The Effect of JAK Inhibitors on Patient-Reported Outcomes in Psoriatic Arthritis.

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.

Proteomics in Patients with Fibromyalgia Syndrome: A Systematic Review of Observational Studies.

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.

PDE4 Gene Family Variants Are Associated with Response to Apremilast Treatment in Psoriasis.

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.

Cannabidiol Mediates In Vitro Attenuation of Proinflammatory Cytokine Responses in Psoriatic Disease.

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.

Gallic acid diminishes pro-inflammatory interferon-γ- and interleukin-17-producing sub-populations in vitro in patients with psoriasis.

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.

Delphinidin diminishes in vitro interferon-γ and interleukin-17 producing cells in patients with psoriatic disease.

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.

Effect of Crocus sativus (Saffron) Intake on Top of Standard Treatment, on Disease Outcomes and Comorbidities in Patients with Rheumatic Diseases: Synthesis without Meta-Analysis (SWiM) and Level of Adherence to the CONSORT Statement for Randomized Controlled Trials Delivering Herbal Medicine Interventions.

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.