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.

Evolution of musculoskeletal symptoms in Long COVID syndrome: a lexical analysis to approach requirements for an interdisciplinary management.

Long COVID syndrome is characterized by new, returning, or persistent symptoms after the initial SARS-CoV-2 infection. Among the potential long-term effects of COVID-19, several different musculoskeletal symptoms have been reported in many patients with an important impact on quality of life. The rehabilitation needs of Long COVID patients could be dynamic. However, to date there are no studies that have evaluated how the rehabilitation needs of patients with Long COVID syndrome have changed over time. We conducted a literature review to summarize the most recurrent manifestations of the Long COVID syndrome during the three years of the pandemic, as well as the evolution of musculoskeletal symptoms, through lexical analysis. This approach allowed us to investigate the literature, highlighting how the most used words to describe Long COVID symptoms and outcomes have changed over different periods. Our analysis showed an increasing involvement of the musculoskeletal system in Long COVID symptomatology, as evidenced by the progressive growth of fatigue and weakness symptoms over time. In addition, arthralgia has always been associated with Long COVID. The lexical analysis we conducted emphasizes the need for interdisciplinary management, as the symptoms reported are interconnected. Moreover, this novel approach highlights that the Long COVID syndrome can be interpreted as a dynamic entity requiring up-to-date rehabilitative interventions. The worldwide healthcare systems should be founded on multidisciplinary teams to guarantee early and comprehensive rehabilitation to reduce the socio-sanitary burden associated with this syndrome.

Effect of intra-articular injection of a hyaluronic acid-alendronate conjugate on post-traumatic osteoarthritis induced by destabilization of the medial meniscus in rats.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by pain and cartilage damage. Intra-articular (i.a) viscosupplementation with hyaluronic acid (HA) is frequently used for the management of OA. Preclinical studies have reported that bisphosphonates (BPs) may have a therapeutic potential to slow down or reverse the progression of OA. Among these, alendronate (ALN) has demonstrated chondroprotective effects in both in vitro and vivo experiments. This study evaluated the effects of a novel alendronate-hyaluronic acid (ALN-HA) conjugate on an OA in vivo model induced by medial meniscus destabilization (DMM). DMM surgery was performed on the knees of Sprague Dawley rats that received, after four weeks, one intra-articular (i.a.) injection of: (1) ALN-HA; (2) HA; (3) sodium chloride (NaCl). Sham-operated rats were used as control. Allodynia was assessed by Von Frey test. Joint degeneration was evaluated eight weeks after treatment by micro-computed tomography (micro-CT), histology, and immunohistochemistry. Collagen cross-linked C-telopeptides (CTX-I and CTX-II) serum levels were determined by ELISA. Paw withdrawal threshold increased in ALN-HA group when compared to rats treated with NaCl or HA. Micro-CT did not show differences between ALN-HA, HA and NaCl groups. ALN-HA injection produced significant improvements in articular cartilage degeneration showing an OARSI score lower than those of HA and NaCl, and reduced matrix metalloproteinase (MMP)-13, MMP-3, interleukin-6, vascular endothelial growth factor and Caspase-3 expression. CTX-I was reduced after ALN-HA treatment when compared to NaCl. Our results indicate that i.a. use of ALN after conjugation with HA limits OA development and progression in the rat DMM model, and may lead to the development of novel therapeutic strategies in OA management.

The Potential Role of Spa Therapy in Managing Frailty in Rheumatic Patients: A Scoping Review.

Frailty is not limited to the elderly, as patients with rheumatic diseases can also experience this condition. The present scoping review aimed to investigate the possibility of using the health resort setting as an alternative location for managing rheumatic patients with frailty. The research resulted in finding several in vitro, in vivo, and clinical studies, resulting in evidence supporting the effectiveness of spa treatments in reducing pain, improving function, and managing comorbidity in rheumatic diseases. Additionally, spa treatments were demonstrated to modulate the MAPK/ERK pathway and the NF-kB pathway's activation and to reduce proinflammatory molecules' secretion in rheumatic diseases, thus suggesting their potential effective role in the regulation of inflammaging in frailty. Moreover, the health resort setting may offer potential resources to reduce risk factors, such as drug consumption, inactivity, and disease severity, and may serve as a setting for developing prevention protocols for frailty. Future research should explore innovative approaches, such as exercise training and early diagnostics, for the overall management of frailty in rheumatic patients in the spa setting.

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.

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.

Reliability and Diagnostic Accuracy of Radiography for the Diagnosis of Calcium Pyrophosphate Deposition: Performance of the Novel Definitions Developed by an International Multidisciplinary Working Group.

OBJECTIVE: To assess the reliability and diagnostic accuracy of new radiographic imaging definitions developed by an international multidisciplinary working group for identification of calcium pyrophosphate deposition (CPPD). METHODS: Patients with knee osteoarthritis scheduled for knee replacement were enrolled. Two radiologists and 2 rheumatologists twice assessed radiographic images for presence or absence of CPPD in menisci, hyaline cartilage, tendons, joint capsule, or synovial membrane, using the new definitions. In case of disagreement, a consensus decision was made and considered for the assessment of diagnostic performance. Histologic examination of postsurgical specimens under compensated polarized light microscopy was the reference standard. Prevalence-adjusted bias-adjusted kappa values were used to assess reliability, and diagnostic performance statistics were calculated. RESULTS: Sixty-seven patients were enrolled for the reliability study. The interobserver reliability was substantial in most of the assessed structures when considering all 4 readers (κ range 0.59-0.90), substantial to almost perfect among radiologists (κ range 0.70-0.91), and moderate to almost perfect among rheumatologists (κ range 0.46-0.88). The intraobserver reliability was substantial to almost perfect for all the observers (κ range 0.70-1). Fifty-one patients were included in the accuracy study. Radiography demonstrated an overall specificity of 92% for CPPD, but sensitivity remained low for all sites and for the overall diagnosis (54%). CONCLUSION: The new radiographic definitions of CPPD are highly specific against the gold standard of histologic diagnosis. When the described radiographic findings are present, these definitions allow for a definitive diagnosis of CPPD, rather than other calcium-containing crystal depositions; however, a negative radiographic finding does not exclude the diagnosis.

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.

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.

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.

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.

Therapeutic Exercise and Conservative Injection Treatment for Early Knee Osteoarthritis in Athletes: A Scoping Review.

Background and Objectives: Recent evidence highlighted a higher prevalence of knee osteoarthritis (kOA) among young and former ex-professional athletes. Although the practice of a highly demanding sport is considered a predisposing factor for the knee joint cartilage degeneration, articular cartilage seems to positively respond to a moderate load increase. We aim to investigate recent evidence on the conservative management of early kOA in athletes, with a particular emphasis on therapeutic exercise and injection treatment, in order to highlight whether there are any indications that can influence clinical and rehabilitation practice. Materials and Methods: A scoping review was conducted, screening MEDLINE and PEDro databases for studies published over the past twenty years on the topic. Studies in English, with accessible abstracts, were included in the review. The PICO framework was used (P-patient: athletes, I-Intervention: conservative treatment with therapeutic exercise or injection therapies, C-Comparison: not needed, O-Outcomes: clinical outcomes). Clinical trials, randomized controlled trials, and longitudinal studies were considered. Results: Four studies were finally included in the review. Therapeutic exercise seems to have beneficial effects on prevention of cartilage degeneration, on pain reduction, and on physical function enhancement. On the other hand, in mild to moderate stages of kOA the intra-articular viscosupplementation with Hyaluronic Acid showed a medium to long-term improvement in joint pain and function. The Platelet Rich Plasma treatment also showed a significant improvement in pain and function up to 12 months. Conclusions: Despite the heterogeneity of the studies considered, a multimodal treatment combining therapeutic exercise and moderate aerobic activity (such as running) should be indicated to prevent kOA development. In cases of symptomatic kOA it may be indicated to add minimally invasive injection therapy that seems to contribute to the improvement of motor function and symptomatology.

Biobanking in dentistry: A review.

Biobanks are not-for-profit services for the collection, processing, storage and distribution of biological samples and data for research and diagnostic purposes. In dentistry, biological materials and data obtained from questionnaires investigating oral conditions can be stored and used for large-scale studies on oral and systemic diseases. To give some examples: gene expression microarrays obtained on biobanked specimens were used in the identification of genetic alterations in oral cancer; efforts to identify genetic mechanisms behind dental caries have been based on an integrative analysis of transcriptome-wide associations and messenger RNA expression. One of the largest studies on facial pain was conducted using Biobank data. Cryopreservation of dental pulp stem cells is a common practice in tooth biobanks. With the exception of teeth and pulp, also leftover oral soft and hard tissues may represent a source of healthy samples that has rarely been exploited as yet. While biobanks are increasingly attracting the attention of the scientific community and becoming economically sustainable, a systematic approach to this resource in dentistry seems to be lacking. This review illustrates the applications of biobanking in dentistry, describing biobanked pathological and healthy samples and data, and discussing future developments.

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.

Lifetime Prevalence of Nonspecific Low Back Pain in Adolescents: A Cross-sectional Epidemiologic Survey.

BACKGROUND: Many nonconclusive studies have been conducted on low back pain (LBP) in adolescents and associated factors. OBJECTIVE: The aim was to assess the lifetime prevalence and associated factors of LBP in adolescents. MATERIALS AND METHODS: A questionnaire was administered in high school students (14-19-yr-old participants) in Veneto region (Italy). The self-administered, structured questionnaire included anthropometric data; psychologic factors and lifestyle; presence, intensity, and family history of LBP; referral to professional health care for LBP; and a short version of the International Physical Activity Questionnaire. RESULTS: A total of 6281 adolescents were recruited; 5204 questionnaires were included in the final analysis. A total of 2549 (48.98%) students reported one or more LBP episodes and 723 (13.89%) reported nonspecific disabling lumbar pain (i.e., no underlying pathology); 1040 (41.11%) subjects with LBP consulted a healthcare professional. A significant association emerged for LBP with sex (female), positive family history, time spent sitting or using electronic devices, sleep deprivation (<5 hrs/night), and low level of physical activity. CONCLUSION: In a large sample of adolescents, LBP lifetime prevalence is high and often associated with disabling pain and sedentary lifestyle, requiring professional care. These findings may support the development of prevention and treatment strategies of LBP in adolescents, reducing the risk of developing chronic pain.