Gout: one year in review 2023.

Gout is a chronic joint disease caused by the deposition of monosodium urate crystals into and around the articular tissues. In the last two years, new insights regarding diagnosis, genetic involvement, pathogenesis, comorbidities, and clinical data, have allowed the identification of new strategies to improve the control of the disease and its flares. In keeping, the discover of new mechanisms concerning crystal-induced inflammation have suggested new ways for the management not only of gout, but also other systemic diseases, mainly including renal and cardiovascular disorders. In this context it is very representative the case of colchicine which, given the surprising results obtained both in laboratory and clinical experiments, has recently received by FDA the approval for the prevention of cardiovascular disorders.

Synovial fluid analysis: Relevance for daily clinical practice.

Synovial fluid analysis can provide a prompt and definite diagnosis of crystal-induced arthritis, the most common acute inflammatory arthritis and a cause of chronic arthritis that may mimic rheumatoid, psoriatic, or peripheral spondyloarthritis. In many patients the diagnosis of gout or calcium pyrophosphate arthritis cannot be made with certainty without synovial fluid analysis. Additional information from fluid analysis can assist the clinician in honing the differential diagnosis of non-crystalline arthritis.

IL-18 in Autoinflammatory Diseases: Focus on Adult Onset Still Disease and Macrophages Activation Syndrome.

Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine that is involved in various innate and adaptive immune processes related to infection, inflammation, and autoimmunity. Therefore, it is described as a key mediator of autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS), including systemic juvenile idiopathic arthritis and adult-onset Still's disease. This review focuses on the role of IL-18 in inflammatory responses, placing emphasis on autoinflammatory diseases associated with chronic excess of serum IL-18, which correlate with clinical and biological signs of the disease. Therefore, it is useful for the diagnosis and monitoring of disease activity. Researchers are currently investigating IL-18's role as a therapeutic target for the treatment of inflammatory diseases. The inhibition of IL-18 signaling through recombinant human IL-18BP (IL-18 binding protein) seems to be an effective therapeutic strategy, though further studies are necessary to clarify its importance as a therapeutic target.

Seasonal variation and disease distribution of cytophagocytic mononuclear cells in synovial fluid: A medical record study.

Cytophagocytic mononuclear (CPM) cells, previously known as Reiter's cells, are macrophages containing apoptotic polymorphonuclear leucocytes. Although they can be found in synovial fluid (SF) from different arthropathies, their role remains unclear. This study was performed to determine the frequency and disease distribution of CPM cells in SF in a large cohort of patients with rheumatic diseases over a 12-year period. We also investigated the seasonal variation in their incidence. This record review study included the reports pertaining to SF analyses performed between January 2010 and December 2021. Data were retrieved from the charts of inpatients and outpatients at Rheumatology and Emergency Departments of Padova. The total number of SF samples containing CPM cells was 189: 69% was from patients with seronegative spondyloarthritis (SpA), thus indicating a strong association between CPM cells and SpA. SF samples containing CPM cells were predominantly inflammatory. Our analyses demonstrated a 6-month cyclical fluctuation in concentrations of CPM cells, with an increase in spring and autumn. The presence of CPM cells in SF might offer diagnostic insight into the definition of SpA. Further studies are warranted to ascertain the link between CPM cells and the apoptotic process, shedding light on the mechanisms leading to their formation.

Sex-dependent PD-L1/sPD-L1 trafficking in human endothelial cells in response to inflammatory cytokines and VEGF.

Programmed cell death 1 ligand 1 (PD-L1) expressed in non-immune cells is involved in immune-mediated tissue damage in the context of inflammatory conditions and tumor immune escape. Emerging evidence suggests soluble (s)PD-L1 as a marker of inflammation. Based on well-established sex-specific differences in immunity, we tested the novel hypotheses that (i) endothelial cell PD-L1 is modulated by inflammatory cytokines and vascular endothelial growth factor (VEGF) in a sex-specific fashion, and (ii) the endothelium is a source of sPD-L1. After exposure of human umbilical vein endothelial cells (HUVECs) to lipopolysaccharide, interleukin (IL)1ß or VEGF for 24 h, total PD-L1 levels were upregulated solely in cells from female donors, while being unchanged in those from male donors. Accordingly, exposure to synovial fluids from patients with inflammatory arthritis upregulated PD-L1 levels in HUVECs from female donors only. Membrane PD-L1 expression as measured by flow cytometry was unchanged in response to inflammatory stimuli. However, exposure to 2 ng/mL IL-1ß or 50 ng/mL VEGF time-dependently increased sPD-L1 release by HUVECs from female donors. Treatment with the metalloproteinase (MMP) inhibitor GM6001 (10 µM) prevented IL-1ß-induced sPD-L1 release and enhanced membrane PD-L1 levels. The anti-VEGF agents bevacizumab and sunitinib reduced both VEGF-induced PD-L1 accumulation and sPD-L1 secretion. Thus, inflammatory agents and VEGF rapidly increased endothelial PD-L1 levels in a sex-specific fashion. Furthermore, the vascular endothelium may be a sPD-L1 source, whose production is MMP-dependent and modulated by anti-VEGF agents. These findings may have implications for sex-specific immunity, vascular inflammation and response to anti-angiogenic therapy.

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies.

Genome damage has been related to the induction of autoimmune processes, chronic inflammation, and apoptosis. Recent studies suggest that some rheumatological diseases are associated with overall genomic instability in the T cell compartment. However, no data regarding leucocyte abnormalities in synovial fluid (SF) and their relationship with inflammation are available. The aim of this study was to investigate cellular phenotypes in SF collected from patients with different inflammatory arthropathies, including rhematoid arthritis (RA), psoriatic arthritis (PsA), crystal-induced arthritis (CIA), and non-inflammatory arthropathies, such as osteoarthritis (OA). We found high percentage of micronuclei in SF from CIA compared to the other groups and a high frequency of pyknotic cell in RA and CIA patients. A correlation between pyknosis and immature polymorphonuclear cells with local inflammatory indices was observed. The study of the apoptosis process revealed an increased BAX expression in CIA and RA compared to OA and PsA, while Bcl-2 was higher in CIA. Caspase-3 activity was increased in SF from RA patients and correlates with inflammatory and anti-inflammatory cytokines. In conclusion, our results showed that inflammatory SF is associated with genomic instability and abnormal cell subsets.

Fetuin-A: A Novel Biomarker of Bone Damage in Early Axial Spondyloarthritis. Results of an Interim Analysis of the SPACE Study.

Our study aimed to evaluate the association between fetuin-A levels and the presence of radiographic sacroiliitis and syndesmophytes in patients with early axial spondyloarthritis (axSpA) and to identify potential predictors of radiographic damage in the sacroiliac joints (SIJs) after 24 months. Patients diagnosed with axSpA in the Italian cohort of the SpondyloArthritis-Caught-Early (SPACE) study were included. Physical examinations, laboratory tests (including fetuin-A), SIJ,+ and spinal X-rays and MRIs at T0 (diagnosis) and at T24 were considered. Radiographic damage in the SIJs was defined according to the modified New York criteria (mNY). Fifty-seven patients were included in this analysis (41.2% male, median (interquartile range), chronic back pain [CBP] duration of 12 (8-18) months). Fetuin-A levels were significantly lower in patients with radiographic sacroiliitis compared to those without at T0 (207.9 (181.7-215.9) vs. 239.9 (217.9-286.9), respectively, p < 0.001) and at T24 (207.6 (182.5-246.5) vs. 261.1 (210.2-286.6) µg/mL, p = 0.03). At T0, fetuin-A levels were significantly higher in non-smokers, in patients with heel enthesitis and in those with a family history of axSpA; fetuin-A levels at T24 were higher in females, in patients with higher ESR or CRP at T0 and in those with radiographic sacroiliitis at T0. Fetuin-A levels at T0 were independently negatively associated with the likelihood of radiographic sacroiliitis (OR = 0.9 per 10-unit increase (95% CI 0.8, 0.999), p = 0.048); but not with the presence of syndesmophytes. After adjustment for confounders, fetuin-A levels at T0 and T24 were also negatively associated with mNY at T0 (ß -0.5, p < 0.001) and at T24 (ß -0.3, p < 0.001), respectively. Among other variables at T0, fetuin-A levels did not achieve statistical significance in predicting mNY at T24. Fetuin-A levels were negatively associated with radiographic damage of the SIJs, but not of the spine, in early axSpA and after 2 years of follow-up. Our findings suggest that fetuin-A levels may serve as a biomarker to identify patients with a higher risk of developing severe disease and early structural damage.

Synovial Fluid from Patients with Osteoarthritis Shows Different Inflammatory Features Depending on the Presence of Calcium Pyrophosphate Crystals.

The role of calcium pyrophosphate (CPP) crystals in osteoarthritis (OA) is still a matter of debate. With this study we aimed to investigate the inflammatory features of synovial fluid (SF) collected from patients with OA with CPP crystals compared with those without crystals. We also explored the effect of OA SF on monocytes response. SFs were collected from adult patients with OA and subdivided according to the presence of crystals. Local cellular and humoral inflammatory mediators were analysed in the SF samples. The expression levels of IL-1ß, IL-18, CASP-1, NLRP3, and GAPDH were measured by RT-PCR in the cells obtained by pelleting the SF samples. For the in vitro study, a monocytic cell line was treated with selected SF samples. SF with CPP crystals showed a significant increase in inflammatory cellular indices and higher levels of IL-1ß, IL-8, and caspase-1 transcript with respect to SF without crystals. Higher concentrations of VEGF were also observed in the early stages of the whole OA patients. THP-1 cells stimulated with OA SF released a significant amount of IL-1 ß in culture supernatants. This study demonstrated that SF collected from patients with OA shows different inflammatory features depending on the presence of CPP crystals.

Bactericidal/Permeability-Increasing Protein Downregulates the Inflammatory Response in In Vivo Models of Arthritis.

We investigated the effects of bactericidal/permeability-increasing protein (BPI) alone or in combination with hyaluronic acid (HA) in two animal models: collagen-induced arthritis (CIA) and crystal-induced inflammation. In CIA, mice were intraperitoneally injected with PBS, HA, or BPI plus or minus HA, twice a week for 2 months, and then euthanized to collect paw and blood. Arthritis was assessed in ankle joints by clinical and histological evaluation. Pathogenic crystals were intraperitoneally injected in mice plus or minus BPI, or with a composition of BPI and HA. After sacrifice, total and differential leukocyte counts were determined. Cytokine levels were measured in serum and peritoneal fluids. In CIA mice, BPI improved clinical and histological outcomes (histological scores ≥2-fold), and downregulated inflammatory mediators (47-93%). In crystal-induced inflammation, BPI reduced leukocyte infiltration (total count: ≥60%; polymorphonuclear cells: ≥36%) and inhibited cytokine production (35-74%). In both models, when mice were co-treated with BPI and HA, the improvement of all parameters was greater than that observed after administration of the two substances alone. Results show that BPI attenuates CIA and inflammation in mice, and this effect is enhanced by HA co-administration. Combined use of BPI and HA represents an interesting perspective for new potential treatments in arthritis.

Anti-Inflammatory and Hypouricemic Effect of Bioactive Compounds: Molecular Evidence and Potential Application in the Management of Gout.

Gout is caused by the deposition of monosodium urate crystals in the joint and represents the most common form of inflammatory arthritis in men. Its prevalence is rising worldwide mainly due to the increase of risk factors associated with the disease, in particular hyperuricemia. Besides gout, hyperuricemia leads to an increased inflammatory state of the body with consequent increased risk of comorbidities such as cardiovascular diseases. Increasing evidence shows that bioactive compounds have a significant role in fighting inflammatory and immune chronic conditions. In gout and hyperuricemia, these molecules can exert their effects at two levels. They can either decrease serum uric acid concentrations or fight inflammation associated with monosodium urate crystals deposits and hyperuricemia. In this view, they might be considered valuable support to the pharmacological therapy and prevention of the disease. This review aims to provide an overview of the beneficial role of bioactive compounds in hyperuricemia, gout development, and inflammatory pathways of the disease.

Synovial Fluid Analysis to Identify Osteoarthritis.

Synovial fluid (SF) analysis is important in diagnosing osteoarthritis (OA). Macroscopic and microscopic features, including total and differential white blood cell (WBC) count, help define the non-inflammatory nature of SF, which is a hallmark of OA. In patients with OA, WBC in SF samples usually does not exceed 2000 cells per microliter, and the percentage of inflammatory cells, such as neutrophils, is very low or absent. Calcium crystals are frequent in SF collected from OA patients. Although their role in the pathogenesis of OA remains unclear, they have been associated with a mild inflammatory process and a more severe disease progression. Recently, calcium crystals have been described in both the early and late stages of OA, indicating that they may play a vital role in diagnosing different clinical subsets of OA and pharmacological treatment. The overall goal of SF analysis in OA is two-fold: to ascertain the non-inflammatory degree of SF and to highlight the presence of calcium crystals.

Acute joint swelling in psoriatic arthritis: Flare or "psout"-A 10-year-monocentric study on synovial fluid.

Psoriatic arthritis (PsA) is a multifaceted inflammatory disease associated with psoriasis that can affect peripheral joints, entheses, and the axial skeleton with a variable clinical course. Acute episodes of joint swelling in PsA patients can have different causes and require specific treatments. We aimed to describe the acute joint swelling in PsA patients via synovial fluid (SF) analyses, assessing in particular the presence of pathogenic crystals, to determine whether it is a flare or an acute episode of gout ("psout") during the course of the disease. This retrospective study was based on the results of SF analysis of samples collected from unselected adult PsA patients referred to our clinic for acute joint swelling. Demographic characteristics, disease involvement, laboratory findings on SF, and treatment options were recorded and reviewed. Among 5,478 SF samples analyzed in a 10-year time span, 213 complete SF records from PsA patients were evaluated. Overall, after adjustment for the degree of synovial inflammation, significant differences were observed in term of sex (p = 0.0017) and ongoing therapy (p = 0.0246). Non-inflammatory SFs, indeed, were mainly described for female PsA patients under therapy. Regarding serum uric acid levels, there were 19/213 (8.9%) PsA with hyperuricemia (HU), who were older, mostly male, patients with mild articular involvement and rare pathogenic crystals in their SF. Although it is known that the risk of gout is higher among patients with PsA ("psout"), monosodium urate crystals were reported only in 5/213 SFs (2.4%) of our cohort and in 2/19 SFs (10.5%) of HU PsA patients. Moreover, hyperuricemia seems not to modify the SF features in PsA patients. This study results seem to suggest that the convergence of gout and PsA, involving the role of urate crystals, is a more intricate relationship, which needs further insights to be unraveled.

Gender differences and pharmacological regulation of angiogenesis induced by synovial fluids in inflammatory arthritis.

Several mediators including cytokines, growth factors and metalloproteinases (MMP) modulate pathological angiogenesis associated with inflammatory arthritis. The biological factors underlying sex disparities in the incidence and severity of rheumatic musculoskeletal diseases are only partially understood. We hypothesized that synovial fluids (SFs) from rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients would impact on endothelial biology in a sexually dimorphic fashion. Immune cell counts and levels of pro-angiogenic cytokines found in SFs from RA and PsA patients (n = 17) were higher than in osteoarthritis patients (n = 6). Synovial VEGF concentration was significantly higher in male than in female RA patients. Zymography revealed that SFs comprised solely MMP-9 and MMP-2, with significantly higher MMP-9 levels in male than female RA patients. Using in vitro approaches that mimic the major steps of the angiogenic process, SFs from RA and PsA patients induced endothelial migration and formation of capillary-like structures compared to control. Notably, endothelial cells from female donors displayed enhanced angiogenic response to SFs with respect to males. Treatment with the established anti-angiogenic agent digitoxin prevented activation of focal adhesion kinase and SF-induced in vitro angiogenesis. Thus, despite higher synovial VEGF and MMP-9 levels in male patients, the responsiveness of vascular endothelium to SF priming was higher in females, suggesting that gender differences in angiogenic responses were mainly related to the endothelial genotype. These findings may have implications for pathogenesis and targeted therapies of inflammatory arthritis.

Identification in synovial fluid of a new potential pathogenic player in arthropathies.

STING (stimulator of interferon genes) has been recognized as an important signaling molecule in the innate immune response to cytosolic nucleic acids. Although it has been proposed that STING signaling pathway may play a pathogenic role in developing autoimmune and autoinflammatory diseases, its involvement in rheumatic disease processes remains to be elucidated. Here, we evaluated STING protein levels, expression and relationship with inflammatory parameters in synovial fluid (SF) of patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), gout, calcium pyrophosphate crystal-induced arthritis (CPP-IA), osteoarthritis (OA), and OA with CPP crystals (OA + CPP). The correlation with its negative regulator, nuclear factor erythroid 2-related factor 2 (Nrf2), was also investigated. SFs from 72 patients were analyzed for white blood cell (WBC) count, polymorphonuclear cell percentage (PMN%), and IL-1ß, IL-6, IL-8, extra- and intracellular STING levels. STING and Nrf2 expression was also determined. WBC count and PMN% were greater in SF from inflammatory arthritis, while they were lower in OA groups. RA and gouty SFs have the highest levels of IL-1ß, IL-8, and IL-6; while OA and OA + CPP showed the lowest concentrations. Gout and RA had the highest intracellular STING levels, while extracellular STING was greater in CPP-IA and OA SFs. STING was not detectable in PsA. STING mRNA was lower in PsA than other arthritides. Nrf2 mRNA was not detectable in OA. This study determines the presence of STING in SF of different arthritides, except for PsA, and suggests that it may be involved in pathogenesis and progression of arthropathies.

Erosive hand osteoarthritis: latest findings and outlook.

Osteoarthritis (OA) most commonly affects knee joints, and the next most commonly affected sites are the hands and hips. Three distinct hand OA phenotypes have been described: erosive hand OA (EHOA), nodal hand OA - also known as non-erosive hand OA (non-EHOA) - and first carpometacarpal joint OA. EHOA predominantly affects women and is the most aggressive form of hand OA, characterized by a severe clinical onset and progression, leading to joint damage, disability and reduction of quality of life. Clinical signs of inflammation associated with EHOA include the acute onset of pain, swelling and redness. Moreover, EHOA is characterized by radiographic features such as central erosion, saw-tooth and gull-wing lesions and, rarely, ankylosis. The aim of this Review is to report the latest findings on epidemiology, clinical features, pathology and aetiopathogenesis, biomarkers, imaging modalities and treatments for EHOA. The ongoing development of new hand OA classification criteria should facilitate standardization between studies.

Regulation of crystal induced inflammation: current understandings and clinical implications.

Introduction: Accumulation of abnormal crystals in the body, derived from endogenous or exogenous materials can drive a wide spectrum of inflammatory disease states. It is well established that intra-articular deposition of monosodium urate (MSU) and calcium pyrophoshate (CPP) crystals contributes to joint destruction through pro-inflammatory processes.Areas covered: This review will focus on current understanding and recent novelty about the mechanisms and the clinical implications of the inflammation induced by MSU and CPP crystals.Expert opinion: Advances in molecular biology reveal that at the base of the inflammatory cascade, stimulated by MSU or CPP crystals, there are many complex cellular mechanisms mainly involving the NLRP3 inflammasome, the hallmark of autoinflammatory syndromes. The extensive studies carried out through in vitro and in vivo models along with a better clinical definition of the disease has led to an optimized use of existing drugs and the introduction of novel therapeutic strategies. In particular, the identification of IL-1 as the most important target in gout and pseudogout has made it possible to expand the pharmacological indications of anti-IL-1 biological drugs, opening new therapeutic perspectives for patients.

Polydatin Prevents Calcium Pyrophosphate Crystal-Induced Arthritis in Mice.

BACKGROUND: Polydatin is a stilbenoid with important antioxidant, anti-inflammatory, and immunomodulating properties. The aim of this study was to assess the anti-inflammatory preventive effect of polydatin in the mouse model of acute arthritis induced by calcium pyrophosphate (CPP) crystals. METHODS: Acute arthritis was induced by the injection of a suspension of sterile CPP crystals into the ankle joint of Balb/c mice. Animals were randomized to receive polydatin or colchicine (the control drug) according to a prophylactic and a therapeutic protocol. The primary outcome was the variation of ankle swelling obtained after crystal injection and treatment, while histological parameters such as leukocyte infiltration, IL-1ß and CXCL1 levels and tissue expression were considered as secondary outcomes. RESULTS: Prophylactic treatment with PD significantly diminished ankle swelling after 48 h from crystal injection. Secondary outcomes such as leukocyte infiltration, necrosis, edema, and synovitis were also decreased. PD caused a reduction in circulating levels of IL-1ß and CXCL1, as well as their tissue expression. By contrast, the therapeutic administration of PD did not have any beneficial effect. CONCLUSIONS: PD can effectively prevent acute inflammatory response to crystals in the mouse model of CPP crystal-induced arthritis. These results suggest that this bioactive compound might be used in the prevention of crystal-induced acute attacks in humans.