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.

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.

Acute Calcium Pyrophosphate Crystal Arthritis of the Wrist Elicited by Anti-COVID-19 Vaccination After Carpal Tunnel Release.

BACKGROUND Calcium pyrophosphate dihydrate deposition disease includes a variety of clinical syndromes, including acute calcium pyrophosphate (CPP) crystal arthritis. Most patients with CPP crystal arthritis have a primary/idiopathic form presenting with severe pain, swelling, and stiffness. COVID-19 infection, which originated in China in December 2019, required extraordinary efforts to develop and test new vaccines to halt the pandemic. The Vaxzervria vaccine has shown excellent safety and efficacy in phase 3 trials with a mechanism based on the expression of the SARS-CoV-2 spike protein gene coding for the S-antigen, which stimulates the immune response. CASE REPORT We describe an acute event of crystal arthritis after a carpal tunnel syndrome release followed by administration of the second dose of anti-COVID-19 Vaccine Oxford-AstraZeneca (ChAdOx1 nCoV-19). Medical treatment resulted in full resolution of the symptoms in 2 weeks. CONCLUSIONS Although most episodes of acute arthritis happen spontaneously, certain factors may trigger the acute CPP crystal arthritis such as intercurrent illnesses or surgeries. Although the association between carpal tunnel syndrome and CPP arthritis has been known for over 40 years, surgical release of the carpal ligament has always been associated with full resolution of symptoms. This is the first case report describing an exacerbation after carpal canal release, concomitant with the administration of the vaccine. According to our opinion, the vaccination associated with a prior surgery in the same anatomical site could have synergically triggered the arthritis flare-up, in a predisposed patient, with a mechanism still unknown.

A Pro-Inflammatory Signature Constitutively Activated in Monogenic Autoinflammatory Diseases.

Autoinflammatory diseases (AIDs) are disorders characterised by recurrent inflammatory episodes in charge of different organs with no apparent involvement of autoantibodies or antigen-specific T lymphocytes. Few common clinical features have been identified among all monogenic AIDs (mAIDs), while the search for a common molecular pattern is still ongoing. The aim of this study was to increase knowledge on the inflammatory pathways in the development of mAIDs in order to identify possible predictive or diagnostic biomarkers for each disease and to develop future preventive and therapeutic strategies. Using protein array-based systems, we evaluated two signalling pathways known to be involved in inflammation and a wide range of inflammatory mediators (pro-inflammatory cytokines and chemokines) in a cohort of 23 patients affected by different mAIDs, as FMF, TRAPS, MKD, Blau syndrome (BS), and NLRP12D. Overall, we observed upregulation of multiple signalling pathway intermediates at protein levels in mAIDs patients' PBMCs, compared with healthy controls, with significant differences also between patients. FMF, TRAPS, and BS presented also peculiar activations of inflammatory pathways that can distinguish them. MAPK pathway activation, however, seems to be a common feature. The serum level of cytokines and chemokines produced clear differences between patients with distinct diseases, which can help distinguish each autoinflammatory disease. The FMF cytokine production profile appears broader than that of TRAPS, which, in turn, has higher cytokine levels than BS. Our findings suggest an ongoing subclinical inflammation related to the abnormal and constitutive signalling pathways and define an elevated inflammatory cytokine signature. Moreover, the upregulation of Th17-related cytokines emphasises the important role for Th17 and/or Th17-like cells also in monogenic AIDs.

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.

NKG2D ligands in inflammatory joint diseases: analysis in human samples and mouse models.

OBJECTIVES: NKG2D ligands (NKG2DLs) are stress-inducible molecules involved in multiple inflammatory settings. In this work, we quantified MICA, an NKG2DL, in the synovial fluid of patients suffering various arthritides and measured Nkg2dLs gene expression in murine models of acute joint inflammation. METHODS: Soluble MICA (sMICA) was quantified by ELISA is synovial fluids harvested from patients suffering osteoarthritis, rheumatoid arthritis, psoriatic arthritis, calcium pyrophosphate crystal arthritis, urate crystal arthritis and reactive arthritis. Transcripts encoding murine NKG2DLs were quantified by RT-qPCR in the joints of mouse models of rheumatoid arthritis, urate crystal arthritis and osteoarthritis. RESULTS: Marked overproduction of sMICA was observed in the synovial fluid of RA patients. Mouse studies highlighted the complex transcriptional regulation of Nkg2d ligands encoding genes depending on the inflammatory setting and microenvironment CONCLUSIONS: sMICA quantification could be an interesting biomarker to identify acute inflammation in RA patients in whom classical markers (i.e. anti-citrullinated protein antibodies, ACPA) are undetectable.

The two faces of the same medal or maybe not? Comparing osteoarthritis and calcium pyrophosphate deposition disease: a laboratory and ultrasonographic study.

OBJECTIVES: Osteoarthritis (OA) and calcium pyrophosphate deposition disease (CPPD) are frequently associated but the real relation between these diseases is not still understood. The aim of this paper is to investigate the characteristics in terms of inflammation, anatomical changes and synovial fluid (SF) features in knees of patients with OA and CPPD. METHODS: Consecutive patients older than 55 years with knee pain and swelling were enrolled. All patients underwent a complete clinical examination, a US examination of the affected joint, arthrocentesis of the knee and analysis of synovial fluid, including dosing of inorganic ions and number of crystals. The gold standard for the diagnosis was the microscopic analysis of the SF. RESULTS: Sixty-seven patients were enrolled, 25 affected by OA and 42 by CPPD. At US, a significantly higher amount of effusion and synovitis was identified in patients with CPPD but there were no significant differences regarding structural changes. At the SF analysis, the white blood cell (WBC) count was higher in patients with CPPD who also presented a higher number of polymorphonuclear cells and a lower number of monocytes. Regarding the inorganic ion concentration, the statistical analysis did not reveal any differences. The number of crystals in the SF, correlated with a larger effusion, higher grade of synovitis and a higher WBC count. CONCLUSIONS: A higher degree of inflammation was found in patients with CPPD. The findings suggest that longitudinal studies would be useful to better understand the evolution of the diseases and highlight the need for different treatment strategies.

Effect of pathogenic crystals on the production of pro- and anti-inflammatory cytokines by different leukocyte populations.

PURPOSE: To evaluate cytokine production in vitro by different types of leukocytes stimulated with monosodium urate (MSU), calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals. MATERIAL AND METHODS: Polymorphonuclear cells (PMN), monocytes and lymphocytes, isolated from healthy volunteer blood, were stimulated for different time periods with increasing MSU, CPP or BCP crystal concentrations. IL-1ß, IL-8, IL-6, CCL2, IL-1Ra and TGFß1 were determined by ELISA. RESULTS: Exposure of PMN to different crystals resulted in a moderate IL-8 and IL-1Ra release. Stimulation of monocytes induced a significant production of all the cytokines evaluated. The highest levels of IL-1ß, IL-6, CCL2 and IL-8 were observed with MSU at 0.5 mg/ml, CPP at 0.01-0.05 mg/ml and BCP at 1 mg/ml after 18-48 h and then decreased. At the same crystal concentrations, IL-1Ra and TGFß1 increased until the end of the experiment. Treatment of lymphocytes with different crystals did not induce cytokine release. CONCLUSION: This study demonstrates that PMN, monocytes and lymphocytes from the same donor respond differently after stimulation with MSU, CPP or BCP crystals, depending on the dose and the time of exposure. Crystals induce a rapid increase of pro-inflammatory cytokines, whereas longer time is required to release high levels of anti-inflammatory cytokines.

Criterion validity of ultrasound in the identification of calcium pyrophosphate crystal deposits at the knee: an OMERACT ultrasound study.

OBJECTIVE: To evaluate the discriminatory ability of ultrasound in calcium pyrophosphate deposition disease (CPPD), using microscopic analysis of menisci and knee hyaline cartilage (HC) as reference standard. METHODS: Consecutive patients scheduled for knee replacement surgery, due to osteoarthritis (OA), were enrolled. Each patient underwent ultrasound examination of the menisci and HC of the knee, scoring each site for presence/absence of CPPD. Ultrasound signs of inflammation (effusion, synovial proliferation and power Doppler) were assessed semiquantitatively (0-3). The menisci and condyles, retrieved during surgery, were examined microscopically by optical light microscopy and by compensated polarised microscopy. CPPs were scored as present/absent in six different samples from the surface and from the internal part of menisci and cartilage. Ultrasound and microscopic analysis were performed by different operators, blinded to each other's findings. RESULTS: 11 researchers from seven countries participated in the study. Of 101 enrolled patients, 68 were included in the analysis. In 38 patients, the surgical specimens were insufficient. The overall diagnostic accuracy of ultrasound for CPPD was of 75%-sensitivity of 91% (range 71%-87% in single sites) and specificity of 59% (range 68%-92%). The best sensitivity and specificity were obtained by assessing in combination by ultrasound the medial meniscus and the medial condyle HC (88% and 76%, respectively). No differences were found between patients with and without CPPD regarding ultrasound signs of inflammation. CONCLUSION: Ultrasound demonstrated to be an accurate tool for discriminating CPPD. No differences were found between patents with OA alone and CPPD plus OA regarding inflammation.

Efficacy of conservative treatments for hand osteoarthritis : An umbrella review of interventional studies.

BACKGROUND: Hand osteoarthritis (OA) is common, but the efficacy/safety of treatment interventions aimed to improve health outcomes in this population are not well understood. Therefore, the aim of this study was to map and grade the effect of interventions for health outcomes in hand OA. METHODS: Umbrella review of systematic reviews with meta-analyses of randomized controlled trials (RCTs) using placebo/no intervention as control group. For outcomes with a p-value <0.05, the certainty of the evidence was evaluated using the grading of recommendations assessment, development and evaluation (GRADE) assessment. RESULTS: From 189 abstracts, 9 meta-analyses (24 outcomes) were included, with 8 reporting significant summary results. The use of splints was associated with reduced pain at medium term in thumb carpometacarpal OA (standardized mean difference [SMD] = -0.70; 95% confidence intervals [95% CI]: -1.05 to -0.35; low certainty), reduced pain in long follow-up RCTs in symptomatic hand OA (SMD = -0.80; 95% CI: -1.16; -0.45; moderate certainty), and better function (SMD = 0.42; 95% CI: 0.08; 0.70; low certainty). The use of resistance training (SMD = -0.27; 95% CI: -0.47; -0.07) or physical exercise (SMD = -0.23; 95% CI: -0.42; -0.04) in improving hand pain and in improving finger joint stiffness (SMD = -0.36; 95%CI: -0.58; -0.15) was supported by a moderate certainty of evidence. The use of intra-articular hyaluronic acid in improving function (MD = 1.12; 95% CI: 0.61; 1.64; moderate certainty of evidence) was the only statistically significant pharmacological intervention. CONCLUSION: Only some non-pharmacological interventions are effective in improving health outcomes in hand OA and this evidence is supported by a moderate/low certainty, indicating the necessity of further interventional research.

Validation of the Italian Version of the Educational Needs Assessment Tool in Rheumatoid Arthritis Patients and Factors Associated with Educational Needs.

The educational needs assessment tool (ENAT) is a seven-domain questionnaire assessing the educational needs (EN) of patients with rheumatoid arthritis (RA). The aim of this study was to validate the Italian version of the ENAT and to identify factors associated with EN in people with RA. The original English ENAT version was translated into Italian according to Beaton's method and subjected to Rasch analysis for validity testing. Socio-demographic and clinical variables were tested for associations with the ENAT domain scores using a multivariable linear regression model. The ENAT translated well into Italian and retained its construct validity. Some adjustments were needed when pooling the Italian and English datasets. The overall score of the ENAT had a high median: 82.8 (interquartile range (IQR): 57.5 to 100) i.e., 72.4% of the maximum score. The highest score was observed in the domain "Arthritis process" and the lowest was in "Support systems". Only gender was independently associated with EN (females having higher EN than males). The Italian ENAT is feasible for the use in the clinical setting and may help the health care practitioners to tailor educational interventions for RA patients. The characteristics of the patients, particularly female gender, may be associated with higher EN.

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.

Biologics in the treatment of calcium pyrophosphate deposition disease: a systematic literature review.

The main aim of this systematic literature review (SLR) was to summarise the evidence in the use of biological therapies in calcium pyrophosphate deposition disease (CPPD). We performed a SLR using PubMed, Embase and Cochrane databases. Only studies reporting the efficacy of biologics in CPPD were selected. The search resulted in 83 articles; 11 were further evaluated in the SLR. Seventy-six patients were included: 2 received infliximab, whereas 74 anakinra. Anakinra was used in refractory disease (85.1%) or in patients with contraindications to standard treatments (23.0%). Clinical response to anakinra was observed in 80.6% of patients with acute and 42.9% of those with chronic CPPD. Short-term treatment was well tolerated and adverse events were reported in 4.1% of the cases. This review provides evidence in favour of the use of anakinra as a therapeutic option in patients with CPPD, especially in acute refractory CPPD or when standard treatments are contraindicated.

Effectiveness of steroid injection for hand psoriatic dactylitis: results from a multicentre prospective observational study.

OBJECTIVE: To assess the effectiveness of steroid injection (local treatment, LT) into the digital flexor tendon sheath of dactylitis in psoriatic arthritis (PsA) patients as compared with systemic treatment (ST). METHODS: Forty-six PsA patients with a total of 73 dactylitic fingers were assessed in an observational, multicentre, prospective study by the Leeds Dactylitis Index basic (LDI-b) score and evaluated for local pain (visual analogue scale-VAS pain) and functional impairment (VAS-FI). Steroid injection was proposed to all patients. Patients refusing LT were treated with oral NSAIDs. Both the groups continued baseline csDMARDs and/or corticosteroids therapy. The clinical outcomes were measured at baseline, 1 month (T1) and 3 months (T3). RESULTS: The reduction of VAS-pain, VAS-FI and LDI-b values was statistically significant higher in the LT group (24 patients, 38 dactylitic fingers) as compared with the ST group (22 patients, 35 dactylitic fingers), both at T1 (p < 0.001, p < 0.001 and p = 0.008, respectively) and at T3 (p < 0.001, p < 0.001 and p < 0.001, respectively). A clinically meaningful treatment response (defined as a contemporary reduction of at least 5 points in VAS-pain and VAS-FI or as values of VAS-pain and VAS-FI were both ≤ 2) was observed at T1 in 33 (87%) digits in LT group and in 6 (17%) digits in ST group (p < 0.001). At T3, clinical response improved significantly in both the groups, with significant difference (94% vs 31%, p < 0.001). CONCLUSIONS: For the first time, we show the effectiveness of steroid injection into the digital flexor tendon sheath in improving clinical aspects of hand psoriatic dactylitis. Key Points • Therapy with steroid injection (local treatment, LT), into the digital flexor tendon sheath for the treatment of active dactylitis in psoriatic arthritis patients, is more effective when compared with systemic treatment (ST) alone. • The reduction of VAS-pain, VAS-functional impairment (VAS-FI) and Leeds Dactylitis Index basic values was statistically significant higher in the LT group as compared with the ST group, both at T1and at T3. • A clinically meaningful response was observed at T1 in 87% of digits of patients treated with steroid injection and in 17% of digits of the systemic treatment group (p < 0.001). At T3, clinical response improved significantly in both the groups, with significant difference. • For the first time, findings from this study show that the use of steroid injections into the digital flexor tendon sheath for psoriatic dactylitis could be an effective and safe first-line therapy for psoriatic dactylitis.

Multiple Dimensions of Self-Esteem and Their Relationship with Health in Adolescence.

The aim of the present study was to examine how different domains of self-esteem (social, competence, affect, academic, family, and physical) relate to self-reported physical and mental health, lower back pain (LBP), smoking, and physical exercise in a sample of adolescents. A sample of 326 adolescents 14-19 years old completed several self-report questionnaires collecting epidemiological data, and information on their LBP, smoking, and physical exercise, the Short Form Health Survey (SF-36), and the Multidimensional Self-Concept Scale. Pearson's correlations were calculated between their self-esteem scores and their physical and mental health scores. Three multivariate analyses of variance (MANOVAs) were performed to estimate associations between self-esteem and LBP, smoking, and physical exercise. Self-esteem (total and subcomponent scores) correlated positively with physical and mental health, and with physical exercise, and negatively with smoking. The results also confirm gender-related differences in self-esteem, in favor of boys. This study offers the first findings on the relationship between different domains of self-esteem and a variety of health outcomes in an adolescent population. The results suggest that multidimensional interventions could be devised to improve adolescents' physical health by promoting their physical exercise, and to prevent their smoking by nurturing their self-esteem.

A long-term nationwide study on mortality associated to rheumatoid arthritis in Italy.

OBJECTIVES: We aimed to evaluate trends of rheumatoid arthritis (RA) mortality reported as the underlying cause of death (UCD) and as multiple causes of death (MCD) in Italy between 2003 and 2015. METHODS: Analyses were carried out on the Italian National Cause of Death Register, managed by the Italian National Institute of Statistics (ISTAT). Deaths from January 1, 2003 to December 31, 2015 with any mention of RA were included. Diseases are coded according to the International Classification of Diseases, 10th Edition (ICD- 10, 2009 version). Time trends of age-standardised rates were analysed for RA both as UCD and MCD, and the annual percent change (APC) was estimated. RESULTS: Overall, 26,564 deaths with a mention of RA were retrieved out of 7,595,214 deaths (0.35% of all certificates). The mention of RA as MCD increased throughout the study period, meanwhile the selection as the UCD decreased. RA mortality rates based on the UCD declined (males APC -3.1%, CI -3.9, -2.3; females APC -3.3%, CI -4.1, -2.4); while rates based on the MCD were stable. Specifically, rates were stable or declined among younger subjects and increased in subjects aged ≥80 years. CONCLUSIONS: RA was found to be increasingly reported in death certificates in the last two decades in Italy, although it is less frequently reported as the UCD. Due to the increased survival of patients, we observed a shift of RA-related mortality towards the elderly, making RA a comorbidity contributing to death in these patients.

Improvement of Function and Its Determinants in a Group of Axial Spondyloarthritis Patients Treated with TNF Inhibitors: A Real-Life Study.

INTRODUCTION: The aim of this work is to investigate the improvement of physical function and its determinants in axial spondyloarthritis (SpA) patients treated with tumor necrosis factor (TNF) inhibitors in a real clinical practice setting. METHODS: An observational study was conducted in patients with axial SpA treated with anti-TNF from 2010 to 2018 with a minimum 6 months of follow-up. All patients fulfilled ASAS or the modified New York criteria. The Bath Ankylosing Spondylitis Metrology Index (BASMI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) were used as objective and self-reported functional indices. The improvement of function and factors associated were evaluated for the present study, as well as disease activity and patient-reported outcome measures. RESULTS: A total of 183 patients with axial SpA were examined. Among them, 27 were non-radiographic axial SpA, while the remaining 156 were ankylosing spondylitis patients. BASFI and BASMI significantly improved during follow-up. Improvement of metrology index BASMI inverse correlated with disease duration (rho - 0.2, p = 0.009) and directly correlated with the improvement of BASDAI (rho 0.26, p = 0.003) and CRP (rho 0.26, p = 0.0003). Improvement of BASFI significantly inversely correlated with disease duration and directly correlated with the improvement of BASDAI, CRP, and baseline ESR. Male sex, lower disease duration, high ESR, and the improvement of BASDAI were found to be associated with the improvement of BASFI. CONCLUSIONS: Our results showed that in real-life settings, patients improve in BASMI and BASFI. Furthermore, factors associated with this improvement were identified.