Explore the vast range of titles available.

Interleukin-17 (IL-17) is an essential proinflammatory cytokine, which is mainly secreted by the CD4 helper T cells (Th17 cells) and subsets of innate lymphoid cells. IL-17A is associated with the pathogenesis of inflammatory diseases, including psoriasis, atopic dermatitis, hidradenitis suppurativa, alopecia areata, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Interleukin-23 (IL-23) plays a pivotal role in stimulating the production of IL-17 by activating the Th17 cells. The IL-23/IL-17 axis is an important pathway for targeted therapy for inflammatory diseases. Emerging evidence from clinical trials has shown that monoclonal antibodies against IL-23, IL-17, and tumor necrosis factor are effective in the treatment of patients with psoriasis, atopic dermatitis, hidradenitis suppurativa, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Here, we summarize the latest knowledge about the biology, signaling, and pathophysiological functions of the IL-23/IL-17 axis in inflammatory skin diseases. The currently available biologics targeting the axis is also discussed.

Interleukin-23 (IL-23) is a pro-inflammatory cytokine composed of two subunits, IL-23A (p19) and IL-12/23B (p40), the latter shared with Interleukin-12 (IL-12). IL-23 is mainly produced by macrophages and dendritic cells, in response to exogenous or endogenous signals, and drives the differentiation and activation of T helper 17 (Th17) cells with subsequent production of IL-17A, IL-17F, IL-6, IL-22, and tumor necrosis factor α (TNF-α). Although IL-23 plays a pivotal role in the protective immune response to bacterial and fungal infections, its dysregulation has been shown to exacerbate chronic immune-mediated inflammation. Well-established experimental data support the concept that IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as PsA, Psoriasis, Psoriatic Arthritis; AS, Ankylosing Spondylitis; IBD, Inflammatory Bowel Disease; RA, Rheumatoid Arthritis; SS, Sjogren Syndrome; MS, Multiple Sclerosis. As a result, emerging clinical studies have focused on the blockade of this pathogenic axis as a promising therapeutic target in several autoimmune disorders; nevertheless, a greater understanding of its contribution still requires further investigation. This review aims to elucidate the most recent studies and literature data on the pathogenetic role of IL-23 and Th17 cells in inflammatory rheumatic diseases.

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by erythematous plaques covered with silvery-white scales, often accompanied by systemic complications such as psoriatic arthritis and cardiovascular diseases. The disease and its systemic complications substantially impair quality of life, compromise socioeconomic status, and threaten patient safety. The occurrence and progression of this disease are related to the IL-23/IL-17 axis and involve the aberrant activation and interactions of multiple immune cells, along with genetic predispositions and environmental triggers. Although current therapeutic approaches, including topical agents, systemic medications, biologic agents targeting key cytokines, and Janus Kinase inhibitors, can control symptoms and delay disease progression, a complete cure has not been achieved. Furthermore, these strategies face challenges relating to the cost, safety, efficacy and precision of targeting. This review summarizes recent advances in mechanistic research, highlighting the interplay among microorganisms, innate and adaptive immunity in psoriasis. We also evaluate a range of emerging therapies, including biologics, small-molecule inhibitors, Chimeric antigen receptor T-cell cell therapy, RNA interference-based strategies, and alternative medicine. Specifically, we focus on their novel mechanisms, efficacy challenges, safety profiles, and targeting accuracy. Finally, we assess their potential in personalized treatment, aiming to achieve long-term remission, and propose the future prospects of precision medicine in psoriasis management.

Psoriasis is a chronic, systemic, immune-mediated inflammatory disorder that is associated with a significantly increased risk of cardiovascular disease (CVD). Studies have shown that psoriasis often coexists with atherosclerosis, a chronic inflammatory disease of large and medium-sized arteries, which is a major cause of CVD. Although the molecular mechanisms underlying this comorbidity are not fully understood, clinical studies have shown that when interleukin (IL)-17A inhibitors effectively improve psoriatic lesions, atherosclerotic symptoms are also ameliorated in patients with both psoriasis and atherosclerosis. Also, IL-17A levels are highly expressed in the psoriatic lesions and atherosclerotic plaques. These clinical observations implicit that IL-17A could be a crucial link for psoriasis and atherosclerosis and IL-17A-induced inflammatory responses are the major contribution to the pathogenesis of comorbid psoriasis and atherosclerosis. In this review, the current literature related to epidemiology, genetic predisposition, and inflammatory mechanisms of comorbidity of psoriasis and atherosclerosis is summarized. We focus on the immunopathological effects of IL-17A in both diseases. The goal of this review is to provide the theoretical base for future preventing or treating psoriasis patients with atherosclerosis comorbidity. The current evidence support the notion that treatments targeting IL-17 seem to be hold some promise to reduce cardiovascular risk in patients with psoriasis.

Sex-bias is more obvious in several autoimmune disorders, but not in psoriasis. However, estrogen levels fluctuate during puberty, menstrual cycle, pregnancy, and menopause, which are related to variations in psoriasis symptoms observed in female patients. Estrogen has disease promoting or ameliorating functions based on the type of immune responses and tissues involved. To investigate the effects of estrogen on psoriasis, at first, we developed an innate immunity dependent mannan-induced psoriasis model, which showed a clear female preponderance in disease severity in several mouse strains. Next, we investigated the effects of endogenous and exogenous estrogen using ovariectomy and sham operated mice. 17-β-estradiol (E2) alone promoted the skin inflammation and it also significantly enhanced mannan-induced skin inflammation. We also observed a prominent estrogen receptor-β (ER-β) expression in the skin samples, especially on keratinocytes. Subsequently, we confirmed the effects of E2 on psoriasis using ER-β antagonist (PHTPP) and agonist (DPN). In addition, estrogen was found to affect the expression of certain genes ( vgll3 and cebpb ), microRNAs (miR146a and miR21), and immune cells (DCs and γδ T cells) as well as chemokines (CCL5 and CXCL10) and cytokines (TNF-α, IL-6, IL-22, IL-23, and IL-17 family), which promoted the skin inflammation. Thus, we demonstrate a pathogenic role for 17-β-estradiol in promoting skin inflammation, which should be considered while designing new treatment strategies for psoriasis patients.

Heritability of Spondyloarthritis (SpA) is highlighted by several familial studies and a high association with the presence of human leukocyte antigen (HLA)-B * 27. Though it has been over four decades since the association of HLA-B * 27 with SpA was first determined, the pathophysiological roles played by specific HLA-B * 27 allotypes are not fully understood. Popular hypotheses include the presentation of arthritogenic peptides, triggering of endoplasmic reticulum (ER) stress by misfolded HLA-B * 27, and the interaction between free heavy chains or heavy chain homodimers of HLA-B * 27 and immune receptors to drive IL-17 responses. Several non-HLA susceptibility loci have also been identified for SpA, including endoplasmic reticulum aminopeptidases (ERAP) and those related to the IL-23/IL-17 axes. In this review, we summarize clinical aspects of SpA including known characteristics of gut inflammation, enthesitis and new bone formation and the existing models for understanding the association of HLA-B * 27 with disease pathogenesis. We also examine newer insights into the biology of HLA class I (HLA-I) proteins and their implications for expanding our understanding of HLA-B * 27 contributions to SpA pathogenesis.

Recently, a major single nucleotide variant on the NCF1 gene, leading to an amino acid replacement from arginine to histidine at position 90 (NCF1[sup.R90H]), associated with low production of reactive oxygen species (ROS), was found to be causative for several autoimmune diseases. Psoriasis in the skin (PsO) and psoriatic arthritis (PsA) were induced with mannan by intraperitoneal injection or epicutaneous application, evaluated by visual and histology scoring. Immunostaining was used to identify macrophages, NCF1, and keratinocytes. The population of immune cells was quantified by flow cytometry, gene expression was analyzed by RT-qPCR, and the JAK/STAT signaling pathway was investigated by immunohistochemical staining and western blot. We found that the low ROS responder NCF1[sup.90H] variant promotes PsO and PsA (the MIP model). The NCF1[sup.90H]-expressing mice had hyperactivated macrophages, expanded keratinocytes, and dramatically increased numbers of γδT17 cells with upregulated IL-17A, IL-23, and TNF-α. In addition, the JAK1/STAT3 signaling pathway was also upregulated in cells in the psoriatic skin tissues of Ncf190H mice. To summarize, a defined SNP (NCF1-339, also named NCF1[sup.90H]) was found to activate the IL-23/IL-17 axis and JAK-STAT signaling pathways, leading to hyperactivation of macrophages and keratinocytes and causing mouse psoriasis and psoriatic arthritis.

In inflammatory rheumatic disorders, the immune system attacks and damages the connective tissues and invariably internal organs. During the past decade, remarkable advances having been made towards our understanding on the cellular and molecular mechanisms involved in rheumatic diseases. The discovery of IL-23/IL-17 axis and the delineation of its important role in the inflammation led to the introduction of many needed new therapeutic tools. We will present an overview of the rationale for targeting therapeutically the IL-23/IL-17 axis in rheumatic diseases and the clinical benefit which has been realized so far. Finally, we will discuss the complex interrelationship between IL-23 and IL-17 and the possible uncoupling in certain disease settings.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear. Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients. Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR). Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis. Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway.

Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically “predictive”: the expected response is based on stratification according to clinical, imaging, and laboratory data, with a “heuristic” approach based on “trial and error”. Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially “broad-spectrum” mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g., TNF-α or the IL-23/IL-17 axis) could result in discordant effects over other approaches. In particular, in the case of “refractory to a treatment” patients, other pathways might be hyperactivated, with opposing, synergistic, or redundant biological significance. On the contrary, refractory states could be purely resistant to treatment as a whole. Since chronic synovitis is one of the primary targets of inflammation in PsA, synovial biomarkers could be useful in depicting specific biological characteristics of the inflammatory burden at the single-patient level, and despite not yet being implemented in clinical practice, these biomarkers might help in selecting the proper treatment. In this narrative review, we will provide an up-to-date overview of the knowledge in the field of psoriatic synovitis regarding studies investigating the relationships among different activated proinflammatory processes suitable for targeting by different available drugs. The final objective is to clarify the state of the art in the field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules toward a patient-centered approach.