Anti IL-17A Research Articles

52433 The efficacy of Bimekizumab, an anti IL-17A/17F agent, in patients with moderate-severe plaque psoriasis who had failed others IL-17 inhibitors. Real life data from a Greek private office

52433 The efficacy of Bimekizumab, an anti IL-17A/17F agent, in patients with moderate-severe plaque psoriasis who had failed others IL-17 inhibitors. Real life data from a Greek private office

Paradoxical reaction to IL-17A inhibitor: a case report and literature review.

A case of pustular psoriasis after treatment with secukinumab in a patient with plaque psoriasis is reported, which is the first case in China. To summarize the clinical characteristics of patients who developed the rare paradoxical reaction and treatment options received IL-17A antagonist therapy, we conducted a further literature review. Data were analyzed from a patient with plaque psoriasis who developed pustular psoriasis after treatment with secukinumab. A comprehensive review of relevant domestic and international literature was conducted, focusing on cases that met our inclusion criteria for analysis and synthesis. Anti IL-17A therapy may lead to type conversion, with reported cases more prevalent in women and varying in onset time, predominantly involving palmoplantar pustulosis. Given the increasing use of IL-17A antagonists in psoriasis treatment, it is crucial to monitor for rare adverse reactions, including the paradoxical induction of pustular psoriasis.

Case report: Interleukin-17 targeted biological therapy in netherton syndrome

Netherton syndrome (NS) is rare and multisystemic congenital skin disorder classically distinguied as a triad of congenital ichthyosiform erythroderma, trichorrhexis invaginata (TI), and an atopic diathesis. Recent advances in pathogenesis have explored the role of IL-23/Th17 pathway in NS. Herein, we present a 17 years old girl harbouring homozygous four base pair deletion in exon 26 of the SPINK5 gene, presented with pruritus, scaling, dry skin and generalized eczematous lesions. She was administered anti IL17A (subcutaneous secukinumab) therapy. The treatment was well tolerated and resulted in a favourable clinical response, reduction of the IL17A gene expression and CD4 + Th17 cell population after 6 months which revealed an abrogation of Th17-skewing during therapy.

CARD14 Missense Variant Underlying CARD14-Associated Papulosquamous Eruption with Beneficial Response to Secukinumab

CARD14-associated papulosquamous eruption is an autosomal dominant genodermatosis characterized by early-onset, generalized erythematous patches and plaques with prominent scales, mostly with facial involvement. Heterozygous gain-of-function variants in the CARD14 gene have been reported to be causative for this entity. The pathogenesis mainly involves the IL-23‒IL-17 inflammatory circuit, yet the efficacy of anti‒IL-17 treatment remained less examined. In this study, we report one previously unidentified variant underlying the CARD14-associated papulosquamous eruption and showed its gain-of-function property. Furthermore, we present the beneficial effect of anti‒IL-17A treatment in our patient.

Staphylococcus aureus skin colonization promotes SLE-like autoimmune inflammation via neutrophil activation and the IL-23/IL-17 axis.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation of various organs such as skin, kidneys, bones, and brain and the presence of autoantibodies. Although the cause of SLE is not completely understood, environmental factors, genetic susceptibility, hormone factors, and environmental factors are thought to play essential roles in the pathogenesis of SLE. Among environmental factors, the microbiota are linked to the development of different autoimmune diseases. The microbiota in the nasal cavity and gut are involved in SLE development, but the influence of skin microbiota is still unclear. Here, we demonstrated that epithelial cell-specific IκBζ-deficient (NfkbizΔK5) mice showed spontaneous skin inflammation with increased abundance of Staphylococcus aureus on the skin. When S. aureus was epicutaneously applied on NfkbizΔK5 mice, NfkbizΔK5 mice developed SLE-associated autoantibodies, anti-dsDNA antibodies, anti-Sm antibodies, and glomerulonephritis with IgG deposition. Epicutaneous S. aureus application significantly increased staphylococcal colonization on the skin of NfkbizΔK5 mice with reduced expression of several antimicrobial peptides in the skin. This staphylococcal skin colonization promoted caspase-mediated keratinocyte apoptosis and neutrophil activation, inducing the interleukin-23 (IL-23)/IL-17 immune response by activating dendritic cells and T cells. Furthermore, the subcutaneous administration of anti-IL-23p19 and anti-IL-17A antibodies alleviated the systemic autoimmune response. Together, these findings underscore epithelial-immune cross-talk disturbances caused by skin dysbiosis as an essential mediator inducing autoimmune diseases.

Absence of NC14A Domain of COLXVII/BP180 in Mice Results in IL-17‒Associated Skin Inflammation

The deletion of exon 18 from Col17a1 in transgenic ΔNC14A mice results in the absence of the NC14Adomain. NC14A corresponds to the human NC16A domain, the immunodominant epitope in bullous pemphigoid. Before the age of 1 year, 84% of ΔNC14A mice have developed severe itch and skin erosion. Further characterization of mice with mutated CoLXVII (Bp180) revealed acanthosis; subepidermal blistering; and inflammatory cell infiltrates, especially neutrophils, eosinophils, and mast cells in the lesional skin. Direct immunofluorescence analysis detected linear complement C3, IgG, and/or IgA deposition in the dermo‒epidermal junction of symptomatic ΔNC14A mice. Elevated gene expression of IL-17‒associated cytokines was detected in the lesional skin. An increased proportion of dendritic cells, myeloid-derived suppressor cells, and NK cells and a decrease of T cells were found in both the spleen and lymph nodes of symptomatic ΔNC14A mice. The proportions of B cells and regulatory T cells were increased in lymph nodes. An 8-week treatment with an anti‒IL-17A decreased the expression of Il6, Il23a, and Cxcl1 in the nonlesional skin. Our results suggest that the absence of the NC14A domain of CoLXVII in mice causes an autoimmune response against the cutaneous basement membrane and manifests as an IL-17‒associated inflammation in the skin.

Defining the Molecular Landscape of Cancer-Associated Stroma in Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide. Cancer-associated stroma (CAS) is central to tumor development and strongly influences therapy response. Perineural infiltration (PNI) represents a major risk factor for cSCC and likely influences CAS reprogramming. However, stromal reprogramming in cSCC remains poorly characterized, and it is unknown whether and how PNI influences CAS. To address these questions, we analyzed CAS and matched normal stroma from 20 cSCC cases (11 without PNI and 9 with PNI) by laser-capture microdissection using RNA sequencing. Our analysis reveals extensive stromal reprogramming strongly driven by changes in immune cells, as validated using immunohistochemistry. Furthermore, CAS of cSCC displays markers of immune exhaustion, and multiplex spatial analysis suggests that PD-L1 expression on NK T cells contributes to T-cell exhaustion and immunosuppression. Finally, PNI is characterized by increased IL-17A. In PNI-negative cases, IL-17A derives predominantly from CD3+ cells. However, with PNI, we observe an increased contribution of fibroblasts to high IL-17A, which coincides with a significant increase in FAP+ cells. Our analysis elucidates the molecular landscape of CAS in cSCC and identifies the presence of immunosuppressive mechanisms, supporting further research into immunotherapy and anti‒IL-17A in cSCC, especially for cases with PNI.

2021 clinical practice guidelines for the diagnosis, treatment, and follow-up of patients with peripheral spondyloarthritis. Colombian Association of Rheumatology

BackgroundPeripheral spondyloarthritis is a chronic inflammatory disease in which clinical presentation is related to the presence of arthritis, enthesitis and/or dactylitis. This term is used interchangeably with some of its subtypes such as psoriatic arthritis, reactive arthritis, and undifferentiated spondyloarthritis. ObjectiveTo develop and formulate a set of specific recommendations based on the best available evidence for the diagnosis, treatment and monitoring of adult patients with peripheral spondyloarthritis. MethodsA working group was established, clinical questions were formulated, outcomes were graded, and a systematic search for evidence was conducted. The guideline panel was multidisciplinary (including patient representatives) and balanced. Following the formal expert consensus method, the GRADE methodology “Grading of Recommendations Assessment, Development and Evaluation” was used to assess the quality of the evidence and generate the recommendations. The Clinical Practice Guideline includes ten recommendations; related to monitoring of disease activity (n = 1) and treatment (n = 9). ResultsIn patients with peripheral spondyloarthritis, the use of methotrexate or sulfasalazine as the first line of treatment is suggested, and local injections of glucocorticoids is recommended conditionally. In patients with failure to cDMARDs, an anti TNFα or an anti IL17A is recommended. In case of failure to bDMARDs, it is suggested to use another bDMARD or JAK inhibitor. In patients with peripheral spondyloarthritis associated to inflammatory bowel disease, it is recommended to start treatment with cDMARDs; in the absence of response, the use of an anti TNFα over an anti-IL-17 or an anti-IL-12-23 is recommended as a second line of treatment. In patients with psoriatic arthritis, the combined use of methotrexate with bDMARD is conditionally recommended for optimization of dosing. To assess disease activity in Psoriatic Arthritis, the use of DAPSA or MDA is suggested for patient monitoring. ConclusionsThis set of recommendations provides an updated guide on the diagnosis and treatment of peripheral spondyloarthritis.

Disseminated mucocutaneous Candida infection during anti IL-17A therapy in a psoriatic patient.

article: Disseminated mucocutaneous Candida infection during anti IL-17A therapy in a psoriatic patient - Italian Journal of Dermatology and Venereology 2021 June;156(3):400-1 - Minerva Medica - Journals

Severe psoriatic arthritis patient being managed by anti IL-17A inhibition therapy in 108 Military Central Hospital

The article would like to introduce a psoriatic arthritis (PsA) patient in the Department of Rheumatology of 108 Military Central Hospital. This case of PsA had the secondary tuberculosis infection after Tumor necrotic factor inhibitor (TNFi) treatment, nevertheless the articular destruction caused by PsA still went on. The next management in these patients is always a controversy among the rheumatologists because the lack of international and national recommendation of management step-by-step. In addition, there were not many articles mentioning about this problem. After doctors-patient discussion, patient decided to be administered with Interleukin 17A inhibitor (IL-17Ai) (four doses secukinumab 300mg SC) plus methotrexate, then the disease remission (Minimal disease activity) was achieved without burden of tuberculosis. This success could contribute to the clinical experiences of biologic therapy in patients with severe side effects of TNFi treatment which becomes the more and more popular and causing many difficulties for clinicians.

Deletion of S100a8 and S100a9 Enhances Skin Hyperplasia and Promotes the Th17 Response in Imiquimod-Induced Psoriasis.

High concentrations of the damage-associated molecular patterns S100A8 and S100A9 are found in skin and serum from patients suffering from psoriasis, an IL-17-related disease. Notably, although the expression of these proteins correlates with psoriatic disease severity, the exact function of S100A8 and S100A9 in psoriasis pathogenesis remains unclear. In this study, we investigated the role of S100A8 and S100A9 in psoriasis-associated skin hyperplasia and immune responses using S100a8-/- and S100a9-/- mice in an imiquimod-induced model of psoriasis. We found that S100a8-/- and S100a9-/- psoriatic mice exhibit worsened clinical symptoms relative to wild-type mice and increased expression of S100A9 and S100A8 proteins in keratinocytes, respectively. In addition, the loss of S100A8 enhances proliferation of keratinocytes and disrupts keratinocyte differentiation. We further detected elevated production of IL-17A and -F from CD4+ T cells in the absence of S100A8 and S100A9, as well as increased infiltration of neutrophils in the skin. In addition, treatment with anti-IL-17A and -F was found to reduce psoriasis symptoms and skin hyperplasia in S100a8-/- and S100a9-/- mice. These data suggest that S100A8 and S100A9 regulate psoriasis by inhibiting production of IL-17A and -F, thereby, to our knowledge, providing new insights into their biological functions.

Active implications for dermatologists in 'SARS-CoV-2 ERA': Personal experience and review of literature.

Linked articles: COVID‐19 SPECIAL FORUM. J Eur Acad Dermatol Venereol 2020; 34: e346–e380.

IL-17A inhibitions of indole alkaloids from traditional Chinese medicine Qing Dai

Ethnopharmacological relevanceQing Dai, a famous traditional Chinese medicine (TCM), is prepared by a traditional fermentation process with the aerial part of Strobilanthes cusia. Currently, this TCM could treat various clinical inflammatory diseases, such as ulcerative colitis and psoriasis, however, the bioactive components of Qing Dai are unknown clearly. Aim of the studyTo isolate and identify the anti-IL-17A components of Qing Dai. Materials and methodsSilica, RP-18 gels, and size exclusion resin were used for column chromatography to isolate the pure compounds. The structures of isolates were elucidated by NMR, MS, UV, IR spectra, and optical rotation. IL-17A protein and gene expressions were also evaluated in the Th17 cell model and luciferase reporter assay, respectively. ResultsTwo indole alkaloids, including one new indigodole D and cephalandole B, were isolated from Qing Dai. Indigodole D could inhibit IL-17A protein production during the Th17 polarization (EC50: 2.16 μg/mL) or after the polarization (EC50: 5.99 μg/mL) without cytotoxicity toward Th17 cells. Cephalandole B did not inhibit the IL-17A protein secretion. Nevertheless, both isolates notably inhibited IL-17A gene expression, especially cephalandole B, in a dose-dependent manner in Jukat cells with IL-17A luciferase reporter. ConclusionsIndole alkaloids, indigodoles A, C, D, tryptanthrin, and indirubin could contribute to anti-IL 17A properties of Qing Dai. The possible biogenetic mechanisms of above-mentioned indoles were also speculated in this investigation for further promising anti-IL-17 lead drugs development.

Clinical and histopathological characterization of eczematous eruptions occurring in course of anti IL-17 treatment: a case series and review of the literature

ABSTRACTBackground: Real-life data often highlight the side effects of certain drugs not previously reported in randomized controlled trials (RCTs).Objective: To describe cutaneous inflammatory eruptions in psoriatic patients treated with an anti IL-17A agent (secukinumab or ixekizumab).Methods: Retrospective analysis of a cohort of patients with chronic plaque psoriasis who started an anti IL-17A agent between September 2016-February 2019 and who developed cutaneous inflammatory eruptions during treatment. A systematic review of similar events reported in the literature was performed.Results: Data of 468 patients were reviewed and 27 cutaneous inflammatory eruptions of 27 (5.8%) patients were collected. The eruptions appeared after a mean of 16.9 ± 17.0 weeks of therapy showing a classical acute eczema in 11 patients (40.7%), an atopic dermatitis-like rash in 11 patients (40.7%) and a psoriasiform eruption in 5 patients (18.5%). Histopathology of 12/27 cases showed epidermal spongiosis in all these variants.Conclusion: We described the clinic-pathologic features of some eczematous eruptions occurring in psoriatic patients, 3–4 months after treatment initiation with an anti IL-17A agent. Further investigations are needed to explain this phenomenon, that might be defined a paradoxical adverse event, based upon the role of IL17 in eczema pathogenesis.

Neurokinin-1 Receptor Antagonism Ameliorates Dry Eye Disease by Inhibiting Antigen-Presenting Cell Maturation and T Helper 17 Cell Activation

Neuroinflammation plays an important role in the pathogenesis of ocular surface disease, including dry eye disease (DED), but little is known about the contribution of substance P (SP) to DED. In this study, we investigated the expression of SP at the ocular surface and evaluated its effect on maturation of antigen-presenting cells (APCs), the key cell component involved in the induction of type 17 helper T-cell (Th17) response in DED. The effect of topical blockade of SP signaling was further investigated using neurokinin-1 receptor (NK1R) inhibitors on APC maturation, Th17 cell activation, and disease severity in a mouse model of DED. The results demonstrate that SP is constitutively expressed at the ocular surface, and trigeminal ganglion neurons are the major source of SP in DED. SP derived from trigeminal ganglion enhanced the expression of major histocompatibility complex class II maturation marker by bone marrow-derived dendritic cells, an effect that is abrogated by blockade of SP signaling using NK1R antagonist spantide. Finally, using a well-established murine model of DED, topical treatment of DED mice with NK1R antagonists CP-99,994 and L-733,060 suppressed APC acquisition of major histocompatibility complex class II, reduced Th17 cell activity, and ameliorated DED severity. These findings are of translational value, as they suggest that antagonizing NK1R-mediated SP signaling may be an effective strategy in suppressing Th17-mediated ocular surface disease.

IL-17A induces osteoblast differentiation by activating JAK2/STAT3 in ankylosing spondylitis

BackgroundIL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS.MethodsTNFα, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS.ResultsBasal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events.ConclusionsOur findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.

IL-17A Produced by Innate Lymphoid Cells Is Essential for Intestinal Ischemia-Reperfusion Injury.

Ischemia-reperfusion (IR) injury to the small intestine following clamping of the superior mesenteric artery results in an intense local inflammatory response that is characterized by villous damage and neutrophil infiltration. IL-17A, a cytokine produced by a variety of cells in response to inflammatory cytokines released following tissue injury, has been implicated in IR injury. Using Il17a-/- , Il23r-/- , and Rorc-/- mice and administration of anti-IL-17A and anti-IL-23 neutralizing Abs to wild-type mice, we demonstrate that intestinal IR injury depends on IL-17A and that IL-17A is downstream of the binding of autoantibody to ischemia-conditioned tissues and subsequent complement activation. Using bone marrow chimeras, we demonstrate that the IL-17A required for intestinal IR injury is derived from hematopoietic cells. Finally, by transferring autoantibody-rich sera into Rag2γc-/- and Rag2-/- mice, we demonstrate that innate lymphoid cells are the main producers of IL-17A in intestinal IR injury. We propose that local production of IL-17A by innate lymphoid cells is crucial for the development of intestinal IR injury and may provide a therapeutic target for clinical exploitation.

A combination of dexamethasone and anti–IL-17A treatment can alleviate diesel exhaust particle–induced steroid insensitive asthma

A combination of dexamethasone and anti–IL-17A treatment can alleviate diesel exhaust particle–induced steroid insensitive asthma

Secukinumab, a new anti–il-17a biologic therapy, induces rapid clinical, histologic, and molecular resolution of psoriasis while preserving full T cell activation potential

Secukinumab, a new anti–il-17a biologic therapy, induces rapid clinical, histologic, and molecular resolution of psoriasis while preserving full T cell activation potential

Ixekizumab, a novel anti–IL-17A antibody, exhibits low immunogenicity during long-term treatment in patients with psoriasis

388 Ixekizumab, a novel anti-IL-17A antibody, exhibits low immunogenicity during long-term treatment in patients with psoriasis A Blauvelt, R Langley, C Leonardi, K Gordon, T Luger, M Ohtsuki, B Nickoloff, L Kerr, L Mallbris and K Reich 1 Oregon Medical Research Center, Portland, OR, 2 Dalhousie University, Halifax, NS, Canada, 3 Saint Louis University, St. Louis, MO, 4 Northwestern University Feinberg School of Medicine, St. Louis, MO, 5 University of Munster, Munster, Germany, 6 Jichi Medical University, Shimotsuke, Japan, 7 Eli Lilly and Company, Indianapolis, IN and 8 Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany The potential association of treatment-emergent anti-drug antibodies (TE-ADAs) with efficacy and safety in patients treated with ixekizumab (IXE), a high binding affinity monoclonal antibody that selectively targets interleukin-17A, was evaluated. TE-ADAs were evaluated in patients randomized to 80 mg IXE either every 2 weeks (IXE Q2W; N1⁄41150) or 4 weeks (IXE Q4W; N1⁄41143) for up to 12 weeks following a 160-mg starting dose. IXE responders at Week 12 were re-randomized to IXE Q4W (N1⁄4397) or IXE Q12W (N1⁄4382) until Week 60. A highaffinity capture elution screening assay was used to assess ADA serum trough levels. Serum TE-ADAs were divided into four titer groups (negative, low, moderate, and high). At 12 weeks, the majority of patients were TE-ADA negative (IXE Q2W: 91.0%; IXE Q4W: 86.6%). TE-ADE titers at 12 weeks for IXE Q2W and IXE Q4W patients were, respectively, 5.7% and 8.0% (low), 1.6% and 3.0% (moderate), and 1.7% and 2.4% (high). IXE Q2W patients with high TEADA titers had reduced PASI responses versus TE-ADA negative patients; 12-week mean percent PASI improvement was 91.7% (negative), 85.7% (low), 88.7% (moderate), and 53.5% (high); 12-week PASI 75 response rates were 90.7% (negative), 84.8% (low), 83.3% (moderate), and 36.8% (high). Mean percent improvement from baseline to 60 weeks PASI was 94.3% (negative), 97.0% (low), and 100% (moderate) for TE-ADA titer patients. IXE Q4W data were similar. No safety findings were correlated to TE-ADAs. TE-ADA levels in IXE patients did not affect maintenance of response and safety up to 60 weeks among initial IXE responders. 389 The extravesicular miRNome of senescent human fibroblasts and its impact on keratinocyte functionality L Terlecki-Zaniewicz, V Pils, J Schwestka, J Latreille, I Lammermann, R Weinmullner, I Berlin, M Hackl, F Morizot and J Grillari 1 Dept. of Biotechnology, BOKU University Vienna, Austria, Christian Doppler Laboratory for Biotechnology of Skin Aging, Vienna, Austria, 2 CE.R.I.E.S. (Research Centre on Human Skin of CHANEL), Neuilly sur Seine, France and 3 TAmiRNA GmbH, Vienna, Austria In aged skin up to 25% of senescent cells are present and supposed to impair tissue homeostasis and regeneration resulting in a gradual loss of juvenile appearance and functionality, while transiently the presence of senescent cells might be beneficial for cutaneous wound healing. The senescence associated secretory phenotype (SASP) is one pivotal hallmark of senescent cells, whereby proinflammtory cytokines, chemokines and metalloproteases are secreted and alter the tissue microenvironment. Recently, micro RNAs (miRNAs) packaged into extracellular vesicles (EV) have been found as part of SASP (miRSASP). Here, we report the identification of EV-miRNAs as part of the human dermal skin fibroblasts’ SASP. For this purpose, stress induced premature senescence was triggered by repeated low doses of H2O2 in cells of 3 donors and EV of senescent and control cells were harvested by ultracentrifugation for miRNomics and functional biological studies. We identified differentially secreted miRNAs by qPCR arrays and correlated their extracellular and intracellular abundance. Based on that, we have confirmed selected prominent, highly secreted miRNAs to be more abundant in EVs of senescent cells. Furthermore, by nanoparticle tracking analysis we observed that senescent fibroblasts secrete more vesicles than controls. In order to test if EV-miRNAs might be part of a paracrine cross-talk between dermal fibroblasts and epidermal keratinocytes, we confirmed uptake of cel-miR-39 enclosed in fibroblast derived EV by keratinocytes in monolayers and in full thickness skin-equivalents. To summarize, our data indicate that extravesicular miRNAs of senescent fibroblasts are bona fide members of the SASP and that they contribute to the communication between fibroblasts and keratinocytes in 2D and 3D human skin models.