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Targeted therapies. Mechanism of action of the latest approved or in-development molecules for the treatment of PsA. Interleukin 17 (IL-17) and isoforms IL-17A/F/E and IL17 receptor (IL-17R); janus kinase 1, 2, 3 (JAK1, JAK2, JAK3) and tyrosine kinase 2 (TYK2).
Source publication
Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory immune-mediated disease characterized by musculoskeletal inflammation (arthritis, enthesitis, spondylitis, and dactylitis), generally occurs in patients with psoriasis. PsA is also associated with uveitis and inflammatory bowel disease (Crohn’s disease and ulcerative colitis). To captu...
Contexts in source publication
Context 1
... the inhibition of JAK can inhibit/reduce the signaling effects of multiple cytokines and growth factor on targeted cells. Figure 2 describes the main immune-inflammatory pathways and their targeted therapies, which we review below. ...
Context 2
... the inhibition of JAK can inhibit/reduce the signaling effects of multiple cytokines and growth factor on targeted cells. Figure 2 describes the main immune-inflammatory pathways and their targeted therapies, which we review below. (IL-17R); janus kinase 1, 2, 3 (JAK1, JAK2, JAK3) and tyrosine kinase 2 (TYK2). ...
Context 3
... the other hand, a variety of innate cells, including MAIT, ILC3, iNKT, and γδ T cells, can produce IL-17 in an IL-23-independent manner [146,147], implicating them in disease pathogenesis. These observations could explain the differential response seen with IL-23 and IL-17A inhibitors (IL-23i, IL-17i) in clinical trials in axSpA [142][143][144]. The effectiveness of IL-23i in axial PsA (axPsA) has been explored in a post-hoc analysis of the DISCOVER trials, where patients with axial involvement assessed by the clinician and the presence of sacroiliitis on magnetic resonance imaging (MRI) were evaluated, suggesting that this target might be effective in axPsA [148]. ...
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Citations
... Patients with psoriasis have numerous associated manifestations, among which, in this work, we will address psoriatic arthritis and cardiovascular diseases. Psoriatic arthritis can occur in up to 30% of patients with psoriasis [9], particularly in severe cases or those involving the nails or scalp. This chronic inflammatory condition significantly affects the joints, mainly generating arthritis, spondylitis, enthesitis, and dactylitis, which can cause joint deterioration and consequent disability. ...
... This chronic inflammatory condition significantly affects the joints, mainly generating arthritis, spondylitis, enthesitis, and dactylitis, which can cause joint deterioration and consequent disability. It has been seen that patients who present with psoriasis or psoriatic arthritis are at a higher risk of developing extra-musculoskeletal inflammation and other comorbidities, such as metabolic syndrome and cardiovascular diseases [9] with a higher prevalence and mortality due to cardiovascular disease due to various mechanisms that we will explain below. Although there is evidence that these patients develop modifiable cardiovascular risk factors (such as hypertension, diabetes, hyperlipidemia, and nonalcoholic fatty liver), psoriasis is still considered an independent cardiovascular risk factor [10]. ...
... The pathogenesis of the disease is not entirely elucidated due to its heterogeneity, both in terms of the tissues and pathways involved, as well as its clinical manifestations ( Figure 2). Its pathogenesis begins with a genetic predisposition associated with triggers such as cutaneous changes or biomechanical stress, which, through Damage-Associated Molecular Patterns (DAMPs) and Pathogen-Associated Molecular Patterns (PAMPs), activate Toll-Like Receptors (TLRs) on dendritic cells and macrophages to present their antigens via Major Histocompatibility Complex I (MHC I) to T cells, mainly CD8, stimulating the release of various pro-inflammatory cytokines that activate Th1 and Th17 [9]. This leads, as mentioned above, to the release of various molecules, among which we highlight IL-17, IL-22, and TNF-α, which further release pro-inflammatory cells and attract chondrocytes, synovial fibroblasts, osteoclasts, endothelial cells, and keratinocytes [9]. ...
Psoriasis is a chronic inflammatory condition affecting 2% of the Western population. It includes diverse manifestations influenced by genetic predisposition, environmental factors, and immune status. The sustained activation of mTOR is a key element in psoriasis pathogenesis, leading to an uncontrolled proliferation of cytokines. Furthermore, mTOR activation has been linked with the transition from psoriasis to non-skin manifestations such as psoriatic arthritis and cardiovascular events. While therapies targeting pro-inflammatory cytokines have shown efficacy, additional pathways may offer therapeutic potential. The PI3K/Akt/mTOR pathway, known for its role in cell growth, proliferation, and metabolism, has emerged as a potential therapeutic target in psoriasis. This review explores the relevance of mTOR in psoriasis pathophysiology, focusing on its involvement in cutaneous and atheromatous plaque proliferation, psoriatic arthritis, and cardiovascular disease. The activation of mTOR promotes keratinocyte and synovial cell proliferation, contributing to plaque formation and joint inflammation. Moreover, mTOR activation may exacerbate the cardiovascular risk by promoting pro-inflammatory cytokine production and dysregulation lipid and glucose metabolism. The inhibition of mTOR has shown promise in preclinical studies, reducing skin inflammation and plaque proliferation. Furthermore, mTOR inhibition may mitigate cardiovascular risk by modulating cholesterol metabolism and attenuating atherosclerosis progression. Understanding the role of mTOR in psoriasis, psoriatic arthritis, and cardiovascular disease provides insight into the potential treatment avenues and sheds light on the complex interplay of the immune and metabolic pathways in these conditions.
... About 30-50% of patients with psoriasis are diagnosed as having psoriatic arthritis (PsA) because of coexistent clinical musculoskeletal manifestations [1][2][3]. PsA is characterized by enthesitis, which is the inflammation of the entheses located on tendons or ligament insertion to a bone [4]. Additionally, inflammation of a joint (arthritis), finger (dactylitis), and spine (spondylitis) are common manifestations of enthesitis. ...
Background: Psoriatic arthritis (PsA) is characterized by enthesitis. As persistent inflammation around joints results in bone and cartilage destruction and physical impairment, a detailed assessment of inflammation is essential. We previously reported the difference between clinical assessment (tenderness) and ultrasound (US) assessment (inflammation) of entheses. Herein, we investigated whether clinical or US assessment of joints and entheses can predict the progression of joint destruction in Japanese patients with PsA. Methods: Thirty joints and 14 entheses in 47 patients were assessed using US and clinical examination. The US greyscale (GS) and power Doppler (PD) scores at the ultrasonographic synovitis, the US active enthesitis count, and the clinical tender joint/entheses count were assessed. Additionally, the yearly radiographic progression of the Sharp–van der Heijde scoring method for PsA was assessed. Their correlations were investigated. Results: About half of the patients with PsA experienced joint destruction during a follow-up period of 20.4 months. Progression of joint destruction in patients with PsA only correlated with joint GS and PD scores, reflecting the severity of ultrasonographic synovitis, not with the tender joint/entheses count. Conclusions: US examinations are essential for preventing joint destruction and physical impairment in patients with PsA.
... This results in a local production of pro-inflammatory cytokines by activating the innate and adaptive immune response. The released cytokines stimulate their transmembrane receptors, which causes a constant increase in their level and stimulates the migration of endothelial cells, fibroblasts, macrophages, dendritic cells, epithelial cells, keratinocytes, chondrocytes, osteoclasts, and osteoblasts, leading to enthesitis, synovium, and damage to articular cartilage and skin [16]. ...
Introduction: JAK inhibitors are used in the treatment of psoriatic arthritis when there is a lack of effective response or intolerance to first-line drugs or their use must be discontinued due to the presence of side effects. JAK inhibitors inhibit the JAK-STAT signaling pathway which plays a significant role in the pathogenesis of many inflammatory and autoimmune diseases. This mechanism leads to a reduction in the level of pro-inflammatory cytokines which causes rapid improvement in the patient's clinical condition. Tofacitinib is the best-known drug in this group; its use carries an increased risk of cardiovascular events and reactivation of the varicella-zoster virus. Regular monitoring of patients results in faster detection of the first signs of undesirable effects and the cessation of their progression. The drug's safety profile is acceptable and the benefits outweigh possible complications. Aim of the study: The aim of the study is to summarize the available knowledge about tofacitinib treatment in psoriatic arthritis. The way of work, effectiveness of treatment and potential side effects were summarized and described. Materials and methods: The literature available in PubMed database was reviewed using the following keywords: “Psoriatic arthritis”, “Tofacitinib”, “JAK inhibitors”, “JAK-STAT” Conclusion: Tofacitinib treatment in rheumatology is used in psoriatic arthritis. The rapid improvement in the clinical condition of patients treated with JAK inhibitors is due to their direct impact on the modulation of the pathogenesis of the disease. The predictable benefits of therapy outweigh the side effects which can be detected at an early stage with regular monitoring of the patient.
... Psoriatic arthritis (PsA) is a heterogeneous condition characterized by several distinct manifestations that can be present with varying degrees of severity simultaneously, posing challenges to both diagnosis and monitoring. Moreover, the different patterns of involvement of PsA can mimic other inflammatory arthritis, making thorough investigation crucial [1]. Peripheral joint disease includes polyarticular, oligoarticular, distal, and mutilans subtypes. ...
... Recognizing these patterns is necessary for the prompt diagnosis of PsA [2]. Once diagnosed, it is essential to conduct a comprehensive assessment of the disease, encompassing arthritis, enthesitis, dactylitis, skin and nail disease, and axial involvement [1]. Additionally, research indicates a pre-diagnostic phase in psoriasis (PsO) patients, marked by nonspecific musculoskeletal symptoms, preceding PsA onset [3], and there are no current biomarkers that allow for the early detection of the disease. ...
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis, characterized by heterogeneous clinical manifestations and variable disease progression. Ultrasonography has emerged as a valuable tool in the diagnosis and monitoring of PsA, providing real-time visualization of joint and soft tissue abnormalities. This review highlights recent advancements in ultrasonographic techniques for the assessment of PsA, including the identification of typical features, the role of power Doppler imaging in detecting active inflammation, and the potential of ultrasound for guiding treatment decisions. Additionally, we discuss the utility of ultrasound in assessing treatment response and monitoring disease progression in patients with PsA, with a focus on novel imaging modalities. By elucidating the evolving role of ultrasonography in PsA management, this article aims to enhance clinicians’ understanding of its utility in facilitating early diagnosis, optimizing treatment strategies, and improving patient outcomes.
... The interplay among different immune cell types triggers the secretion of diverse cytokines, including IL-23, TNF-α, IL-17, and IL-22, and these cytokines play pivotal roles in fostering inflammation and activating resident cells within joint and enthesis tissues [11]. These cells, which include fibroblast-like synoviocytes, chondrocytes, osteoblasts, and osteoclasts, cause cartilage degradation, bone erosion, and joint destruction [12]. ...
Background: Delay in diagnosis and therapy in patients with arthritis commonly leads to progressive articular damage. The study aimed to investigate the immunohistochemical reactivity of synovial cytokines associated with inflammation and the bone erosives/neoformatives processes among individuals diagnosed with psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), and radiographic axial spondyloarthritis (r-axSpA), with the intention of identifying potential biomarkers. Methods: Specimens were collected from the inflamed knee joints of patients referred for arthroscopic procedures, and the synovial tissue (ST) was prepared for quantifying protein expression through immunohistochemical analysis (% expressed in Ratio_Area-Intensity) for TGF-β1, IL-17A, Dkk1, BMP2, BMP4, and Wnt5b. The collected data underwent thorough analysis and examination of their predictive capabilities utilising receiver operating characteristic (ROC) curves. Results: Valid synovial tissue samples were acquired from 40 patients for IHC quantification analysis. Initially, these patients had not undergone treatment with biologics. However, after 5 years, 4 out of 13 patients diagnosed with PsA and two out of nine patients diagnosed with RA had commenced biologic treatments. Individuals with early PsA who received subsequent biologic treatment exhibited significantly elevated IHC reactivity in ST for TGF-β1 (p = 0.015). Additionally, patients with both PsA and RA who underwent biologic therapy displayed increased IHC reactivity for IL-17A (p = 0.016), TGF-β1 (p = 0.009), and Dkk1 (p = 0.042). ROC curve analysis of IHC reactivity for TGF-β1, Dkk1, and IL-17A in the synovial seems to predict future treatment with biologics in the next 5 years with the area under the curve (AUC) of a combined sum of the three values: AUC: 0.828 (95% CI: 0.689–0.968; p 0.005) S 75% E 84.4%. Conclusions: Higher synovial immunohistochemistry reactivity of IL-17A, Dkk1, and TGF-β1 in patients with early psoriatic arthritis and rheumatoid arthritis may serve as potential indicators for predicting the necessity of utilising biologic treatments.
... Skin lesions are usually accompanied by itching, pain, and cracking, with consequent bleeding and flaking of the skin. Due to the autoimmune and inflammatory etiology, the usual clinical course of psoriasis is often complicated by disorders of many organ systems, including psoriatic arthritis, cardiometabolic diseases, gastrointestinal and urogenital disorders, infections, and malignancies [3,4]. It is assumed that various external stimuli, such as stress, trauma, or infection, initiate immune-mediated aberrant differentiation of keratinocytes and disruption of skin homeostasis [5,6]. ...
Given that oxidative stress represents an important etiological factor in the pathogenesis of psoriasis, the aim of this study was to assess the effects of different therapeutic approaches, methotrexate, secukinumab, and ustekinumab on systemic oxidative stress biomarkers in psoriatic patients. This study involved 78 psoriatic patients, divided into the group treated with methotrexate (23 patients), secukinumab (28 patients), and ustekinumab (27 patients), and 15 healthy controls. Oxidative stress biomarkers (index of lipid peroxidation measured as TBARS, nitrites (NO2−), superoxide anion radical (O2−), and hydrogen peroxide (H2O2)) and antioxidative defense system (superoxide dismutase (SOD) activity, catalase (CAT) activity, and reduced glutathione (GSH)) were determined spectrophotometrically from the blood before the initiation of therapy in 16th, 28th, and 52nd week. O2− and SOD showed the most prominent changes comparing the psoriatic patients and healthy controls. CAT activity was significantly lower in psoriatic patients, and methotrexate induced a further decline in CAT activity. Ustekinumab induced a significant increase in GSH level after 52 weeks of treatment, while methotrexate reduced GSH. All applied therapeutic options induced a reduction in PASI, BSA, DLQI, and EARP. Biological drugs exert more pronounced antioxidant effects compared to methotrexate, which is most clearly observed in the values of O2− and SOD.
... [1] and becoming more common all over the world [2]. Each year, 1.03 million cases of leptospirosis are reported, with 58,900 fatalities [3]. Leptospirosis is anticipated to be the primary zoonotic cause of sickness and mortality. ...
... Leptospirosis is anticipated to be the primary zoonotic cause of sickness and mortality. Furthermore, illness and death rates were the highest in the world's poorest regions and in regions where monitoring is not frequently done [3]. Cuts and abrasions, as well as mucous membranes such as the conjunctiva, and oral, or vaginal surfaces, may serve as entrance points. ...
... Leptospirosis is a zoonosis that is prevalent in tropical countries and poses a considerable public health risk, with an estimated annual morbidity of 39.2 cases per 100.000 people in Indonesia [3,11]. Mud fever, slime fever, swamp fever, autumnal fever, infectious jaundice, field fever, and cane fever are all names for Leptospirosis. ...
Leptospirosis is an uncommon infectious illness – a spirochetal zoonosis – caused by Leptospira species and the primary cause of human leptospirosis is exposure to the urine of infected rodents. Clinical manifestations of human leptospirosis are diverse, ranging from asymptomatic infection to severe life-threatening with multiorgan dysfunction. The severe condition is known as Weil's disease, which is characterized by feverish illness with jaundice, acute kidney damage, and bleeding. The aim of this case report was to present a Weil's disease which occurred simultaneously with a community-acquired pneumonia (CAP) resulting in serious complications. A 41-year-old man with Weil's disease, as well as CAP caused by Streptococcus pneumoniae, and septic shock was presented. The patient was treated accordingly after establishing the diagnosis through history taking, physical examination, and laboratory tests. In this instance, the score for diagnosing leptospirosis based on Modified Faine's Criteria was calculated resulting possible diagnoses; and therefore, therapeutic management was initiated. Despite presenting with severe symptoms, the patient recovered completely after receiving antibiotics and supportive care. This study highlights that when a patient has Weil’s disease and a CAP infection, which could cause unfavorable consequence, a prompt diagnosis and proper treatment could result satisfied patient recovery.
... The aetiology and pathophysiology of PsA are not fully understood, but they are thought to involve a complex interplay of genetic and environmental factors that trigger an abnormal immune and inflammatory response. 5 Several genes have been associated with PsA susceptibility and severity, such as HLA-B27, IL23R. 6 Environmental factors that may influence PsA development and progression include infections, trauma, stress, smoking, and alcohol consumption. ...
Objective
Psoriatic arthritis (PsA) is a chronic inflammatory disease that affects the joints and skin of patients with psoriasis. In this review we aimed to summarise the available evidence regarding the effect of Janus kinase inhibitors (JAKi) on patient-reported outcomes (PROs) when used for the management of PsA.
Methods
We utilised a narrative review approach as we searched the available literature for articles to be included in our study.
Results
JAKi have been found to be effective in inducing better PRO responses compared to placebo. These findings have been consistent across various patient populations, including those with active PsA, those with an inadequate response to conventional therapies, and those with comorbidities. The evidence supporting the benefits of JAKi on PROs in PsA is compelling, demonstrating consistent improvements in pain, physical function, fatigue, and quality of life.
Conclusion
Numerous studies have demonstrated the the efficacy of JAKi in improving PROs in patients with PsA.
... PsO condition runs a chronic course with recurrent disease flares and infrequent periods of prolonged drug-free remission (14). Immune inflammatory pathways associated with IL-23, IL-17 and TNF have been identified as also being relevant in PsA, which has led to the development of therapeutic agents targeting these cytokines (15). However, the great variability of response across different therapies suppressing specific inflammatory pathways is not yet fully understood (14,15). ...
... Immune inflammatory pathways associated with IL-23, IL-17 and TNF have been identified as also being relevant in PsA, which has led to the development of therapeutic agents targeting these cytokines (15). However, the great variability of response across different therapies suppressing specific inflammatory pathways is not yet fully understood (14,15). ...
Introduction
Psoriasis (PsO) is a chronic skin condition driven by immune mediators like TNFα, INFγ, IL-17, and IL-23. Psoriatic arthritis (PsA) can develop in PsO patients. Although psoriatic lesions may apparently resolve with therapy, subclinical cutaneous inflammation may persist. The role of tissue-resident memory T-cells (TRM), and regulatory T cells (Tregs) that also contribute to chronic inflammation are being explored in this context. This systematic review explores TRM and Tregs in psoriatic disease (PsD) and its progression.
Methods
A systematic review, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed using Pubmed® and Web of Science™ databases on June 3rd 2023, using patient/population, intervention, comparison, and outcomes (PICO) criteria limited to the English language.
Results
A total of 62 reports were identified and included. In PsO, chronic inflammation is driven by cytokines including IL-17 and IL-23, and cellular mediators such as CD8⁺ and CD4⁺ T cells. TRM contributes to local inflammation, while Tregs may be dysfunctional in psoriatic skin lesions. Secukinumab and guselkumab, which target IL-17A and the IL-23p19 subunit, respectively, have different effects on CD8⁺ TRM and Tregs during PsO treatment. Inhibition of IL-23 may provide better long-term results due to its impact on the Treg to CD8⁺ TRM ratio. IL-23 may contribute to inflammation persisting even after treatment. In PsA, subclinical enthesitis is perceived as an early occurence, and Th17 cells are involved in this pathogenic process. Recent EULAR guidelines highlight the importance of early diagnosis and treatment to intercept PsA. In PsA, CD8⁺ TRM cells are present in synovial fluid and Tregs are reduced in peripheral blood. The progression from PsO to PsA is marked by a shift in immune profiles, with specific T-cells subsets playing key roles in perpetuating inflammation. Early intervention targeting TRM cells may hold promising, but clinical studies are limited. Ongoing studies such as IVEPSA and PAMPA aim to improve our knowledge regarding PsA interception in high-risk PsO patients, emphasizing the need for further research in this area.
Conclusion
Early intervention is crucial for PsO patients at high risk of PsA; T cells, particularly type 17 helper T cells, and CD8⁺ cells are key in the progression from PsO-to-PsA. Early targeting of TRM in PsD shows promise but more research is needed.
... Reduced Treg function and numbers have been observed in PsA, contributing to the dysregulated immune responses and disease progression. Restoring Treg function may hold therapeutic potential in managing TMJ involvement in PsA [24]. ...
Psoriatic arthritis is defined as chronic inflammatory arthritis associated with psoriasis. The current data regarding gender differences in clinical manifestation and therapeutic outcomes of psoriatic arthritis are limited. Generally, men show a peripheral disease manifestation, while women have an axial distribution of the lesions. If we look at temporomandibular joint (TMJ) involvement, epidemiological data on the involvement of the TMJ are hard to find. Few studies on therapeutic management and the related impact on the quality of life are reported in the literature. Given the morpho-functional peculiarities of the TMJ and the different pain burdens between male and female genders, when manifestation of psoriatic arthritis occurs, clinicians should face it using a multidisciplinary approach for a correct diagnosis and successful treatment. This review aims to examine the diagnostic signs of psoriatic arthritis in the TMJ, the eventual variations of this disease in male and female patients, and the therapeutical strategies. The coordination of different specialties is fundamental to the remission of clinical symptoms and lesion regression.
