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CD21low B cells have recently been found increased in SSc-associated digital ulcers (DUs) or interstitial lung disease (ILD). To further characterize CD21low B cells which encompass autoreactive cells, we analyzed their expression of the inhibitory CD32 receptor in SSc. Peripheral blood mononuclear cells from 27 patients with SSc and 15 age-and sex-matched healthy controls (HCs) were analyzed with multicolor flow cytometry. CD21low B cells were significantly increased in patients with DUs (51.3%) compared to HCs (28.1%) and in patients with ILD (53.1%) compared to HCs. CD21lowCD32low B cells were significantly increased in patients with DUs (23.8%) compared to HCs (4.4%), in patients with ILD (28.4%) compared to HCs, and in anti-topoisomerase I (+) patients (21.5%) compared to HCs and to anti-topoisomerase I (-) patients (2.4%). Autoreactive B cells recognizing Topoisomerase I were predominantly within CD32low cell fraction. Our study further supports the autoreactive status of CD21lowCD32low B cells in SSc patients.
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DNA Topoisomerases Tipo I , Doenças Pulmonares Intersticiais , Proteínas Nucleares , Escleroderma Sistêmico , Úlcera Cutânea , Humanos , Leucócitos MononuclearesRESUMO
PURPOSE OF REVIEW: Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide significant biological information for the pathophysiology of the disease but may also reveal biomarkers for diagnosis or therapeutic targets. The present systematic review aims to synthesize the evidence regarding the proteome of adult patients with FMS using data from observational studies. RECENT FINDINGS: An extensive literature search was conducted in MEDLINE/PubMed, CENTRAL, and clinicaltrials.gov from inception until November 2022. The study protocol was published in OSF. Two independent reviewers evaluated the studies and extracted data. The quality of studies was assessed using the modified Newcastle-Ottawa scale adjusted for proteomic research. Ten studies fulfilled the protocol criteria, identifying 3328 proteins, 145 of which were differentially expressed among patients with FMS against controls. The proteins were identified in plasma, serum, cerebrospinal fluid, and saliva samples. The control groups included healthy individuals and patients with pain (inflammatory and non-inflammatory). The most important proteins identified involved transferrin, α-, ß-, and γ-fibrinogen chains, profilin-1, transaldolase, PGAM1, apolipoprotein-C3, complement C4A and C1QC, immunoglobin parts, and acute phase reactants. Weak correlations were observed between proteins and pain sensation, or quality of life scales, apart from the association of transferrin and a2-macroglobulin with moderate-to-severe pain sensation. The quality of included studies was moderate-to-good. FMS appears to be related to protein dysregulation in the complement and coagulation cascades and the metabolism of iron. Several proteins may be dysregulated due to the excessive oxidative stress response.
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Fibromialgia , Estudos Observacionais como Assunto , Proteômica , Humanos , Biomarcadores/sangue , Biomarcadores/metabolismo , Fibromialgia/metabolismo , Fibromialgia/sangue , Proteômica/métodosRESUMO
Psoriasis-an immune-mediated skin disease-implicates in its pathophysiology by circulating pro-inflammatory cell populations, cytokines, and their interactions with the epidermis. The direct effect of approved anti-interleukin- (IL-)17A and anti-IL-17R biologic therapy on immunophenotyping of peripheral blood mononuclear lymphocytes' (PBMCs) relative sub-population frequencies in psoriasis patients has not yet been described. Using multiparameter flow cytometry we examined T-cell subpopulations characterized by CCR6, CCR4, and CXCR3 chemokine receptor surface expression at baseline and after initiation of biologic therapy in PBMCs collected from 30 psoriasis patients. Increased CD3+CD4+CXCR3+, CD3+CD4+CCR6+CCR4+CXCR3+(CXCR3+-Th17), and CD3+CD4+CCR6+CCR4-CXCR3+(Th17.1) cell populations were observed in patients with psoriasis in comparison to healthy individuals (nâ =â 10). IL-17 therapeutic blockade decreased CD3+CD4+CCR6+, CD3+CD4+CXCR3+, CD3+CD4+CCR6-CXCR3+(Th1), CD3+CD4+CCR6+CCR4+(Th17), CD3+CD4+CCR6+CCR4+CXCR3+(CXCR3+-Th17), and CD3+CD4+CCR6+CCR4-CXCR3+(Th17.1) cell populations in responding psoriasis patients. Moreover, CD3+CD4-CCR6+, CD3+CD4-CXCR3+, CD3+CD4-CCR6+CCR4+(Tc17), and CD3+CD4-CCR6-CXCR3+(Tc1) percentages were also inhibited. Modulation of the same cell sub-populations was also assessed in patients treated with methotrexate (nâ =â 4), apremilast (nâ =â 4), and anti-IL-23 biologic treatment (nâ =â 4). In our study, the levels and functional capacity of peripheral pro-inflammatory Th1, Th17, and additional CCR6+T cell sub-gated populations from psoriasis patients that were treated with anti-IL-17 or anti-IL-17R targeted biologic therapy were explored for the first time. Our data clearly demonstrate that early anti-IL-17 mediated clinical remission is accompanied by a significant decrease of Th1, Th17, CXCR3+-Th17, and Th17.1 cells.
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Produtos Biológicos , Psoríase , Humanos , Leucócitos Mononucleares/metabolismo , Metotrexato , Células Th17/metabolismo , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Interleucinas/metabolismo , Citocinas/metabolismo , Receptores CXCR3RESUMO
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.
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Introduction: Circulating T follicular helper (cTfh) cells and circulating T peripheral helper (cTph) cells (which share common characteristics with the cTfh population) are implicated in the pathogenesis of immune-mediated and autoimmune diseases such as psoriasis (Ps). Their close interplay with the interleukin 17 (IL-17) axis and the ex vivo effect of IL-17-targeting biologic agents used to treat Ps on them are elusive. This study aimed to investigate the effect of biologics targeting IL-17 on cTfh and cTph cell subpopulations isolated from the blood of patients with Ps. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with Ps at treatment initiation and three months later. Samples were also collected from controls. Cells were stained using monoclonal antibodies. Flow cytometry assessed the fraction of cTfh (CD3+CD4+CXCR5+) and cTph (CD3+CD4+CXCR5-PD-1hi) cells.. Results: Flow cytometric analysis showed increased fractions of activated cTfh subsets including ICOS+ and ICOS+PD-1+ expressing cells, in patients compared to controls. Biologic blocking of IL-17A diminished the cTfh population. Furthermore, ICOS+ and ICOS+PD-1+ sub-populations were also inhibited. Finally, the cTph cell fraction significantly decreased after three months of successful treatment with biologics. Conclusion: Early anti-IL-17-mediated clinical remission in Ps is associated with decreased cTfh and cTph cell subpopulations.
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Produtos Biológicos , Interleucina-17 , Psoríase , Humanos , Psoríase/imunologia , Psoríase/tratamento farmacológico , Masculino , Feminino , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inibidores , Adulto , Pessoa de Meia-Idade , Produtos Biológicos/uso terapêutico , Produtos Biológicos/farmacologia , Células T Auxiliares Foliculares/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacosRESUMO
OBJECTIVES: Psoriasis of the scalp is challenging to manage. The only approved oral tyrosine kinase 2 and phosphodiesterase 4 inhibitors for psoriasis are deucravacitinib and apremilast. The aim of this study was to explore their efficacy for scalp psoriasis utilizing data from randomized controlled trials. METHODS: We searched Medline, Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov up to August 4, 2023. To determine risk of bias, the revised Risk of Bias assessment tool 2.0 was used. Inverse variance random effects meta-analyses were executed. Heterogeneity was assessed utilizing Q and I2 statistics. Pre-determined outcomes included the proportion of participants with cleared scalp skin (Scalp Physician's Global Assessment [ScPGA] of 0/1), mean change in Psoriasis Scalp Severity Index (PSSI), and mean improvement in Dermatology Life Quality Index (DLQI). RESULTS: Ten RCTs fulfilled inclusion criteria. Both apremilast (RR = 2.41, 95% CI = 2.08-2.79, Tau2 = 0, I2 = 0) and deucravacitinib (RR = 3.86, 95% CI = 3.02-4.94, Tau2 = 0, I2 = 0) were more effective in inducing ScPGA of 0/1 at 16 weeks compared to placebo. Furthermore, deucravacitinib was more effective than apremilast (RR = 1.70, 95% CI = 1.44-2.00, Tau2 = 0, I2 = 0). An analysis could not be executed for the rest of the outcomes. CONCLUSIONS: Apremilast and deucravacitinib are effective for scalp psoriasis. Deucravacitinib may be more efficient in clearing the scalp.
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Inibidores da Fosfodiesterase 4 , Psoríase , Talidomida/análogos & derivados , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/uso terapêutico , TYK2 Quinase/uso terapêutico , Couro Cabeludo , Psoríase/tratamento farmacológico , Tirosina/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: Cannabidiol (CBD), a substance that belongs to the phytocannabinoids, appears to exert antioxidant, neuroprotective, antipsychotic, anticonvulsant, and anticancer properties. Recent evidence supports the immunoregulatory effect of CBD on autoimmune and/or inflammatory disease. Psoriasis is a chronic skin disease. The main immune cell population involved in the pathogenesis of the disease is the interleukin- (IL-) 17-producing T helper (Th) 17 subset. Other subpopulations, such as interferon-γ (IFNγ) -producing Th1 and T cytotoxic (Tc) 1, IL-17-producing Tc17, as well as natural killer (NK) and natural killer T cells (NKT) have been implicated in psoriasis development. Purpose: The aim of the present study was to evaluate the in vitro effect of CBD on the aforementioned subpopulations isolated from patients with psoriasis using flow cytometry. Methods: Cells were stimulated in the presence or absence of CBD, stained and examined using surface and intracellular markers. Results: CBD decreased IL-17 production within the CD3, Th, and NKT cell compartments and IFNγ production within the CD3 compartment in cells isolated from patients with psoriasis. Interestingly, CBD supplementation did not inhibit production of proinflammatory cytokines in cells isolated from healthy individuals. On the contrary, IFNγ-producing Th, Tc, and NK cells increased after CBD supplementation. Conclusion: CBD provides anti-inflammatory effects in T cells isolated from patients with psoriasis. Our results could be the impetus for future investigations regarding the immunomodulatory properties of CBD and its utilization for development of CBD-containing antipsoriatic agents.
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Canabidiol , Psoríase , Humanos , Citocinas/metabolismo , Interleucina-17/metabolismo , Canabidiol/farmacologia , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Interleucinas , Interferon gamaRESUMO
Biologics approved for psoriasis exhibit favorable safety profiles, and serious adverse events have rarely been reported. In this report, we present the case of a patient treated with ixekizumab, an anti-interleukin (IL)-17 agent, who 8 months later developed multiple sclerosis (MS). We also review the available literature regarding the use of anti-IL-17 agents in the context of psoriasis and pre-existing or new-onset demyelination. Eight case reports were evaluated as relevant and are presented in our report. In most of the cases secukinumab or ixekizumab administration adequately controlled both skin and pre-existing neurological clinical manifestations. However, there has been a report of MS exacerbation under secukinumab treatment and the occurrence of myelitis in a patient receiving ixekizumab. While the anti-IL-17-biologic-mediated induction of inflammatory events in the central nervous system has not been proven and a causal relationship is lacking, such a probability should be considered in extremely rare cases.
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Anticorpos Monoclonais Humanizados , Interleucina-17 , Esclerose Múltipla , Psoríase , Humanos , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Anticorpos Monoclonais Humanizados/efeitos adversos , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/complicações , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Imageamento por Ressonância MagnéticaRESUMO
Moderate-to-severe psoriasis (Ps) treatment includes systemic drugs and biological agents. Apremilast, a small molecule primarily metabolized by cytochrome CYP3A4, modulates the immune system by specifically inhibiting phosphodiesterase type 4 (PDE4) isoforms and is currently used for the treatment of Ps and psoriatic arthritis (PsA). Clinical trials and real-world data showed variable efficacy in response among Ps patients underlying the need for personalized therapy. This study implements a candidate-gene and a network-based approach to identify genetic markers associated with apremilast response in forty-nine Greek Ps patients. Our data revealed an association of sixty-four SNPs within or near PDE4 and CYP3A4 genes, four SNPs in ncRNAs ANRIL, LINC00941 and miR4706, which influence the abundance or function of PDE4s, and thirty-three SNPs within fourteen genes whose protein products either interact directly with PDE4 proteins or constitute components of the cAMP signaling pathway which is modulated by PDE4s. Notably, fifty-six of the aforementioned SNPs constitute eQTLs for the respective genes in relevant to psoriasis tissues/cells implying that these variants could be causal. Our analysis provides a number of novel genetic variants that, upon validation in larger cohorts, could be utilized as predictive markers regarding the response of Ps patients to apremilast treatment.
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Artrite Psoriásica , Psoríase , Talidomida/análogos & derivados , Humanos , Artrite Psoriásica/induzido quimicamente , Artrite Psoriásica/tratamento farmacológico , Citocromo P-450 CYP3A , Psoríase/tratamento farmacológico , Psoríase/genética , Talidomida/uso terapêutico , Talidomida/efeitos adversosRESUMO
In recent years, the role of interleukin-17 (IL-17) in orchestrating and manipulating proinflammatory immune responses has received special attention. It has become apparent from murine studies and clinical trials that due to its inhibitory effect on immunoregulation and its stimulatory action on promoting proinflammatory responses, IL-17 is an ideal cytokine to target for drug development, in order to cease its induction or eliminate IL-17-producing cells of any kind. Several monoclonal antibodies have been developed and tested as potent inhibitors of IL-17 in various inflammatory diseases. This review summarizes data from relevant clinical trials on recent developments of the application of inhibitors of IL-17 in psoriasis and psoriatic arthritis, namely secukinumab, ixekizumab, bimekizumab and brodalumab.
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Artrite Psoriásica , Psoríase , Humanos , Animais , Camundongos , Artrite Psoriásica/tratamento farmacológico , Interleucina-17 , Psoríase/tratamento farmacológicoRESUMO
Psoriasis is an inflammation of the skin mediated via the IL-23/Thl17/IL-17 pathway. We have previously demonstrated that the anthocyanin delphinidin diminishes in vitro the IL-17 and IFN-γ production of peripheral monocytes isolated by psoriasis patients (PBMCs). The degradation product of delphinidin is gallic acid (GA). This phenolic acid compound found in fruits, red wine, or green tea exerts pleiotropic antioxidant, anticarcinogenic, antimicrobial, and anti-inflammatory properties. Previous research has demonstrated the inhibitory effect of GA on pro-inflammatory transcription factors, such as STAT3, RORγt, and NF-κB, or cytokines as IL-1ß and TNF, which contribute to psoriasis development. We investigated the effect of GA in vitro on PBMCs, which were stimulated ex vivo, from 40 individuals (28 diagnosed with psoriasis vulgaris and 12 healthy controls (HCs)). In our experiments, PBMCs were cultured untreated or were activated in the presence of phorbol 12-myristate 13-acetate/ionomycin with or without GA. We utilized multicolor flow cytometry to assess the production of inteleukin-17 (IL-17) and interferon-γ (IFN-γ) in T and NK cells. GA did not alter the fractions of IL-17- or IFN-γ-producing T and IFN-γ-producing NK cells in HCs. However, in psoriasis patients, the effect of GA on that cell population was significant. Specifically, GA decreased the frequency of IL-17-producing cells within the CD3+ (T) and CD3+CD4+ (Th) compartment; the frequency of IFN-γ-producing cells within the CD3+, CD3+CD4+, and CD3+CD4- (Tc) compartment, and the frequency of IFN-γ-producing cells within the CD3-CD56+ (NK) compartment. Whether GA's effect also appears in vivo needs to be investigated in future.
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Interferon gama , Psoríase , Humanos , Interferon gama/metabolismo , Interleucina-17 , Ácido Gálico/farmacologia , Citocinas/metabolismo , Psoríase/tratamento farmacológicoRESUMO
BACKGROUND: Palmoplantar psoriasis (PP) represents a localized type of disease. While controversy over its' classification exists, a hyperkeratotic type, a pustular type and palmoplantar pustulosis (PPP) have been recognized. PP management is regularly supported by biologic agents. Our study aimed to review and synthesize available data regarding the efficacy of approved biologics for PP and PPP. RESEARCH DESIGN AND METHODS: A literature search was conducted in PubMed, CENTRAL, Scopus, and ClinicalTrilas.gov. Utilizing random-effects inverse-variance frequentist network meta-analyses (NMAs), we ranked interventions. The proportion of participants with cleared skin was the primary outcome. Fifty and 75% improvement in palmoplantar psoriasis area severity index (PPASI) were also explored (PPASI50, PPASI75). RESULTS: In total, 15 randomized controlled trials (RCTs) exploring the efficacy of on-label adalimumab, bimekizumab, etanercept, guselkumab, infliximab, ixekizumab, secukinumab, and ustekinumab were included. Data for PP were synthesized. Every biologic agent examined, except from infliximab, outperformed placebo. On-label secukinumab exhibited the highest probability of inducing complete resolution. Ixekizumab and infliximab ranked best on inducing PPASI50 and PPASI75. Our review supports that guselkumab is effective for PPP. CONCLUSIONS: Secukinumab, ixekizumab and infliximab are effective for PP. Research is warranted to produce evidence about the efficacy of biologics in PP and PPP.
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Produtos Biológicos , Psoríase , Humanos , Infliximab/uso terapêutico , Metanálise em Rede , Fatores Biológicos/uso terapêutico , Psoríase/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The anthocyanidin delphinidin reduces psoriasiform lesions and inflammatory mediators in human cell culture systems. Its role in psoriatic disease has not yet been investigated. We assessed delphinidin's in vitro immunomodulatory effect on ex vivo stimulated peripheral blood mononuclear cells (PBMCs) from 50 individuals [26 with psoriasis, 10 with psoriatic arthritis (PsA) and 14 healthy controls (HCs)]. Cells were either left untreated or stimulated with PMA plus ionomycin in the presence or absence of delphinidin. Intracellular production of interferon-γ (IFNγ), interleukin-17A (IL-17A), and interleukin-10 (IL-10) was measured flow cytometrically. Delphinidin dose-dependently reduced IFNγ+ T cells from patients and HCs. The mean IFNγ decrease in CD4+ T subpopulations was 42.5 ± 28% for psoriasis patients, 51.8 ± 21.5% for PsA patients and 49 ± 17% for HCs (p < 0.001 for all). Similarly, IFNγ reduction in CD8+ T cells was 34 ± 21.6% for psoriasis patients, 47.1 ± 22.8% for PsA and 44.8 ± 14.3% for HCs (P < 0.001 for all). An inhibitory effect of delphinidin was also noted in IFNγ producing NKs and NKTs from psoriasis individuals. Delphinidin also significantly decreased IL-17+ CD4+ T cells in all tested subjects, with marginal effect on the increase of IL-10-producing T regulatory subsets. In conclusion, delphinidin exerts a profound in vitro anti-inflammatory effect in psoriasis and psoriatic arthritis by inhibiting IFNγ+ innate and adaptive cells and T helper (Th) 17 cells. If this effect is also exerted in vivo, delphinidin may be regarded as a nutraceutical with immunosuppressive potential.
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Antocianinas , Artrite Psoriásica , Interferon gama , Interleucina-17 , Antocianinas/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Linfócitos T CD8-Positivos , Humanos , Interleucina-10 , Leucócitos MononuclearesRESUMO
Rheumatic diseases (RDs) are often complicated by chronic symptoms and frequent side-effects associated with their treatment. Saffron, a spice derived from the Crocus sativus L. flower, is a popular complementary and alternative medicine among patients with RDs. The present systematic review aimed to summarize the available evidence regarding the efficacy of supplementation with saffron on disease outcomes and comorbidities in patients with RD diagnoses. PubMed, CENTRAL, clinicaltrials.gov and the grey literature were searched until October 2021, and relevant randomized controlled trials (RCTs) were screened for eligibility using Rayyan. Risk of bias was assessed using the Cochrane's Risk of Bias-2.0 (RoB) tool. A synthesis without meta-analysis (SWiM) was performed by vote counting and an effect direction plot was created. Out of 125 reports, seven fulfilled the eligibility criteria belonging to five RCTs and were included in the SWiM. The RCTs involved patients with rheumatoid arthritis, osteoarthritis and fibromyalgia, and evaluated outcomes related to pain, disease activity, depression, immune response, inflammation, oxidative stress, health, fatigue and functional ability. The majority of trials demonstrated some concerns regarding overall bias. Moreover, the majority of trialists failed to adhere to the formula elaborations suggested by the CONSORT statement for RCTs incorporating herbal medicine interventions. Standardization of herbal medicine confirms its identity, purity and quality; however, the majority of trials failed to adhere to these guidelines. Due to the great heterogeneity and the lack of important information regarding the standardization and content of herbal interventions, it appears that the evidence is not enough to secure a direction of effect for any of the examined outcomes.