Microbiota and arthritis: cause or consequence?

The relationship between intestinal microbiota and arthritis has garnered significant attention, with emerging evidence suggesting a potential association between dysbiosis and various forms of inflammatory arthropathies. While observational studies have provided valuable insights into microbiota alterations in patients with arthritis, establishing causality remains challenging. Observational data, influenced by multiple confounders such as environmental factors, medication effects, and dietary habits, are insufficient to conclusively determine whether microbiota changes are somehow causally linked to arthritis. The heterogeneity of results across independent studies further complicates interpretation. To further support this hypothesis, interventional randomised trials are deemed necessary, yet their implementation in this area presents significant technical limitations. Experimental animal models offer insights into potential pathogenic mechanisms linking dysbiosis to arthritis, including compromised intestinal barrier function, the role of microbiota-derived metabolites and molecular mimicry. However, conflicting findings underscore the complexity of hostmicrobiota interactions and the challenges in establishing causality.Efforts to modulate the microbiota for arthritis treatment or prevention have shown promise, yet efficacy and applicability remains uncertain. Antibacterial drugs, dietary interventions, probiotics, and faecal microbiota transplantation have been explored, but their clinical utility awaits further validation. In conclusion, while the association between intestinal microbiota and arthritis is increasingly recognised, establishing causality remains elusive.

Primary Sjögren's syndrome in Italy: Real-world evidence of a rare disease through administrative healthcare data.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with significant impact on morbidity, mortality, and quality of life. This study aimed to evaluate epidemiology, healthcare needs and related costs of pSS patients from the Italian National Health Service perspective. METHODS: From the Fondazione Ricerca e Salute's database (∼5 million inhabitants/year), pSS prevalence in 2018 was calculated. Demographics, mean healthcare consumptions and direct costs at one year following index date (first in-hospital diagnosis/disease waiver claim) were analysed through an individual direct matched pair case-control analysis (age, sex, residency). RESULTS: In Italy, 3.8/10,000 inhabitants were identified as affected by pSS (1,746 case: 1,746 controls) in 2018. In the year following index date, 53.7% of cases and 42.7% of controls received ≥1 drug (p<0.001); mean per capita cost was €501 and €161, respectively (p<0.01). At least one hospitalization occurred to 7.8% of cases and 3.9% of controls (p<0.001) with mean per capita costs of €416 and €129, respectively (p = 0.46). At least one outpatient specialist service was performed in 49.8% of cases and 30.6% of controls (p<0.001); mean per capita costs were €200 and €75, respectively (p<0.01). Overall, mean annual costs were €1,171 per case and €372 per control (p < 0.01). CONCLUSION: According to results of this population-based study, the prevalence of pSS in Italy appears to be consistent with the definition of rare disease. Patients with pSS have higher pharmacological, in-hospital and outpatient specialist care needs, leading to three-times higher overall cost for the INHS, compared to the general population.

Impact of gender and age at onset on Sjögren's syndrome presentation and outcome: state of the art.

Sjögren's syndrome (SS) is a complex and heterogeneous disease that typically affects middle-aged women. However, while it is rare, the disease may occur in male patients and in females during their childhood/adolescence or in the elderly. Contrasting data have been reported on these three subgroups clinical features and long-term outcomes. Notably, recent studies have pinpointed the severity of the disease in male patients and in both the early and the late-onset subgroups.The aim of this review is, therefore, to summarise the available evidence from the recent literature on these phenotypes. The focus will be on the clinical and laboratory features, and on the lymphoma risk observed in the three subgroups distinct phenotypes: of male patients as well as young-onset SS and elderly-onset SS. Ultimately, an accurate phenotypic stratification may represent the first step towards individualised medical approaches.

Autoantibody status according to multiparametric assay accurately estimates connective tissue disease classification and identifies clinically relevant disease clusters.

OBJECTIVE: Assessment of circulating autoantibodies represents one of the earliest diagnostic procedures in patients with suspected connective tissue disease (CTD), providing important information for disease diagnosis, identification and prediction of potential clinical manifestations. The purpose of this study was to evaluate the ability of multiparametric assay to correctly classify patients with multiple CTDs and healthy controls (HC), independent of clinical features, and to evaluate whether serological status could identify clusters of patients with similar clinical features. METHODS: Patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren's syndrome (SjS), undifferentiated connective tissue disease (UCTD), idiopathic inflammatory myopathies (IIM) and HC were enrolled. Serum was tested for 29 autoantibodies. An XGBoost model, exclusively based on autoantibody titres was built and classification accuracy was evaluated. A hierarchical clustering model was subsequently developed and clinical/laboratory features compared among clusters. RESULTS: 908 subjects were enrolled. The classification model showed a mean accuracy of 60.84±4.05% and a mean area under the receiver operator characteristic curve of 88.99±2.50%, with significant discrepancies among groups. Cluster analysis identified four clusters (CL). CL1 included patients with typical features of SLE. CL2 included most patients with SjS, along with some SLE and UCTD patients with SjS-like features. CL4 included anti-Jo1 patients only. CL3 was the largest and most heterogeneous, including all the remaining subjects, overall characterised by low titre or lower-prevalence autoantibodies. CONCLUSION: Extended multiparametric autoantibody assay allowed an accurate classification of CTD patients, independently of clinical features. Clustering according to autoantibody titres is able to identify clusters of CTD subjects with similar clinical features, independently of their final diagnosis.

Exploring the Link between Plasma Levels of PCSK9, Immune Dysregulation and Atherosclerosis in Patients with Primary Sjögren's Syndrome.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates lipid metabolism contributing to cardiovascular (CV) risk in the general population. The relationship between PCSK9 and CV risk in systemic autoimmune diseases has been poorly explored. We investigated the association between plasma PCSK9, measures of immune-inflammatory status and markers of atherosclerosis in 52 consecutive patients with primary Sjögren's syndrome (pSS) in comparison to healthy controls (HCs). Median plasma PCSK9 levels were significantly higher in pSS patients versus HCs (162 (79-255) vs. 53 (39-99) ng/mL). Significantly higher prevalence of subclinical atherosclerosis and lower of dyslipidaemia (61% vs. 85%, p = 0.042) characterized pSS patients versus HCs. In pSS, no significant correlation emerged between PCSK9 and disease activity, atherosclerosis and lipid levels. In HCs, PCSK9 significantly correlated with lipid levels and atherosclerosis. Interestingly, significantly higher PCSK9 levels were found in HCs with high-to-very-high as compared to low-to-moderate CV risk (p = 0.018) while a non-significant trend towards higher PCSK9 levels was detected in pSS patients with low-to-moderate as compared to high-to-very-high CV risk (p = 0.060). This is the first demonstration that pSS patients, despite lower prevalence of dyslipidaemia and higher CV risk profile, are characterized by a 3-fold increase in PCSK9 levels in comparison to HCs. As PCSK9 does not correlate with measures of CV risk, its role in CV morbidity in pSS needs further investigation.

Organ damage in Systemic Lupus Erythematosus patients: A multifactorial phenomenon.

The prevention of chronic damage, especially in early disease phases, remains an unmet need in the management of Systemic Lupus Erythematous (SLE) patients, despite the application of a so-called treat-to-target strategy. The high proportion of SLE patients developing chronic damage suggests a multifactorial aetiology. Thus, besides disease activity, other factors may contribute to the development of damage. The revision of data published so far underlines that, next to disease activity, it is possible to identify other factors playing a relevant role in damage development and progression. In summary, the presence of antiphospholipid antibodies and drugs used to treat SLE patients, in particular glucocorticoids, is strongly associated with SLE-related damage. Furthermore, recent data suggests the possible role of genetic background in determining the development of specific organ damage, in particular renal and neurological. Nonetheless, demographic factors, such as age, sex and disease duration could exert a role along with the presence of comorbidities. The contribution of different factors in determining damage development suggests the need for new outcomes to assess a comprehensive disease control including not only the assessment of disease activity, but also the evaluation of chronic damage development.

Predictors of complete 24-month remission and flare in patients with polymyalgia rheumatica.

To date, few papers investigated the predictive factors of sustained 24-month remission and of flare in patients with polymyalgia rheumatica (PMR). We retrospectively evaluated clinical charts from PMR patients. Patients were evaluated at baseline, at 1 month, 3 months and subsequently at 6, 12 and 24 months. We analyzed the differences between patients who achieved remission within 6 months of diagnosis, those who achieved remission at 24 months, and patients who did not. Among 137 patients, 57 (41.6%) achieved remission at 6 months and complete remission at 24 months was achieved by 104 patients (75.9%). The erythrocyte sedimentation rate at baseline was higher in patients who did not achieve remission than in patients who achieved it (p = 0.012). Female patients were less likely to achieve complete remission (45/68, 66.2% vs. 59/69, 85.5%, p = 0.01) compared to males. Fifty-four patients (39.4%) experienced at least one flare. Patients who did not achieve sustained complete remission suffered a flare more often (22/39 vs. 32/98, p = 0.01) and earlier than patients who did (10.33 ± 7.89 months vs. 13.64 ± 6.97 months, p = 0.011). Multivariate analysis confirmed that female sex (RR = 3.2, 95% CI 1.3-7.9) and higher baseline prednisone dosage (RR = 1.1, 95% CI 1.007-1.109) were negative independent predictors of complete remission at 24 months. A significant percentage of patients with PMR requires prolonged steroid treatment and may experience flares at 24 months of follow-up. Female sex and higher baseline prednisone dosage are negative independent predictors of complete remission at 24 months.

Sjögren's syndrome: one year in review 2022.

Primary Sjögren's syndrome (pSS) is a complex disabling systemic autoimmune disorder. The hallmark of pSS is the T-cell-mediated hyperactivation of B-cells, evolving from asymptomatic conditions to systemic complications and lymphoma development. On tissue level, the typical feature is the lymphocytic infiltration of the salivary gland by B-, T- and antigen presenting cells, as mirrored by the diagnostic cornerstone role of minor salivary gland (MSG) biopsy. B-cells show multiple possible roles in disease pathogenesis, from autoantibody production, to antigen presentation, and cytokine production. B-cells hyperactivation is supported by genetic risk factors, T-cell dependent and independent mechanisms, and the presence of different pathogenic B-cell subsets must be reminded.Many aspects have been investigated in the last year regarding genetic and epigenetics, B- and T-cell role in pSS pathogenesis, their interaction with salivary gland epithelial cells (SGECs) and in their direct or indirect use as biomarkers and predictors of disease development, activity, and lymphomagenesis.In this review, following the others of this series, we will summarise the most recent literature on pSS pathogenesis and clinical features focusing in particular on new insights into pSS molecular stratification and therapeutic advances in the era of precision medicine.

Ultrasound scoring systems affect the distribution of sialadenitis scores in Sjögren's syndrome: an inter-system reproducibility study.

OBJECTIVES: Salivary gland ultrasonography (SGUS) is commonly employed in the diagnosis and follow-up of patients with Sjögren's syndrome (SS) and multiple scoring systems have been developed to quantify the grade of sialadenitis of major salivary glands (SG). Their diagnostic performance seems overall comparable, however, the parameters evaluated by the various systems are different. The objective of this study was to compare how four different scoring systems affect the distribution of sialadenitis grades. METHODS: One hundred and three SGUS images from 26 SS patients were blindly scored by two investigators according to the De Vita, Salaffi, Milic and OMERACT scoring systems in independent sessions. RESULTS: The distribution of SGUS images according to De Vita, Salaffi, Milic and OMERACT systems was significantly different. At post-hoc analysis, Milic system performed differently compared to the De Vita (p<0.0001), OMERACT (p<0.0001) and Salaffi (p<0.0001) systems, showing a relative overestimation of sialadenitis grade. CONCLUSIONS: Milic scoring system showed to relatively overestimate the grade of sialadenitis compared to De Vita, Salaffi and OMERACT systems. Although all scoring systems seem to be comparable in terms of diagnostic accuracy, in the prospect of selecting one system to be potentially included in future versions of SS classification criteria, it is important to compare their ability to classify SGUS images among the various degrees of sialadenitis.

Methotrexate improves endothelial function in early rheumatoid arthritis patients after 3 months of treatment.

BACKGROUND: Endothelial dysfunction contributes to increased cardiovascular (CV) disease in rheumatoid arthritis (RA). Angiogenic T cells (Tang) are a key regulator of vascular function via their interaction with endothelial progenitor cells (EPCs). Methotrexate (MTX) has been associated to reduced CV disease risk, but its effects on endothelial homeostasis have been poorly explored. We investigated MTX effects on endothelial homeostasis in early, treatment-naïve RA patients. METHODS: Fifteen untreated, early RA patients and matched healthy controls (HC) were enrolled. RA patients with long-standing disease in remission or low disease activity treated with MTX for at least 6 months were selected as controls. Circulating CD28+ and CD28null Tang cell, endothelial microparticle (EMP), EPC and soluble vascular cell adhesion molecule (sVCAM)-1 levels were measured. RESULTS: Tang percentage was higher in early RA than in HCs and significantly increased after 3-month MTX treatment. Tang cells in RA were characterized by higher percentage of CD28null and lower CD28-positive cells than HCs. MTX restored a Tang cell phenotype similar to HCs. Altered sVCAM-1, EMP and EPC were restored to levels similar to HCs after a 3-month MTX. Biomarker levels after 3 months of MTX were not different to those of patients with long-standing treatment. CONCLUSIONS: MTX has a positive effect on Tang, sVCAM-1, EPCs and EMPs in RA. Restoration of imbalance between CD28 + and CD28null Tang by MTX may be one of the mechanisms underlying its favourable effects on endothelial dysfunction. These effects seem to be long-lasting and independent from systemic inflammation reduction, suggesting a direct effect of MTX on the endothelium.

C-reactive protein and 10-year cardiovascular risk in rheumatoid arthritis.

OBJECTIVES: To evaluate the association between C-reactive protein (CRP) and 10-year risk of cardiovascular (CV) events using the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), based on conventional and RA-specific risk factors but not CRP, in RA patients without previous cardiovascular events. METHODS: ERS-RA was calculated in 1,251 "Cardiovascular Obesity and Rheumatic Disease Study (CORDIS)" database patients [(age 60.4(9.3) years; 78% female; disease duration, 11.6(8) years; CDAI, 9(9); CRP, 6.8(12) mg/L]. RESULTS: The mean (SD) 10-year risk of CV events was 12.9% (10). After adjusting for the use of DMARDs and biologics, CRP concentrations were significantly associated with 10-year risk of CV events (coefficient=0.005 for each 10 mg/L CRP increment; 95%CI 0.000-0.111; p = 0.047). In mediation analysis, the association between CRP and ERS-RA was not explained by disease activity. CONCLUSION: In a large cohort of RA patients without previous cardiovascular events, a 20 mg/L increase in CRP concentrations was associated with a 1% increase in 10-year risk of CV events. This suggests that actively targeting residual inflammatory risk beyond conventional and RA-specific risk factors might further reduce CV event rates in RA patients.

Cardiovascular Involvement in Sjögren's Syndrome.

Sjögren Syndrome (SS) seems to be associated with a greater "overall risk" of cardiovascular (CV) and cerebrovascular events. Although not conventionally considered a feature of the disease, CV events represent a major burden in SS patients. CV risk is the consequence of a complex combination of multiple factors, including traditional risk factors and disease-related mechanisms. A complex relationships between disease-related features, endothelial dysfunction and traditional risk factor has been suggested. Several drugs are available for treating the systemic manifestations of SS, however they have shown positive effects on different outcomes of the disease, but until today the data on the role of these drugs on CV events are scarse. Given these data, the aim of this review was to evaluate the risk of CV risk in primary SS and the effect of the drugs on this manifestation.

Estimated 10-year cardiovascular risk in a large Italian cohort of rheumatoid arthritis patients: Data from the Cardiovascular Obesity and Rheumatic DISease (CORDIS) Study Group.

BACKGROUND: Several cardiovascular (CV) risk algorithms are available to predict CV events in the general population. However, their performance in patients with rheumatoid arthritis (RA) might differ from the general population. This cross-sectional multicentre study aimed to estimate the 10-year CV risk using two different algorithms in a large RA cohort and in patients with osteoarthritis (OA). METHODS: In a consecutive series of RA patients and matched OA controls without prior CV events, clinical and serologic data and traditional CV risk factors were recorded. The 10-year CV risk was assessed with the Systematic COronary Risk Evaluation (SCORE) and the "Progetto Cuore" algorithms. RESULTS: 1,467 RA patients and 342 OA subjects were included. RA patients were more frequently diabetic (9.9% vs 6.4%; p=0.04) and smokers (20.4% vs 12.5%; p=0.002) but had lower prevalence of obesity (15% vs 21%; p=0.003). Dyslipidaemia was more prevalent in OA (32.5% vs 21.7%; p<0.0001). The 10-year estimated CV risk was 1.6% (95%CI 1.3-1.9) in RA and 1.4% (95%CI 1.3-1.6) in OA (p=0.002) according to SCORE and 6.5% (95%CI 6.1-6.9) in RA and 4.4% (95%CI 3.9-5.1) in OA (p<0.001) according to "Progetto Cuore". Regardless of the score used, RA patients had a 3- to-4-fold increased 10-year risk of CV events compared to OA subjects. CONCLUSION: RA patients have a significantly higher 10-year risk of CV events than OA subjects. In addition to effective disease control and joint damage prevention, specific protective measures targeting modifiable traditional CV risk factors should be implemented in RA.

One year in review 2021: Sjögren's syndrome.

Sjögren's syndrome (SS) is a multifactorial systemic autoimmune disease of unknown aetiology characterised by a wide spectrum of different clinical manifestations and scattered complications. Recently, great efforts have been made to elucidate mechanisms involved in the pathogenesis of the disease in order to identify exploitable therapeutic targets in SS. Similarly, novel insights have enabled to better define disease phenotypes and different outcomes. Ultimately, the discovery of new potential therapeutic targets and a better stratification of patients are paving new avenues for novel treatment options and treat-to-target therapeutic approach. In this review, we will provide a critical digest of the recent literature published in 2020 on SS pathogenesis, clinical manifestations and novel treatment options.

Unattended compared to traditional blood pressure measurement in patients with rheumatoid arthritis: a randomised cross-over study.

BACKGROUND: Hypertension is characterised by a high prevalence, low awareness and poor control among rheumatoid arthritis (RA) patients. Correct blood pressure (BP) measurement is highly important in these subjects. The "unattended" BP measurement aims to reduce the "white-coat effect," a phenomenon associated with cardiovascular risk. Data on "unattended" BP measurement in RA and its impact on hypertensive organ damage are very limited. METHODS: BP was measured in the same patient both traditionally ("attended" BP) and by the "unattended" protocol (3 automated office BP measurements, at 1-min intervals, after 5 min of rest, with patient left alone) by a randomised cross-over design. Patients underwent clinical examination, 12-lead electrocardiography and trans-thoracic echocardiography to evaluate cardiac damage. RESULTS: Sixty-two RA patients (mean age 67 ± 9 years, 87% women) were enrolled. Hypertension was diagnosed in 79% and 66% of patients according to ACC/AHA and ESC/ESH criteria, respectively. Concordance correlation coefficients between the two techniques were 0.55 (95%, CI 0.38-0.68) for systolic BP and 0.73 (95%, CI 0.60-0.82) for diastolic BP. "Unattended" (121.7/68.6 mmHg) was lower than "attended" BP (130.5/72.8 mmHg) for systolic and diastolic BP (both p < .0001). Among the two techniques, only "unattended" systolic BP showed a significant association with left ventricular mass (r = 0.11; p = .40 for "attended" BP; r = 0.27; p = .036 for unattended BP; difference between slopes: z = 3.92; p = .0001). CONCLUSIONS: In RA patients, "unattended" BP is lower than traditional ("attended") BP and more closely associated with LV mass. In these patients, the "unattended" automated BP measurement is a promising tool which requires further evaluation.KEY MESSAGES"Unattended" automated blood pressure registration, aimed to reduce the "white-coat effect" is lower than "attended" value in rheumatoid arthritis patients."Unattended" blood pressure is more closely associated with left ventricular mass than "attende" registration.