Downregulation of type I interferon signalling pathway by urate in primary human PBMCs.

Type I interferons (IFN1s) mediate innate responses to microbial stimuli and regulate interleukin (IL)-1 and IL-1 receptor antagonist (Ra) production in human cells. This study explores interferon-stimulated gene (ISG) alterations in the transcriptome of patients with gout and stimulated human primary cells in vitro in relation to serum urate concentrations. Peripheral blood mononuclear cells (PBMCs) and monocytes of patients with gout were primed in vitro with soluble urate, followed by lipopolysaccharide (LPS) stimulation. Separately, PBMCs were stimulated with various toll-like receptor (TLR) ligands. RNA sequencing and IL-1Ra cytokine measurement were performed. STAT1 phosphorylation was assessed in urate-treated monocytes. Cytokine responses to IFN-ß were evaluated in PBMCs cultured with or without urate and restimulated with LPS and monosodium urate (MSU) crystals. Transcriptomics revealed suppressed IFN-related signalling pathways in urate-exposed PBMCs or monocytes which was supported by diminishment of phosphorylated STAT1. The stimulation of PBMCs with IFN-ß did not modify the urate-induced inflammation. Interestingly, in vivo, serum urate concentrations were inversely correlated to in vitro ISG expression upon stimulations with TLR ligands. These findings support a deficient IFN1 signalling in the presence of elevated serum urate concentrations, which could translate to increased susceptibility to infections.

ERN ReCONNET points to consider for treating patients living with autoimmune rheumatic diseases with antiviral therapies and anti-SARS-CoV-2 antibody products.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

An ultrasonographic insight into musculoskeletal manifestation in 100 systemic lupus erythematosus patients.

OBJECTIVES: We aimed to investigate the prevalence of US findings in the hand joints and related tendons and explore clinical and laboratory associations in SLE patients of the typical lupus clinic. METHODS: One hundred consecutive SLE patients were enrolled in the study. Using B-mode and Doppler US, bilateral wrist, metacarpophalangeal and proximal interphalangeal joints were examined for synovitis and erosions, as well as for signs of hand tenosynovitis. RESULTS: US detected synovitis (grade 1-3) in 75% and erosive changes in 25% of the cohort. We found that clinical examination underestimated grade ≥2 synovitis by 13%, while US detected SH grade ≥2 in 10% of asymptomatic patients. The overall inflammatory burden, reflected by the US score, was associated with disease activity (respectively with CPR, SELENA-2K, MS-BILAG, and hypocomplementemia), as well as the presence of bone erosions. Rhupus patients had higher inflammatory markers, significantly more synovial hypertrophy, more erosions, more grade 3 tenosynovitis, and were more likely to receive methotrexate (p<0.001) than patients with SLE arthritis, while patients with Jaccoud's arthropathy were more likely to accumulate damage. The dominant hand exhibited more inflammatory changes (respectively synovial hypertrophy grade ≥2) at both the wrist and MCP joints; however, handedness was not associated with structural damage. CONCLUSIONS: In conclusion: 1. joint involvement in SLE is frequent and underacknowledged; 2. the overall inflammatory burden is associated with systemic disease activity and joint damage; (3) destructive arthritis is more likely to occur in the context of concomitant RA or within an "RA-like" subtype of SLE arthropathy; 4. hand dominance is associated with synovitis, but not structural changes; 5. US assessment may help tailor the management of joint involvement, thus preventing joint damage and disability in SLE patients.

Rare within rare. Necrotising scleritis and peripheral ulcerative keratitis: eye-threatening complications of relapsing polychondritis.

OBJECTIVES: Relapsing polychondritis (RP) evolves with variable and intermittent involvement of cartilage and proteoglycan-rich structures. Ocular manifestations are present in up to two-thirds of RP patients. Necrotising scleritis (NS) and peripheral ulcerative keratitis (PUK) may be inaugural and may lead to eye perforation and vision loss. We aimed to review NS and PUK in RP, in order to characterise them, to identify successful treatment options and unmet needs. METHODS: A systematic review of the currently available evidence in PubMed, EMBASE and Scopus was performed according to PRISMA, including observational studies, single case reports and case series of NS/PUK in RP. Study design, number of patients, age, gender, treatment and outcome, were extracted. Two RP patients also provided their opinion. RESULTS: Five case reports and two case series were eligible for inclusion. We identified 10 RP patients with eye-threatening complications (NS and/or PUK), 9 adults (2 males, 7 females, aged 35-72, median age 57.6 years) and one paediatric patient (F, 11 years). Apart from glucocorticoids, cyclophosphamide was effective in 4 patients; infliximab, high-dose immunoglobulins, dapsone, or cyclosporine were also successfully employed in a case each. Surgical repair was reported in 2 cases. CONCLUSIONS: Ocular inflammation is often bilateral and recurring in RP; NS/PUK are rare complications. All patients who develop NS/PUK should be specifically questioned for RP signs and symptoms. Early institution of immunosuppressive therapies is mandatory. Increasing awareness, physicians' and patients' education and a multidisciplinary approach may help improve the prognosis of these serious complications of RP.

Rare clinical manifestations in systemic lupus erythematosus: a review on frequency and clinical presentation.

OBJECTIVES: The purpose of this study was to review the frequency and clinical presentation of the rarest clinical manifestations of systemic lupus erythematosus (SLE). METHODS: A list of 6 rare SLE manifestations were defined: gastrointestinal, liver, pulmonary, cardiac, ocular and neurological manifestations. Each topic was assigned to a pair of authors to perform a literature search and article review. RESULTS: In total, 149 articles were included in the literature review: 37 for gastrointestinal manifestations, 6 for liver manifestations, 27 for pulmonary manifestations, 50 for cardiac manifestations, 16 for ocular manifestations, 13 for neurological manifestations. Gastrointestinal disorders included several clinical presentations with variable frequency (from 0.5% to 10.7% of the cases); liver involvement included lupus-related hepatitis (9.3%) and autoimmune hepatitis (2.3%). The rarest pulmonary manifestations identified were shrinking lung syndrome, described in 1.5% of patients, while interstitial lung disease and lupus pneumonia were reported in 4% and 3% of patients respectively. Myocarditis and pulmonary hypertension were also rarely described in SLE patients although ranging from 0.4-16% and 1-14% respectively, depending on the methodology used for its identification. Ocular manifestations in SLE included some rare manifestations (reported in less than 5% of patients) and lupus retinopathy that is described in 1.2-28.8% of patients depending on methods of ascertainment. Aseptic meningitis and chorea were also confirmed as very rare manifestations being reported in less than 1% and in 0.3-2.4% of cases respectively. CONCLUSIONS: The results of this literature review provide the basis for a better understanding of some less-known manifestations of SLE and for stressing the need for a higher awareness in diagnostic and therapeutic protocols regarding these rare disease aspects.

Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity.

OBJECTIVES: Systemic lupus erythematosus (SLE) diagnosis and treatment remain empirical and the molecular basis for its heterogeneity elusive. We explored the genomic basis for disease susceptibility and severity. METHODS: mRNA sequencing and genotyping in blood from 142 patients with SLE and 58 healthy volunteers. Abundances of cell types were assessed by CIBERSORT and cell-specific effects by interaction terms in linear models. Differentially expressed genes (DEGs) were used to train classifiers (linear discriminant analysis) of SLE versus healthy individuals in 80% of the dataset and were validated in the remaining 20% running 1000 iterations. Transcriptome/genotypes were integrated by expression-quantitative trail loci (eQTL) analysis; tissue-specific genetic causality was assessed by regulatory trait concordance (RTC). RESULTS: SLE has a 'susceptibility signature' present in patients in clinical remission, an 'activity signature' linked to genes that regulate immune cell metabolism, protein synthesis and proliferation, and a 'severity signature' best illustrated in active nephritis, enriched in druggable granulocyte and plasmablast/plasma-cell pathways. Patients with SLE have also perturbed mRNA splicing enriched in immune system and interferon signalling genes. A novel transcriptome index distinguished active versus inactive disease-but not low disease activity-and correlated with disease severity. DEGs discriminate SLE versus healthy individuals with median sensitivity 86% and specificity 92% suggesting a potential use in diagnostics. Combined eQTL analysis from the Genotype Tissue Expression (GTEx) project and SLE-associated genetic polymorphisms demonstrates that susceptibility variants may regulate gene expression in the blood but also in other tissues. CONCLUSION: Specific gene networks confer susceptibility to SLE, activity and severity, and may facilitate personalised care.

Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis.

OBJECTIVES: Chronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN. METHODS: We performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples. RESULTS: A group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement. CONCLUSION: Interstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

Functional MRI in rheumatic diseases with a focus on fibromyalgia.

Pain is the most common symptom in rheumatic diseases. However, the severity of pain does not correlate with pathology. The lack of an objective test for pain results in clinicians consider pain in patients with fibromyalgia as psychological. Research over the last two decade using functional neuroimaging especially functional MRI scan have demonstrated objectively that patients with fibromyalgia were not malingering. Pain processing is complex and multiple regions of the brain are involved. One consistent finding is decrease activity in regions of the brain involved in pain inhibitory pathways suggesting this is one of the fundamental pathophysiology processes in fibromyalgia.

Relationship Between Ventricular Arrhythmias, Conduction Disorders, and Myocardial Fibrosis in Patients With Systemic Sclerosis.

BACKGROUND: Delayed-enhancement magnetic resonance imaging (DE-MRI) is a noninvasive diagnostic tool able to identify myocardial fibrosis. In patients with scleroderma, its relationship with arrhythmias and conduction disorders has not been fully explored. OBJECTIVES: The aim of this study was to evaluate the possible correlations between ventricular arrhythmias, conduction disorders, and myocardial fibrosis in patients with systemic sclerosis. METHODS: Thirty-six patients with diffuse or limited cutaneous scleroderma underwent 12-lead electrocardiogram (ECG), 24-hour Holter ECG monitoring, transthoracic echocardiography, and cardiac DE-MRI, with gadolinium administration in 33 patients. RESULTS: High-quality DE-MRI scans were obtained in 30 patients. Myocardial fibrosis was detected in 25 patients (83.3%). Eighteen patients (60%) had ventricular arrhythmias or conduction disorders. There was no significant difference in ventricular arrhythmia burden (the total number of premature ventricular contractions [PVCs]/24 hours) (48 ± 304 vs. 69 ± 236, P = 0.97), ventricular arrhythmia severity (couplets, triplets, runs) on Holter ECG, or in the presence of conduction disorders (36% vs. 40%, P = 0.86) between patients with and without myocardial fibrosis. In univariate analysis, diffuse fibrosis was weakly associated with the number of PVCs/24 hours (R = 0.157, P = 0.03). A number of at least 597 PVCs/24 hours had a sensitivity of 60% and a specificity of 92% in predicting the presence of diffuse fibrosis on DE-MRI (area under the curve = 0.640). CONCLUSIONS: Delayed-enhancement magnetic resonance imaging can identify myocardial fibrosis in a high percentage of scleroderma patients. Its presence does not seem to influence the ventricular arrhythmia burden and severity or the presence of conduction disorders, with the exception of diffuse myocardial fibrosis, which modestly influences the total number of PVCs/24 hours.

Is it primary neuropsychiatric systemic lupus erythematosus? Performance of existing attribution models using physician judgment as the gold standard.

OBJECTIVES: Models for the attribution of neuropsychiatric manifestations to systemic lupus erythematosus (NPSLE) that incorporate timing and type of manifestation, exclusion/confounding or favouring factors have been proposed. We tested their diagnostic performance against expert physician judgment. METHODS: SLE patients with neuropsychiatric manifestations were identified through retrospective chart review. Manifestations were classified according to physician judgment as attributed to SLE, not attributed or uncertain. Results were compared against the Systemic Lupus International Collaborating Clinics (SLICC) attribution models A and B, and one introduced by the Italian Study Group on NPSLE. RESULTS: 191 patients experienced a total 242 neuropsychiatric manifestations, 136 of which were attributed to SLE according to physician. Both SLICC models showed high specificity (96.2% and 79.2% for model A and B, respectively) but low sensitivity (22.8% and 34.6%, respectively) against physician judgment. Exclusion of cases of headache, anxiety disorders, mild mood and cognitive disorders and polyneuropathy without electrophysiologic confirmation led to modest increases in sensitivity (27.7% and 42.0% for SLICC models A and B, respectively) and reductions in specificity (94.8% and 65.5%, respectively). The Italian Group model showed good accuracy in NPSLE attribution with an area under the curve of the receiver operating characteristics analysis of 0.862; values ≥7 showed the best combination of sensitivity and specificity (82.4% and 82.9%, respectively). CONCLUSIONS: Attribution models can be useful in NPSLE diagnosis in routine clinical practice and their performance is superior in major neuropsychiatric manifestations. The Italian Study Group model is accurate, with values ≥7 showing the best combination of sensitivity and specificity.

EULAR recommendations for neuropsychiatric systemic lupus erythematosus vs usual care: results from two European centres.

OBJECTIVE: To compare the European League Against Rheumatism (EULAR) recommendations for the management of NPSLE with usual care in two tertiary centres and to detect potential pitfalls in their use for diagnosis and treatment. METHODS: A chart-based review of NPSLE manifestations was conducted in two European centres. Diagnostic and treatment decisions were compared against the EULAR recommendations for general NPSLE and specific manifestations. RESULTS: We studied a total of 94 patients who experienced 123 lupus-related neuropsychiatric events over 10 years. In 80% of the events, at least one EULAR-defined risk factor (previous NPSLE, generalized disease activity or aPL positivity) was present. Overall, there was good concordance between clinical care and recommendations for diagnosis and treatment (68.7% and 62.7% of events, respectively). Brain MRI was performed in the absence of a clear EULAR recommendation in 42.9% of events; therein, it was more frequently normal compared with imaging performed according to the recommendations (52.4% vs 18.5%, P = 0.008), and it did not influence management. Among patients reporting cognitive dysfunction, only 27.8% underwent the recommended neuropsychological assessment. In line with the recommendations, immunosuppressants were more frequently given in events suggestive of an inflammatory process (80.5% vs 47.6% in non-inflammatory events, P < 0.001). Notably, 52% of cerebrovascular events were managed with combined immunosuppressive/antithrombotic therapy due to either coexisting generalized lupus activity or recurrence despite prior antithrombotic treatment. CONCLUSION: Despite good concordance between EULAR recommendations for NPSLE and usual clinical practice, we identified a number of issues (such as overutilization of brain MRI, suboptimal evaluation of cognitive dysfunction, and frequent use of immunosuppressives in cerebrovascular disease) that need to be investigated further.

Women's health and fertility, family planning and pregnancy in immune-mediated rheumatic diseases: a report from a south-eastern European Expert Meeting.

With current advances in medical treatment, reproductive issues have become more important for women with chronic immune-mediated diseases. Most, if not all, patients report that their disease affects their personal relationships, their decision to have children, and the size of their family. These decisions are multi-factorial, influenced mainly by concerns over the effect of pregnancy on the rheumatic disease, the impact of disease activity during pregnancy on foetal health, the patient's ability to care for the child, and the possible harmful effects medication could have on the child, both pre- and post-natally during breastfeeding. Apart from that, women's health issues tend to be overlooked in favour of the management of the underlying rheumatic disease. To this end, we convened an expert panel to review the published literature on women's health and reproductive issues and provide evidence- and eminence-based points to consider for the treating physicians. We conclude that there is a need for a change in mind-set from one which 'cautions against pregnancy' to one which 'embraces pregnancy' through the practice of individualised, pre- and post-conceptual, multi-disciplinary care.

GWAS-identified hyperuricemia-associated IGF1R variant rs6598541 has a limited role in urate mediated inflammation in human mononuclear cells.

Gout is a common autoinflammatory joint diseases characterized by deposition of monosodium urate (MSU) crystals which trigger an innate immune response mediated by inflammatory cytokines. IGF1R is one of the loci associated with both urate levels and gout susceptibility in GWAS to date, and IGF-1-IGF-1R signaling is implicated in urate control. We investigate the role of IGF-1/IGF1R signaling in the context of gouty inflammation. Also, we test the gout and urate-associated IGF1R rs6598541 polymorphism for association with the inflammatory capacity of mononuclear cells. For this, freshly isolated human peripheral blood mononuclear cells (PBMCs) were exposed to recombinant IGF-1 or anti-IGF1R neutralizing antibody in the presence or absence of solubilized urate, stimulated with LPS/MSU crystals. Also, the association of rs6598541 with IGF1R and protein expression and with ex vivo cytokine production levels after stimulation with gout specific stimuli was tested. Urate exposure was not associated with IGF1R expression in vitro or in vivo. Modulation of IGF1R did not alter urate-induced inflammation. Developing urate-induced trained immunity in vitro was not influenced in cells challenged with IGF-1 recombinant protein. Moreover, the IGF1R rs6598541 SNP was not associated with cytokine production. Our results indicate that urate-induced inflammatory priming is not regulated by IGF-1/IGF1R signaling in vitro. IGF1R rs6598541 status was not asociated with IGF1R expression or cytokine production in primary human PBMCs. This study suggests that the role of IGF1R in gout is tissue-specific and may be more relevant in the control of urate levels rather than in inflammatory signaling in gout.

Insights into the Relationship between Periodontitis and Systemic Sclerosis Based on the New Periodontitis Classification (2018): A Cross-Sectional Study.

(1) Background: This study aimed to assess the periodontitis burden in systemic sclerosis patients and the possible association between them, and the degree to which some potential risk factors and two potential diagnostic biomarkers may account for this association. (2) Methods: This cross-sectional study included a test group (systemic sclerosis patients) and a control group (non-systemic sclerosis patients). Both groups benefited from medical, periodontal examination and saliva sampling to determine the salivary flow rate and two inflammatory biomarkers (calprotectin, psoriasin). A systemic sclerosis severity scale was established. (3) Results: In the studied groups, comparable periodontitis rates of 88.68% and 85.85%, respectively, were identified. There were no significant differences in the severity of periodontitis among different systemic sclerosis severity, or in the positivity for anti-centromere and anti-SCL70 antibodies. Musculoskeletal lesions were significantly more common in stage III/IV periodontitis (n = 33, 86.84%) than in those in stage I/II (n = 1, 100%, and n = 3, 37.5%, respectively) (p = 0.007). Comparable levels of the inflammatory mediators were displayed by the two groups. There were no significant differences in calprotectin and psoriasin levels between diffuse and limited forms of systemic sclerosis. (4) Conclusions: Within the limitations of the current study, no associations between systemic sclerosis and periodontitis, or between their risk factors, could be proven.

Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells.

OBJECTIVE: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation. RESULTS: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate. CONCLUSION: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.

Periodontitis Burden in Diffuse Versus Limited Systemic Sclerosis Subtypes: A Pilot Study.

INTRODUCTION: This study aimed to evaluate the periodontal status of a group of Romanian systemic sclerosis (SSc) patients and to investigate the relationships between periodontitis and SSc subtypes. MATERIALS AND METHODS: This observational study included patients diagnosed with limited SSc (lcSSc) and diffuse SSc (dcSSc). Demographic data were collected from medical records. Each participant underwent a full-mouth periodontal examination including Bleeding on Probing (BoP) index, Oral Hygiene (OH) index, Probing Depth (PD), Gingival Recession (GR), and Clinical Attachment Loss (CAL). The periodontal status was defined according to presently recognised case definition system. RESULTS: The study included 30 patients with lcSSc and 30 patients with dcSSc with a mean age of 52.45±11.75 years. The overall periodontitis frequence in our SSc group was 95%. The frequency of stage III/IV periodontitis was higher in the dcSSc group (90%) than in the lcSSc group (60%). Within the group of SSc patients, significant positive correlations were observed between age, BoP index, OH index, the number of missing teeth, mean PD, mean CAL on one side and periodontitis diagnosis on the other side (r=0.588, p=0.001; r=0.399, p=0.002; r=0.388, p=0.002; r=0.574, p=0.001; r=0.444, p=0.001; r=0.571, p=0.001). A significant positive correlation existed between the diagnostic of periodontitis and SSc subtypes (r=0.327, p <0.001). CONCLUSIONS: Periodontitis was highly prevalent in both lcSSc and dcSSc groups. More stage III/IV periodontitis cases were detected dcSSc group of patients.

Hyperuricemia remodels the serum proteome toward a higher inflammatory state.

Gout is an autoinflammatory disease triggered by a complex innate immune response to MSU crystals and inflammatory triggers. While hyperuricemia is an obligatory risk factor for the development of gout, the majority of individuals with hyperuricemia never develop gout but have an increased risk of developing cardiometabolic disorders. Current management of gout aims at MSU crystal dissolution by lowering serum urate. We apply a targeted proteomic analysis, using Olink inflammation panel, to a large group of individuals with gout, asymptomatic hyperuricemia, and normouricemic controls, and we show a urate-driven inflammatory signature. We add in vivo evidence of persistent immune activation linked to urate exposure and describe immune pathways involved in the pathogenesis of gout. Our results support a pro-inflammatory effect of asymptomatic hyperuricemia and pave the way for new research into targetable mechanisms in gout and cardiometabolic complications of asymptomatic hyperuricemia.

Current Perspectives on Periodontitis in Systemic Sclerosis: Associative Relationships, Pathogenic Links, and Best Practices.

Systemic sclerosis is a chronic, autoimmune, multisystemic disease characterized by aberrant extracellular matrix protein deposition and extreme progressive microvasculopathy. These processes lead to damage within the skin, lungs, or gastrointestinal tract, but also to facial changes with physiognomic and functional alterations, and dental and periodontal lesions. Orofacial manifestations are common in SSc but are frequently overshadowed by systemic complications. In clinical practice, oral manifestations of SSc are suboptimally addressed, while their management is not included in the general treatment recommendations. Periodontitis is associated with autoimmune-mediated systemic diseases, including systemic sclerosis. In periodontitis, the microbial subgingival biofilm induces host-mediated inflammation with subsequent tissue damage, periodontal attachment, and bone loss. When these diseases coexist, patients experience additive damage, increasing malnutrition, and morbidity. The present review discusses the links between SSc and periodontitis, and provides a clinical guide for preventive and therapeutical approaches in the management of these patients.

Rheumatoid Arthritis and CLOVES Syndrome: A Tricky Diagnosis.

The PI3K/AKT/mTOR signaling pathway is significantly activated in rheumatoid arthritis. In addition, somatic activating mutations of the PI3K/AKT/mTOR pathway may result in PIK3CA-related overgrowth spectrum diseases, including CLOVES (Congenital Lipomatous Overgrowth, Vascular malformation, Epidermal nevi, Skeletal abnormalities/Scoliosis) syndrome. We describe the case of a young female patient, with anti-citrullinated peptide antibodies-positive rheumatoid arthritis, referred for persistent finger pain and stiffness. Examination revealed discrete macrodactyly involving two fingers, scoliosis, asymmetrical calves, venectasias, a shoulder nevus and triangular feet with a "sandal gap" between two toes. These mild dysmorphic features with early-onset and the history of surgeries for thoracic lipoma and venous malformation were strongly suggestive of CLOVES syndrome. Confirmatory mutation analysis was not performed, as blood or saliva testing is not contributive for tissue-specific localized effects in the PIK3CA-related overgrowth spectrum. Nevertheless, lack of detection of a PIK3CA mutation does not exclude the diagnosis in patients fulfilling clinical criteria. Due to the patient's wish to plan a pregnancy, therapy consisted in sulfasalazine and hydroxychloroquine, along with orthotic correction of leg length discrepancy. Overgrowth syndromes and arthritis may share common pathways. Mild macrodactyly should be differentiated from dactylitis. Diagnosing patients with minimal dysmorphic features within the PI3K-related overgrowth spectrum may help design better care strategies, in the quest for personalized medicine.

The relationship between epicardial adipose tissue and arterial stiffness in patients with rheumatoid arthritis.

AIM: To evaluate the relationship between epicardial adipose tissue (EAT) and arterial stiffness (AS) in patients with rheumatoid arthritis (RA), considering cardiovascular risk factors and disease characteristics. MATERIAL AND METHODS: A total of 84 RA patients were included in this cross-sectional study. EAT and carotid intima-media thickness (cIMT) were measured ultrasonographically while aortic pulse wave velocity (aPWV), the main AS parameter, was determined using an oscillometric device. RESULTS: Mean duration of RA was 12±9.5 years and disease activity score was 4.3±1.4, as assessed by Disease Activity Score-28 using C-reactive protein (DAS-28 CRP). The correlation analysis displayed a significant positive correlation between cIMT, aPWV and EAT (r= 0.037, p<0.001; r= 0.338, p=0.002 and r= 0.317, p=0.003). When a cutoff value of aPWV ≥10 m/s was established, patients with increased aPWV had significantly higher body mass index (p=0.04), waist circumference (p=0.01), triglycerides (p=0.04), EAT (p<0.001), hypertension (p=0.03) and marginally C-reactive protein (CRP) (p=0.05). Multivariate regression analysis showed that hypertension (p=0.033), increased CRP (p=0.016) and EAT (p=0.005) are the only independent predictors for increased aPWV. CONCLUSIONS: Our study found that increased AS independently correlated with EAT in patients with RA. Although the evaluation of these two parameters awaits further evidence to be included in the risk algorithms for CVD prevention, their role in patients with inflammatory diseases may be even more significant than in the general population.