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.

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.

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.

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.

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.

Phagocytosis and inflammation in crystal-induced arthritis: a synovial fluid and in vitro study.

OBJECTIVES: The aim of this study was to investigate the relationship between the degree of crystal phagocytosis and the magnitude of the local inflammatory process using fresh synovial fluid (SF) collected from patients with crystal-induced arthritis. In parallel, an in vitro model of crystal-induced inflammation was used to assess the effect of cell priming on crystal phagocytosis and IL-1ß production. METHODS: SF was collected from 20 patients with gout and 20 with pyrophosphate crystal-induced arthritis and examined under ordinary and polarised light microscopy for total and differential white blood cell (WBC) count and crystal search. The total phagocytosis index was determined in SF along with IL-1ß, IL-8, IL-10, and TGFß levels. The in vitro studies were performed using primed or unprimed THP-1 cells stimulated with calcium pyrophosphate (CPP) crystals, monosodium urate (MSU) crystals and/or cytochalasin D. RESULTS: We demonstrated that the phagocytosis index calculated on the total number of cells was independent from the inflammatory local indices such as WBC and the percentage of polymorphonuclear cells but showed a positive correlation with pro-inflammatory cytokines. By contrast, the local inflammatory indices (WBC and IL-1ß) showed a strong positive correlation with the percentage of polymorphonuclear cells with crystals internalised and a negative correlation with the percentage of mononuclear cells with crystals internalised. The in vitro study showed that phagocytosis represents a fundamental step in the induction of the inflammatory response to MSU and CPP crystals, but it also occurs in absence of cell priming. CONCLUSIONS: The results of this study indicate a possible role of non-inflammatory phagocytosis in limiting the acute attack of crystal-induced arthritis.

One year in review 2020: gout.

Gout is the most prevalent form of inflammatory arthritis, with a strong impact on individual health and healthcare systems. This article reviews clinical and experimental evidences about gout emerged throughout the 2019. Starting with an epidemiological analysis, the review explores new insights on genetic factors influencing the development of gout flare, pathogenetic mechanisms, risk factors for the disease and comorbidities. An overview on pharmacological therapies and recent knowledge on the impact of lifestyle and dietary habits are also included. Finally, the review contains a novel section on animal models, which reflects the renewed interest of researchers in the acute process triggered by monosodium urate crystals.

Inflammatory and Noninflammatory Synovial Fluids Exhibit New and Distinct Tribological Endotypes.

Inferior synovial lubrication is a hallmark of osteoarthritis (OA), and synovial fluid (SF) lubrication and composition are variable among OA patients. Hyaluronic acid (HA) viscosupplementation is a widely used therapy for improving SF viscoelasticity and lubrication, but it is unclear how the effectiveness of HA viscosupplements varies with arthritic endotype. The objective of this study was to investigate the effects of the HA viscosupplement, Hymovis®, on the lubricating properties of diseased SF from patients with noninflammatory OA and inflammatory arthritis (IA). The composition (cytokine, HA, and lubricin concentrations) of the SF was measured as well as the mechanical properties (rheology, tribology) of the SF alone and in a 1:1 mixture with the HA viscosupplement. Using rotational rheometry, no difference in SF viscosity was detected between disease types, and the addition of HA significantly increased all fluids' viscosities. In noninflammatory OA SF, friction coefficients followed a typical Stribeck pattern, and their magnitude was decreased by the addition of HA. While some of the IA SF also showed typical Stribeck behavior, a subset showed more erratic behavior with highly variable and larger friction coefficients. Interestingly, this aberrant behavior was not eliminated by the addition of HA, and it was associated with low concentrations of lubricin. Aberrant SF exhibited significantly lower effective viscosities compared to noninflammatory OA and IA SF with typical tribological behavior. Collectively, these results suggest that different endotypes of arthritis exist with respect to lubrication, which may impact the effectiveness of HA viscosupplements in reducing friction.

Mud-bath treatment of seronegative spondyloarthritis: experience at the Euganean Thermal Area.

Mud-bath therapy (MBT) has been used as a treatment for rheumatic diseases and musculoskeletal complaints in the Euganean Thermal Area (near Padova, Italy) since ancient time. There is no consensus about the use of MBT in patients with inflammatory rheumatic diseases, although experimental studies have suggested a beneficial effect of MBT on chronic articular inflammation. To evaluate the effects of MBT in patients affected by seronegative spondyloarthritis, very common chronic inflammatory rheumatic diseases, randomized controlled trials (RCT) performed in the Euganean Thermal Area have been reviewed. A significant improvement of spondylitis parameters was observed in enteropathic spondylitis, without bowel symptom exacerbation. A long-term amelioration of clinical evaluation indices was found in ankylosing spondylitis. A significant improvement of cutaneous lesions, arthritis activity, and patient's functional ability was observed in psoriatic arthritis. MBT was usually well tolerated and adverse side effects were rarely reported. The review of the RCT suggests that MBT may exert additional beneficial effects in patients with seronegative spondyloarthritis treated with pharmacological therapy.

Common gene variants interactions related to uric acid transport are associated with knee osteoarthritis susceptibility.

BACKGROUND: The presence of genetic variants in uric acid (UA) transporters can be associated with hyperuricemia, and therefore with an increased risk of monosodium urate (MSU) crystal precipitation. The inflammatory process triggered by these crystals leads to cartilage damage, which, in turn, could promote knee osteoarthritis (KOA). OBJECTIVE: To determine whether genetic polymorphisms of the UA transporters and their interactions are associated with KOA. MATERIALS AND METHODS: Two hundred forty-three unrelated Mexican-mestizo individuals were recruited for this case-control study. Ninety-three of them were KOA patients but without gout, and one hundred and fifty healthy individuals with no symptoms or signs of KOA were recruited as controls. Forty-one single-nucleotide polymorphisms (SNPs) involved in the UA transporters were genotyped with OpenArray technology in a QuantStudio 12K flex-System with both cases and controls. RESULTS: After adjusting by age, gender, BMI, and ancestry, significant associations were found for eight SNPs: rs1260326 (GCKR), rs780093 (GCKR), rs17050272 (INHBB), rs1471633 (PDZK1), rs12129861 (PDZK1), rs7193778 (IGF1R), rs17786744 (STC1), and rs1106766 (R3HDM2). With respect to gene-gene interactions, the pairwise interactions of rs112129861 (PDZK1) and rs7193778 (IGF1R); rs17050272 (INHBB) and rs1106766 (R3HDM2); rs1106766 (R3HDM2) and rs780093 (GCKR); rs1260326 (GCKR) and rs17786744 (STC1); and rs17786744 (STC1) and rs1106766 (R3HDM2) make it possible to visualize the synergistic or antagonistic effect of their genotypes or alleles on KOA development. CONCLUSIONS: Our preliminary results show that the common gene variants related to UA transport are associated with KOA in the Mexican population. Further studies must be carried out to corroborate it.

One year in review 2018: gout.

Gout is the most common form of inflammatory arthropathy, and is associated with excruciating pain, major impairment of quality of life, and increased risk of comorbidities and mortality. Although gout has somehow been neglected by researchers and clinicians in the past, in more recent times there has been a renewed interest in this disease, which has led to major improvements in its management. This article reviews the new clinical and experimental evidence about gout that emerged in 2017 and in the first half of 2018.

Anti-inflammatory effects of polyphenols in arthritis.

Polyphenols have been extensively investigated with regard to their antioxidant, anti-inflammatory, and immunomodulant properties in many inflammatory chronic conditions. The aim of this review is to summarise how these compounds can modulate the inflammatory pathways which characterise the most prevalent arthropathies including osteoarthritis, rheumatoid arthritis and crystal-induced arthritis. Among polyphenols, epigallocatechin gallate, carnosol, hydroxytyrosol, curcumin, resveratrol, kaempferol and genistein have been the most widely investigated in arthritis. The most important results of the studies outlined in this article show how polyphenolic compounds are able to inhibit the expression and the release of a number of pro-inflammatory mediators and proteolytic enzymes, the activity of different transcriptional factors and the production of reactive oxygen species in vitro. Studies on animal models of rheumatoid arthritis, osteoarthritis and gout show interesting results in terms of reduced tissue damage, restored cartilage homeostasis, and decreased levels of uric acid, respectively. Despite the multiple protective effects of polyphenols, there are no dietary recommendations for patients affected by rheumatic diseases. Future studies, including intervention trials, should be conducted to determine the relevance of polyphenols consumption or supplementation in arthritis. © 2017 Society of Chemical Industry.

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis.

OBJECTIVES: While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis. METHODS: Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains. RESULTS: Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA. CONCLUSIONS: Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

The prevalence of monosodium urate and calcium pyrophosphate crystals in synovial fluid from wrist and finger joints.

The aim of this study was to assess the frequency of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluids (SFs) aspirated from wrist and finger joints of patients with previously diagnosed joint diseases. We reviewed the results of SF analysis of 1593 samples and identified 126 patients with effusions in the small joints of the hands and wrists. We reported from patients' medical files data about sex, age, diagnosis, disease duration and the microscopic SF results. The prevalence of CPP crystals in SF was 85.71% in CPP-crystals arthritis (CPP-CA), 19.35% in rheumatoid arthritis (RA), 13.89% in osteoarthritis (OA) and 0% in psoriatic arthritis (PsA), spondyloarthritis (SpA), gout and miscellanea. The prevalence of MSU crystals in SF was 83.3% in gout, 10% in PsA, 2.8% in OA and 0% in RA, SpA, miscellanea and CPP-CA. Consistent with previously reported data concerning the big joints, microcrystals can be frequently found also in the small joints of patients with previous diagnosis. The finding underlines the importance of analyzing SF from the hand and wrist joints in the attempt to identify comorbidities associated with the presence of crystals and to develop targeted treatment strategies.

Detection of Calcium Crystals in Knee Osteoarthritis Synovial Fluid: A Comparison Between Polarized Light and Scanning Electron Microscopy.

BACKGROUND: The identification of calcium crystals in synovial fluid (SF) of patients with osteoarthritis (OA) represents an important step in understanding the role of these crystals in synovial inflammation and disease progression. OBJECTIVES: This study aimed to investigate the presence of calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals in SF collected from patients with symptomatic knee OA by scanning electron microscopy (SEM) coupled to x-ray energy dispersive spectroscopy, compensated polarized light microscopy (CPLM), and alizarin red staining. METHODS: Seventy-four patients with knee OA were included in the study. Synovial fluid samples were collected after arthrocentesis and examined under CPLM for the assessment of CPP crystals. Basic calcium phosphate crystals were evaluated by alizarin red staining. All the samples were examined by SEM. The concordance between the 2 techniques was evaluated by Cohen κ agreement coefficient. RESULTS: Calcium pyrophosphate and BCP crystals were found, respectively, in 23 (31.1%) and 13 (17.5%) of 74 OA SFs by SEM analysis. Calcium pyrophosphate crystals were identified in 23 (31.1%) of 74 samples by CPLM, whereas BCP crystals were suspected in 27 (36.4%) of 74 samples. According to κ coefficient, the concordance between CPLM and SEM was 0.83 for CPP, and that between alizarin red and SEM was 0.68 for BCP. CONCLUSIONS: The results of our study showed a high level of concordance between the 2 microscope techniques as regards CPP crystal identification and a lower agreement for BCP crystals. Although this finding highlights the difficulty in identifying BCP crystals by alizarin red staining, the use of SEM remains unsuitable to apply in the clinical setting. Because of the in vitro inflammatory effect of BCP crystals, further work on their analysis in SF could provide important information about the OA process.

High-density lipoproteins inhibit urate crystal-induced inflammation in mice.

OBJECTIVES: To investigate the effects and mechanisms of action of high-density lipoproteins (HDL) in monosodium urate (MSU) crystal-induced inflammation -that is, gouty inflammation, in vivo. METHODS: Air pouches raised on the backs of mice were injected with MSU crystals or tumour necrosis factor (TNF) in the presence or absence of HDL and/or interleukin (IL)-1 receptor antagonist (IL-1Ra) for 3 h. Leucocyte count and neutrophil percentage in pouch fluids were measured using a haemocytometer and May-Grünwald-Giemsa staining. The cytokine production and expression in the pouch were measured by ELISA and quantitative RT-PCR. RESULTS: MSU crystals induced leucocyte infiltration, mostly neutrophils, and the release of IL-1ß, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C-C motif) ligand 2 (CCL2) and IL-1Ra in pouch fluids. TNF remained under the detection limit. MSU crystals triggered IL-1ß, IL-6 and CXCL1 expression in both pouch exudates and membranes, whereas CCL2 and TNF mRNA were not modulated. The co-injection of MSU crystals and HDL inhibited leucocyte influx by 59% and neutrophil infiltration by 83% and, in turn, both protein and mRNA levels of all assessed proinflammatory cytokines were reduced, but not those of IL-1Ra. Similar results were obtained when mice were injected with MSU crystals pretreated with HDL or TNF instead of crystals. When HDL and IL-1Ra were added together they displayed additional inhibition, suggesting different mechanisms of action. CONCLUSIONS: This study demonstrated that HDL may represent an important factor in the modulation of gouty inflammation by acting on both tissue and infiltrating cells -that is, synovial tissue and synovial fluid cells. HDL display anti-inflammatory activity, in part, by interacting with crystals but also by directly acting on cells.