dermatosis to understanding the complex interactions between keratinocytes, dendritic cells, T-lymphocytes, neutrophils and mast cells, with a significant role of interleukins (IL) 23, 17, 22,10, T-helper cells (Th) 17, 22, T-regulatory cells, transformative growth factor b1 (TGF-b1), in the pathogenesis of the disease. Targeted therapy using new biologics and small molecules, patient education, screening for comorbidities, and regular patient follow-up allow to apply a personalized approach to the patient and achieve impressive results. Achievements in psoriasis research have led to the fact that today we are witnessing the so-called translational revolution in psoriasis therapy, consisting in the fastest possible transfer of fundamental discoveries of the field of theoretical research to the field of practical application.

It has been reported that T helper 17 cells are involved in the pathogenesis of systemic lupus erythematosus, but there is no report on interleukin-17-targeted therapy. We report a case of a 62-year-old female who presented with psoriasis vulgaris and refractory lupus nephritis. Because her conditions were resistant to conventional treatment, and flow cytometry confirmed the proliferation of activated T helper 17 cells in peripheral blood, and examination of a renal biopsy tissue sample confirmed infiltration of numerous interleukin-17-positive lymphocytes to the renal interstitium, administration of the anti-interleukin-17A antibody secukinumab was initiated. After starting secukinumab the clinical and biological features were improved.

Introduction. There is a trend towards rising incidence of psoriasis and increase in the degree of incidence of severe, atypical and treatment-resistant clinical forms of psoriasis in the Russian Federation. In this regard, cases of early disability of patients and deterioration of their quality of life are recorded, which determines the medical and social significance of this disease. In the last few years, a much deeper understanding of the pathogenesis of psoriasis has been gained. This is especially true of the role of T-helper 17 cells, the role of the IL-23 cytokine in the development of the disease, which has resulted in the development of new classes of biological drugs, which creation introduced significant changes in the treatment of psoriasis that has become more effective, safer and convenient for patients. More new biologics undergo clinical trials and receive approvals with each passing year. Among them is risankizumab, interleukin-23 inhibitor, which is a safe and effective drug for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in adult patients. Interleukin-23 inhibitors are not required to be administered as often as interleukin-17 inhibitors and may have a more favourable safety profile without an increased risk of candidiasis or inflammatory bowel disease. Overall, these highly effective drugs contribute to the improvement of the long-term efficacy of psoriasis therapy due to relief of skin lesions and joint symptoms, as well as to the enhancement of patients’ quality of life and lengthening of remissions.Purpose. To analyse key information about risankizumab using the results of clinical trials published in the current scientific literature.Materials and methods. This analysis used literature sources from the international medical databases: PubMed, Cochrane Library, MEDLINE.Results. Presently, a number of phase III registrational trials of risankizumab in 2,109 patients with plaque psoriasis have been published: UltIMMa-1, UltIMMa-2, IMMvent and IMMhance, as well as an additional side by side comparative study of risankizumab with secukinumab (IMMerge) in 327 patients with plaque psoriasis. The results of these studies were used as the grounds for approval of risankizumab for the treatment of patients with moderate to severe plaque psoriasis and psoriatic arthritis by the Russian Ministry of Health on September 14, 2020. There have also been several reports of interim results of the open-label enhanced LIMMitless study, which included patients from pivotal studies. Our records show that the percentage of patients receiving risankizumab for 3 years (172 weeks) and maintaining PASI 90 and PASI 100 was 88 and 63%, respectively, and the percentage of those maintaining sPGA 0/1 was 88%.Conclusion. The analysed data showed that risankizumab is one of the most effective target drugs for the treatment of psoriasis and psoriatic arthritis, it has a favourable safety profile and a more convenient dosage regimen as compared with other genetically engineered biologic drugs (GEBD) (the recommended dose of Skyrizi is 150 mg (two 75 mg injections) administered by subcutaneous injection at week 0, week 4, and every 12 weeks thereafter).

Psoriasis is a chronic, inflammatory skin disease associated with cardiovascular comorbidities, metabolic syndrome, neoplasms, psychiatric impairment, and arthritis, among others, which affect patients’ quality of life, as well as their life expectancy. Even though it is a multifactorial process of unknown causes, its relationship to class 1 HLA alleles and their polymorphisms has been described. Its physiopathology involves a dysregulation of the systemic inflammatory response —mediated by T Helper lymphocytes, dermal cells, cytokines, and interleukins—, as well as their interactions with keratinocytes and synovial cells. This triggers differentiation of lymphocytes towards a Th 17 phenotype, which activates inflammatory processes mediated mainly by interleukin 17 (IL-17), with the subsequent proliferation of keratinocytes and inflammatory and angiogenic mediators, resulting in the typical cutaneous and osteoarticular clinical features. Biological agents are recombinant proteins produced in different cell lines aimed at interrupting inflammatory pathways in psoriasis and psoriatic arthritis, specifically, immune or genetic mediators involved in the progression of these diseases, ultimately targeting the IL-23 / IL-17 axis. This review aims to discuss the most recent literature regarding the use of small molecules, JAK inhibitors, and biological agents (IL-17 inhibitors) in the treatment of psoriasis and psoriatic arthritis, mainly referring to their efficacy and safety. Using these molecules means a fundamental change in the approach to patients with psoriasis and psoriatic arthritis. As a specific mediator-targeted therapy, it enhances effectiveness, and at the same time, reduces the associated adverse effects. Therefore, it is essential to know how they work from a physiopathological point of view, as well as assessing their effectiveness in humans through randomized clinical trials. Current knowledge allows us to conclude that despite biological agents being the best treatment option in psoriasis as well as in psoriatic arthritis, comparative studies —among drugs of the same group and groups— are still required. Besides, their high price is another problem to solve before they can be massively used in these patients.

This article deals with a immunological model, which includes multiple classes of T cells, namely, the naive T cell, type I, type II and type 17 T helper cells (Th1, Th2, Th17), regulatory T cell (Treg) along with the activated natural killer cells (NK cells) and epidermal keratinocytes. In order to describe the etiology of psoriasis development, we have studied the basic mathematical properties of the model, existence and stability of the interior equilibrium. We have also derived the drug-induced mathematical model using impulse differential equation to determine the effects of combined biologics Etanercept (TNF-α inhibitor) and Fezakinumab (IL-22 monoclonal antibody) therapy considering perfect dosing during the inductive phase. We have determined the required dosing interval of both drugs to maintain the keratinocytes concentration below a threshold level. This study shows that Etanercept alone could theoretically maintain the keratinocytes level, whereas frequent dosing of Fezakinumab alone may not be enough to control the hyper-proliferation of keratinocytes. Furthermore, combination of the drugs with perfect dosing has the noticeable effect on keratinocytes dynamics, which may be suitable therapeutic approaches for treatment of psoriasis.

The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

Background:A dysbalance between Th17 and regulatory T cells (Treg) has been suggested for several T cell-mediated autoimmune disorders. Inhibitors of IL-17 are successfully used for treatment of psoriasis arthritis (PsA). However, so far reconstitution of Treg functions has not been studied in detail in PsA eligible for switching to anti-IL-17 treatment.Objectives:The project aims to analyze the reconstitution and maintenance of regulatory T cell (Treg) function after inhibition of inflammatory Th17-inducing pathways mediated by IL-1, IL-6, IL-17 and TNFalpha in a longitudinal manner.Methods:Therefore, Treg derived from 12 PsA patients switching to Th17 inhibition and healthy controls were phenotypically characterized by flow cytometry. Function was investigated by analysis of suppressive activity of Treg on proliferation of autologous effector T cells in vitro utilizing suppression assays.Results:First results at the time-point of switching to anti-IL-17 treatment demonstrated PsA to be an IL-17-driven T cell-mediated autoimmune disorder, as proportions of T cells with Th17 phenotype were increased in PsA compared to controls (CCR6+IL-17 + 4.9% vs. 0.8% of CD4+) and FoxP3+ Treg cells (CD25brightFoxP3 + 0.2% vs. 0.4% of CD4+) were decreased. Higher proportions of FoxP3+ T cells expressing the Th17-characteristic chemokine receptor CCR6 were found in PsA (4.8% vs. 2.7% of CD4+), as well as higher proportions of pro-apoptotic CD95-expressing FoxP3+ T cells (9.8% vs. 2.8% of CD4+). Less suppression of autologous effector T cells co-cultured with CD25+ Treg cells was found in PsA compared to controls (22.2% vs. 28.3% reduction of proliferative activity), whereas CD25- helper T cells did not contribute to the suppression of effectors in PsA and only minimally in controls. Intracellular IL-10 production in Tregs, a key cytokine of Treg-associated regulation of inflammation, was similar between PsA and controls, although a trend to lower CTLA-4 expression involved in inhibition of co-stimulation was found in PsA.Conclusion:The current results indicate a skewed T cell balance towards Th17 cells and Treg cells showing Th17-like features in samples of PsA unsuccessfully pre-treated with different biologics recommending them for a switch to a therapy with selective inhibition of IL-17. Longitudinal results regarding the reconstitution and maintenance of Treg function in those PsA patients have to be awaited.Disclosure of Interests:Timotheos Christoforou: None declared, Giovanni Almanzar Grant/research support from: Pfizer, Franziska Brauneiser: None declared, Nils Buschmann: None declared, Martin Feuchtenberger Consultant of: Abbvie, BMS, Chugai, Sanofi, Speakers bureau: Abbvie, BMS, Celgene, Chugai, Jansen-Cilag, Lilly, Pfizer, Roche, Sanofi, UCB, Marc Schmalzing Consultant of: Paid consultant for Hexal AG, Hans-Peter Tony Consultant of: AbbVie, Astra-Zeneca, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, Matthias Goebeler: None declared, Martina Prelog Grant/research support from: Chugai, Sobi, Novartis, Pfizer, Baxter, Consultant of: GSK, Pfizer, Novartis, MSD, Baxter, Sobi, Johnson, Speakers bureau: GSK, Pfizer, Novartis, MSD, Baxter, Sobi, Johnson

Inflammatory bowel disease (IBD) and psoriasis are chronic inflammatory immune-mediated diseases. The interleukin-23- (IL23-) T helper (Th)17 pathway has been implicated in their pathogenesis, with multiple biologic therapies targeting this pathway. IL-17, the main proinflammatory cytokine produced by (TH)17, has been targeted by antibodies and IL-17 receptor blockers with favorable outcomes in treating psoriasis and psoriatic arthritis. However, their role in IBD is unpredictable as studies reported worsening of IBD with agents targeting IL-17 and rare case reports with new-onset IBD. We present a case of Crohn's-like severe terminal ileitis and worsening diverticulitis complicated by intestinal perforation requiring total parenteral nutrition shortly after being started on secukinumab.

CD4+effector cells, based on cytokine production, nuclear receptors and signaling pathways, have been categorized into four subsets. T-helper-1 cells produce IFN-γ, TNF-β, lymphotoxin and IL-10; T-helper-2 cells produce IL-4, IL-5, IL-10, IL-13, IL-21 and IL-31; T-helper-3, or regulatory T-cells, produce IL-10, TGF-βand IL-35; and the recently discovered T-helper-17 cell produces IL-17, IL-17A, IL-17F, IL-21, IL-26 and CCL20. By producing IL-17 and other signaling molecules, Th17 contributes to the pathogenesis of multiple autoimmune diseases including allergic inflammation, rheumatoid arthritis, autoimmune gastritis, inflammatory bowel disease, psoriasis and multiple sclerosis. In this article, we review the differential regulation of inflammation in different tissues with a major emphasis on enhancement of neuroinflammation by local production of IL-17 in the brain. By understanding the role of pathogenic factors in the induction of autoimmune diseases by Th17 cells, CAM practitioners will be able to design CAM therapies targeting Th17 and associated cytokine activities and signaling pathways to repair the intestinal and blood-brain barriers for their patients with autoimmunities, in particular, those with neuroinflammation and neurodegeneration.

Psoriasis is a chronic inflammatory disorder that is clinically characterized by scaly cutaneous plaques. New evidence suggests that dysregulation of interleukin (IL)-23, a key cytokine in the T-helper-17 pathway, plays a vital role in the development of psoriatic systemic inflammation. The novel biologic medication tildrakizumab is among the first drugs with specific action against IL-23 that has recently been approved by the United States Food and Drug Administration and the European Medicines Agency for moderate-to-severe psoriasis. Tildrakizumab has been shown in large randomized controlled trials to be effective in improving skin manifestations as well as enhancing quality of life outcomes in patients with psoriasis. Its simple dosing, prolonged duration of action, and mild adverse event profile make it a practical option for patients; however, only a small number of trials have investigated the clinical effectiveness of tildrakizumab, and long-term data regarding the drug’s efficacy and safety are currently limited. Hence, further research is needed to better understand the risks and benefits of tildrakizumab. This review summarizes and analyzes phase I, phase II, and phase III clinical trials that investigate the mechanism, pharmacokinetics, efficacy, and safety of tildrakizumab. It also identifies areas in which additional studies are warranted to further elucidate the advantages of tildrakizumab over other biologic therapies.