Cytokines and chemokines in patients with chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: A systematic review.

Advances in the understanding of cytokines have revolutionized mechanistic treatments for chronic inflammatory and autoimmune diseases, as exemplified by rheumatoid arthritis. We conducted a systematic literature review on the role of cytokines and chemokines in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Ovid Medline, EMBASE and Web of Science were searched until August 31, 2022 for human studies investigating cytokines levels in CIDP or MMN. Fifty-five articles on 1061 CIDP patients and 86 MMN patients were included, with a median of 18 patients per study (range 3-71). Studies differed in the inclusion criteria, type of assay, manufacturer, control subjects, and tested biological material. Only a minority of studies reported data on disease activity. Interleukin (IL)-6, IL-17, CXCL10, and tumor necrosis factor alpha (TNF-α), were elevated in CIDP compared to controls in most of the studies. IL-6 and TNF-α levels are also correlated with disability. In MMN patients, IL-1Ra was elevated in the majority of the reports. While acknowledging the challenges in comparing studies and the various limitations of the studies, including small patient numbers, particularly in MMN, our review suggests that IL-6, IL-17, CXCL10, and TNF-α might play a role in CIDP pathogenesis. Larger studies are needed in MMN.

Methotrexate and cardiovascular prevention: an appraisal of the current evidence.

New evidence continues to accumulate regarding a significant association between excessive inflammation and dysregulated immunity (local and systemic) and the risk of cardiovascular events in different patient cohorts. Whilst research has sought to identify novel atheroprotective therapies targeting inflammation and immunity, several marketed drugs for rheumatological conditions may serve a similar purpose. One such drug, methotrexate, has been used since 1948 for treating cancer and, more recently, for a wide range of dysimmune conditions. Over the last 30 years, epidemiological and experimental studies have shown that methotrexate is independently associated with a reduced risk of cardiovascular disease, particularly in rheumatological patients, and exerts several beneficial effects on vascular homeostasis and blood pressure control. This review article discusses the current challenges with managing cardiovascular risk and the new frontiers offered by drug discovery and drug repurposing targeting inflammation and immunity with a focus on methotrexate. Specifically, the article critically appraises the results of observational, cross-sectional and intervention studies investigating the effects of methotrexate on overall cardiovascular risk and individual risk factors. It also discusses the putative molecular mechanisms underpinning the atheroprotective effects of methotrexate and the practical advantages of using methotrexate in cardiovascular prevention, and highlights future research directions in this area.

Effects of cytotoxic T-lymphocyte-associated protein 4 compared to TNF inhibitors on lipid profile: Results from an observational multicentre rheumatoid arthritis cohort.

AIM: To evaluate the impact of selective cytotoxic T-lymphocyte-associated protein 4 (CTLA-4Ig) compared to tumor necrosis factor inhibitors (TNFi) on cardiovascular (CV) clinical and laboratory outcomes in patients with rheumatoid arthritis (RA). METHODS: We performed a prospective observational multicenter study of RA patients included in the "Cardiovascular Obesity and Rheumatic DISease (CORDIS)" Study Group database, collecting demographic, clinical, and laboratory data of those starting a CTLA-4Ig or TNFi at baseline, 6-month, and 12-month follow-up. RESULTS: Of the 206 RA patients without previous CV events enrolled in the study, 64 received a CTLA-4Ig and 142 a TNFi. The two groups did not differ in age, gender, or smoking habits, and the prevalence of hypertension, diabetes, and metabolic syndrome was similar. Over a follow-up period of 12 months, although no significant differences were found in the disease activity course, we observed that LDL cholesterol levels slightly decreased only in the CTLA-4Ig-treated patients. CONCLUSIONS: Patients treated with both CTLA-4Ig and TNFi did not differ in disease activity response and changes in traditional CV risk factors after 12 months of treatment. However, CTL-A-4Ig treatment is associated with a favorable change in lipid profile at 12-month follow-up.

Helicobacter pylori infection and rheumatoid arthritis as risk enhancers' factors for atherosclerotic cardiovascular diseases.

BACKGROUND: In addition to established risk factors for atherosclerotic cardiovascular diseases (aCVDs), infections and autoimmune diseases, such as Helicobacter pylori (H. pylori) and rheumatoid arthritis (RA), have been reported as risk-enhancer factors. In this retrospective single-center, case-control study, the relative weight of RA and H. pylori infection on aCVD was evaluated in a cohort of patients from Northern Sardinia, Italy, where both conditions are frequent. MATERIALS AND METHODS: Data were retrieved from records of subjects undergoing upper endoscopy and screened for H. pylori infection by at least four biopsies. The presence of H. pylori and chronic-active gastritis were labeled as a current infection or a long-lasting infection (LLHp) when atrophy and/or metaplasia and/or dysplasia were detected in at least one gastric specimen. Diagnosis of aCVD and RA was made by the cardiologist and the rheumatologist, respectively, according to guidelines. Odd ratios (ORs) for aCVD were evaluated, adjusting for age, sex, excess weight, cigarette smoking, blood hypertension, dyslipidemia, diabetes, H. pylori status, and RA. RESULTS: Among 4821 records (mean age 52.1 ± 16.7 years; 66.0% female), H. pylori infection was detected in 2262 patients, and more specifically, a LLHp infection was present in 1043 (21.6%). Three-hundred-three (6.3%) patients were diagnosed with aCVD, and 208 (4.3%) with RA. In patients with aCVD (cases), the LLHp infection (33.3% vs. 20.8%, p < 0.0001) and RA (12.2% vs. 3.8%, p < 0.0001) were more frequent in cases compared with controls (patients without aCVD). After adjusting for traditional aCVD risk factors, ORs significantly increased for LLHp infection (1.57; 95% CI 1.20-2.06) and RA (2.63; 95% CI 1.72-4.02). Interestingly, the LLHp infection in patients with RA showed an overall addictive effect on the risk for aCVD (7.89; 95% CI 4.29-14.53). CONCLUSIONS: According to our findings, patients with RA should benefit from being screened and eventually treated for H. pylori infection.

Decoding the Microbiome's Influence on Rheumatoid Arthritis.

The aim is better to understand and critically explore and present the available data from observational studies on the pathogenetic role of the microbiome in the development of rheumatoid arthritis (RA). The electronic databases PubMed, Scopus, and Web of Science were screened for the relevant literature published in the last ten years. The primary outcomes investigated included the influence of the gut microbiome on the pathogenesis and development of rheumatoid arthritis, exploring the changes in microbiota diversity and relative abundance of microbial taxa in individuals with RA and healthy controls (HCs). The risk of bias in the included literature was assessed using the GRADE criteria. Ten observational studies were identified and included in the qualitative assessment. A total of 647 individuals with RA were represented in the literature, in addition to 16 individuals with psoriatic arthritis (PsA) and 247 HCs. The biospecimens comprised fecal samples across all the included literature, with 16S rDNA sequencing representing the primary method of biological analyses. Significant differences were observed in the RA microbiome compared to that of HCs: a decrease in Faecalibacterium, Fusicatenibacter, Enterococcus, and Megamonas and increases in Eggerthellales, Collinsella, Prevotella copri, Klebsiella, Escherichia, Eisenbergiella, and Flavobacterium. There are significant alterations in the microbiome of individuals with RA compared to HCs. This includes an increase in Prevotella copri and Lactobacillus and reductions in Collinsella. Collectively, these alterations are proposed to induce inflammatory responses and degrade the integrity of the intestinal barrier; however, further studies are needed to confirm this relationship.

Disease-Associated Regulation of Non-Coding RNAs by Resveratrol: Molecular Insights and Therapeutic Applications.

There have been significant advances, particularly over the last 20 years, in the identification of non-coding RNAs (ncRNAs) and their pathophysiological role in a wide range of disease states, particularly cancer and other chronic conditions characterized by excess inflammation and oxidative stress such as atherosclerosis, diabetes, obesity, multiple sclerosis, osteoporosis, liver and lung fibrosis. Such discoveries have potential therapeutic implications as a better understanding of the molecular mechanisms underpinning the effects of ncRNAs on critical homeostatic control mechanisms and biochemical pathways might lead to the identification of novel druggable targets. In this context, increasing evidence suggests that several natural compounds can target ncRNAs at different levels and, consequently, influence processes involved in the onset and progression of disease states. The natural phenol resveratrol has been extensively studied for therapeutic purposes in view of its established anti-inflammatory and antioxidant effects, particularly in disease states such as cancer and cardiovascular disease that are associated with human aging. However, increasing in vitro and in vivo evidence also suggests that resveratrol can directly target various ncRNAs and that this mediates, at least in part, its potential therapeutic effects. This review critically appraises the available evidence regarding the resveratrol-mediated modulation of different ncRNAs in a wide range of disease states characterized by a pro-inflammatory state and oxidative stress, the potential therapeutic applications, and future research directions.

Placebo response in psoriatic arthritis clinical trials: a systematic review and meta-analysis.

OBJECTIVE: To determine the placebo response rate in PsA randomized clinical trials (RCTs), its contributing factors and impact on the effect size of active treatments. METHODS: We searched multiple databases, from inception to 20 December 2020, for placebo-controlled RCTs in PsA. We used a random-effects meta-analysis to pool the response rates for the ACR20 criteria in the placebo arm, determined the risk difference for treatment vs placebo, and used meta-regression to determine the factors associated with placebo response rates. The risk of bias was assessed in duplicate. The study protocol was registered with PROSPERO: CRD42021226000. RESULTS: We included 42 RCTs (5050 patients receiving placebo) published between 2000 and 2020. The risk of bias was low in 28 trials, high in four, and with some concerns in 10. The pooled placebo response rate was 20.3% (95% CI: 18.6%, 22.1%; predicted intervals, 11.7-29.0%), with significant between-trial heterogeneity (I2 = 56.8%, P < 0.005). The pooled risk difference for treatment vs placebo was 27% (95% CI: 24%, 31%). In the multivariable meta-regression, there was a 15% (95% CI: 2.9%, 29.8%) increase in the odds of achieving the placebo response for each 5-year increment in publication year (P = 0.016). In addition, the active treatment risk difference decreased for every 5-year increment in publication year (ß = -0.053, 95% CI: -0.099, -0.007; P = 0.024) but was not associated with the placebo response. CONCLUSION: Despite increasing over time, the placebo response for ACR20 in PsA RCTs was not associated with the active treatment effect size.

Patterns of Anti-Inflammatory and Immunomodulating Drug Usage and Microvascular Endothelial Function in Rheumatoid Arthritis.

Objectives: Specific anti-inflammatory and/or immunomodulating drugs (AIDs) can influence endothelial function which is often impaired in patients with rheumatoid arthritis (RA). We sought to determine whether overall patterns of AID usage are similarly associated with endothelial function. Methods: The reactive hyperaemia index (RHI), a marker of microvascular endothelial function, was measured in 868 RA patients reporting their intake of seven AIDs known to affect endothelial function. Latent class analysis (LCA) was performed to characterise patterns of AID usage. Models for 2-6 classes were compared using the AIC and BIC statistics and Lo-Mendell-Rubin likelihood ratio tests. Associations between the classes and RHI were adjusted for age, gender, body mass index, diabetes, HDL-cholesterol, LDL-cholesterol, family history of ischaemic heart disease, smoking status, RA duration, DAS28 score, steroid dose, existing hypertension, and C-reactive protein. Results: LCA identified five distinct AID usage classes: Class 1, generally low medication usage; Class 2, using either sulfasalazine or non-tumour necrosis factor (TNF) inhibitors; Class 3, methotrexate users; Class 4, TNF-inhibitor users; and Class 5, hydroxychloroquine users. The geometric mean for the RHI for subjects in classes 1 to 5 was 1.92, 1.81, 1.94, 2.10, and 2.07, respectively, with subjects in classes 4 and 5 having better endothelial function than subjects in class 2 (p = 0.003 for each). The glucocorticoid dosage did not influence the classes formed or the association between the classes and the RHI in sensitivity analyses. Conclusion: There were five broad patterns (classes) of AID usage in RA patients. The RHI was relatively lower in users of either sulfasalazine or non-TNF inhibitors. TNF inhibitors or hydroxychloroquine may counteract the negative effects of RA on endothelial function.

Current smoking predicts inadequate response to methotrexate monotherapy in rheumatoid arthritis patients naïve to DMARDs: Results from a retrospective cohort study.

ABSTRACT: Identifying predictors of inadequate response to methotrexate (MTX) in rheumatoid arthritis (RA) is key to move from a "trial and error" to a "personalized medicine" treatment approach where patients less likely to adequately respond to MTX monotherapy could start combination therapy at an earlier stage. This study aimed to identify potential predictors of inadequate response to MTX in RA patients naïve to disease modifying anti-rheumatic drugs.Data from a real-life cohort of newly diagnosed RA patients starting MTX (baseline, T0) as first-line therapy were analyzed. Outcomes, assessed after 6 months (T1), were defined as failure to achieve a disease activity score 28 (DAS28) low disease activity (LDA) or a good/moderate response to MTX, according to the European League Against Rheumatism (EULAR) response criteria. Logistic regression was used to assess the associations between baseline variables and the study outcomes.Overall, 294 patients (60.5% females, median age 54.5 years) with a median disease duration of 7.9 months were recruited. At T1, 47.3% of subjects failed to achieve LDA, and 29.3% did not have any EULAR-response. In multivariate analysis, significant associations were observed between no LDA and current smoking (adjusted odds ratio [adjOR] 1.79, P = .037), female gender (adjOR 1.68, P = .048), and higher DAS28 (adjOR 1.31, P = .013); and between no EULAR-response and current smoking (adjOR: 2.04, P = .019), age (adjOR: 0.72 per 10-years increases, P = .001), and higher erythrocyte sedimentation rate (adjOR: 0.49; P = .020). By contrast, there were no associations between past smoker status and study outcomes.In summary, in our real-life cohort of disease modifying anti-rheumatic drug naïve RA patients, current smoking habit independently predicts inadequate response to MTX. This, together with other independent predictors of response to treatment identified in our study, might assist with personalized monitoring in RA patients. Further studies are required to investigate whether smoking quitting strategies enhance the therapeutic response to MTX.

Efficacy, Safety, and Tolerability of Treatments for Systemic Sclerosis-Related Interstitial Lung Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: There is a paucity of head-to-head comparisons of the efficacy and harms of pharmacological treatments for systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: We conducted a network meta-analysis (NMA) in order to compare the effects of different treatments with the placebo on change in forced vital capacity (FVC), change in diffusion lung capacity for CO (DLCO), serious adverse events (SAEs), discontinuation for adverse events and mortality in SSc-ILD. Standardized mean difference (SMD) and log odds ratio were estimated using NMA with fixed effects. RESULTS: Nine randomized clinical trials (926 participants) comparing eight interventions and the placebo for an average follow-up of one year were included. Compared to the placebo, only rituximab significantly reduced FVC decline (SMD (95% CI) = 1.00 (0.39 to 1.61)). Suitable data on FVC outcome for nintedanib were not available for the analysis. No treatments influenced DLCO. Safety and mortality were also not different across treatments and the placebo, although there were few reported events. Cyclophosphamide and pomalidomide were less tolerated than the placebo, mycophenolate, and nintedanib. CONCLUSION: Only rituximab significantly reduced lung function decline compared to the placebo. However, direct head-to-head comparison studies are required to confirm these findings and to better determine the safety profile of various treatments.

Methotrexate therapy is not associated with increased liver stiffness and significant liver fibrosis in rheumatoid arthritis patients: A cross-sectional controlled study with real-time two-dimensional shear wave elastography.

OBJECTIVE: To explore the significance of the association between treatment with methotrexate (MTX) and liver stiffness in rheumatoid arthritis (RA) patients. METHODS: We enrolled 140 consecutive RA patients under MTX treatment (MTX-treated RA; mean treatment duration: 6.2 years; mean MTX cumulative dose: 4.67 g), 33 RA patients naive to MTX (MTX-naive RA) and 100 age and sex-matched healthy blood donors (HD). Liver stiffness was assessed by real time two-dimensional shear wave elastography, with values ≥7.1 Kilopascals (kPa) defining significant liver fibrosis. RESULTS: kPa values in HD (4.32 ±â€¯0.7) were lower than that in MTX-naive RA (4.92 ±â€¯0.8) and MTX-treated RA (4.85 ±â€¯0.9, p < .0005 for trend). On the contrary, the difference in kPa between MTX-naive and MTX-treated RA was not significant (p = .89). Similarly, liver stiffness was not significantly different across strata of cumulative MTX dose (4.95 ±â€¯0.7 kPa in MTX <1 g, 4.90 ±â€¯1.1 kPa in MTX 1-3 g and 4.80 ±â€¯0.9 in MTX >3 g, p = .610). Significant liver fibrosis was diagnosed in 4 patients in the MTX-treated RA (highest kPa value = 7.6; no liver function test abnormalities or clinical signs of hepatic failure) and in none in both the MTX-naive RA and HD groups (p = .145). CONCLUSION: Liver stiffness values, although within the normal range, are significantly higher in RA patients vs. controls, irrespective of MTX treatment. RA patients taking MTX do not have a higher prevalence of significant liver fibrosis when compared to MTX naive RA patients and the general population.

Reactive arthritis secondary to Hafnia alvei enterocolitis.

Diagnosis of postenteritic reactive arthritis (ReA) is a challenge and might have a broad range of differential diagnoses. A 50-year-old man was referred to our attention because of persistent inflammatory low back pain and asymmetric oligoarthritis. The clinical history was positive for diarrhoea in the previous 3 months. Inflammatory bowel disease, Whipple and celiac diseases were carefully excluded. In addition, serology, stool cultures, biopsies from the upper gastrointestinal tract yielded negative results for infections. A presumptive diagnosis of ReA was done and a non-steroidal anti-inflammatory drug trial prescribed. Persistence of symptoms prompted us for a second look of the colon. Biopsy collected from the terminal ileum were cultured and surprisingly colonies of Hafnia alvei, a rod-shaped Enterobacteriaceae, were detected. Treatment with ciprofloxacin leads to fast symptoms resolution. Although enterocolitis from H. alvei has been rarely reported, the culture of intestinal specimens might be recommended in the work-up of patients with suspected postenteritic ReA.

Association Between Exposure to Heavy Metals and Systemic Sclerosis: the Levels of Al, Cd, Hg, and Pb in Blood and Urine of Patients.

Systemic sclerosis (SSc) is a multisystem connective tissue disease; exogenous factors-including heavy metals-may have a role in the disease pathogenesis. In this context, a study on the quantification of Al, Cd, Hg, and Pb in blood and urine of 27 SSc patients and 30 controls was carried out. Main findings were that Al was significantly depleted in blood and increased in urine of SSc patients respect to controls; and Pb was found slightly increased in blood and significantly decreased in SSc group. In addition, higher Hg levels in urine were found in SSc subjects with the higher severity of the disease. Females showed the most marked differences in the levels of blood Al, blood Pb, and urine Cd between patients and controls. Smoking, hobby, ingestion of contaminated food, job exposure may contribute to the bodily levels of Al, Hg, Pb in SSc patients. The results indicated that low, chronic, and multiple exposures to heavy metals-also through habits, diet, and environment-may influence the risk for SSc.

Prevalence and Determinants of Peripheral Microvascular Endothelial Dysfunction in Rheumatoid Arthritis Patients: A Multicenter Cross-Sectional Study.

OBJECTIVES: To define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events. MATERIALS AND METHODS: Data from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis-ClinicalTrials.gov: NCT02341066) were analyzed. Log-transformed reactive hyperemia index (Ln-RHI) was evaluated by peripheral arterial tonometry (PAT) using the EndoPAT2000 device: values of Ln-RHI < 0.51 were considered indicative of peripheral ED. RESULTS: Peripheral microvascular ED was documented in one-third of RA patients (33.5%); in multiple logistic regression analysis, ACPA negativity and higher triglycerides concentrations were independently associated with the presence of peripheral ED [OR (95% CI) = 1.708 (1.218-2.396), p < 0.01 and OR (95% CI) = 1.005 (1.002-1.009), p < 0.01, respectively]. Multiple regression analysis showed a positive correlation between Ln-RHI values and systolic blood pressure and HDL cholesterol levels; furthermore, higher values of Ln-RHI were associated with ACPA positivity, while smoking habit was associated with lower Ln-RHI values. CONCLUSIONS: This study demonstrates for the first time a high prevalence of peripheral microvascular ED in patients with RA free of previous cardiovascular events that appear to be only partially driven by traditional cardiovascular risk factors. The association between ACPA negativity and ED warrants further exploration.

Interferon regulatory factor 5 is a potential target of autoimmune response triggered by Epstein-barr virus and Mycobacterium avium subsp. paratuberculosis in rheumatoid arthritis: investigating a mechanism of molecular mimicry.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic disease characterised by a pro-inflammatory cytokines linked erosive joint damage and by humoral and cellular response against a broad range of self-peptides. Molecular mimicry between Epstein-Barr virus (EBV), Mycobacterium avium subsp. paratuberculosis (MAP) and host peptides has long been regarded as an RA pathogenetic mechanism. Using bioinformatic analysis we identified high sequence homology among interferon regulatory factor 5 (IRF5), EBV antigen BOLF1 and MAP antigen MAP_4027. Our objective was to evaluate the presence in sera of RA patients of antibodies (Abs) directed against human homologous IRF5 cross-reacting with BOLF1 and MAP_4027. METHODS: Frequency of reactivity against IRF5424-434, BOLF1305-320 and MAP_402718-32 was tested by indirect ELISA in sera from 71 RA patients and 60 healthy controls (HCs). RESULTS: RA sera show a remarkable high frequency of reactivity against IRF5424-434 in comparison to HCs (69% vs. 8%; p<0.0001). Similarly, seroreactivity against BOLF1305-320 was more frequently detected in RA sera than in HCs counterpart (58% vs. 8%; p<0.0001). Frequency of Abs against MAP_402718-32 was 17% in RA sera vs. 5% in HCs with a p-value at the threshold level (p<0.051). Prevalence of Abs against at least one of the assessed epitopes reached 72% in RA patients and 15% among HCs. Levels of Abs in RA patients were significantly related to systemic inflammation. CONCLUSIONS: IRF5 is a potential autoimmune target of RA. Our results support the hypothesis that EBV and MAP infections may be involved in the pathogenesis of RA, igniting a secondary immune response that cross-reacts against RA self-peptides.

Rheumatoid arthritis patient antibodies highly recognize IL-2 in the immune response pathway involving IRF5 and EBV antigens.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive joint damage due to largely unknown environmental factors acting in concert with risk alleles conferring genetic susceptibility. A major role has been attributed to viral infections that include past contacts with Epstein-Barr virus (EBV) and, more recently, to non-protein coding sequences of human endogenous retrovirus K (HERV-K) integrated in the human genome. Molecular mimicry between viral and self proteins is supposed to cause the loss of immune tolerance in predisposed hosts. There are evidences that anti-IL-2 antibodies (Abs) are present in subjects affected by autoimmune diseases and may be responsible for alterations in regulatory T cell responses. In this study, we evaluated the levels of Abs against IL-2, viral epitopes and interferon regulatory factor 5 (IRF5) in 140 RA patients and 137 healthy controls (HCs). Ab reactivity reached the highest levels for IRF5, EBV and IL-2 (56%, 44% and 39%, respectively) in RA with significantly lower values among HCs (7-9%, p < 0.0001), which suggests a possible cross-reaction between IRF5/EBV homologous antigens and shifts in T cell balance disrupted by anti-IL-2 Abs.

Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence.

There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis-mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-α, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue.

Ultrasound in psoriatic arthritis. Can it facilitate a best routine practice in the diagnosis and management of psoriatic arthritis?

Important advances from both therapeutic and clinical assessment have recently been reported in psoriatic arthritis (PsA). Moreover, the constant challenge to provide a more comprehensive assessment of this heterogeneous disease results in a variety of clinical instruments that help the clinician for a global evaluation of both disease activity and responsiveness. The current European League Against Rheumatism (EULAR) recommendations on the use of imaging suggest the use of ultrasound (US) in chronic arthritis to increase the diagnostic accuracy and improvement of its management as compared to clinical examination alone. Although US findings are not firmly established in daily clinical practice, it demonstrated several positive aspects such as good sensitivity and specificity, acceptable reliability, and adequate sensitivity to change, especially in the peripheral PsA. Additionally, recent works introduced the role of US in the assessment of skin and nails opening interesting area of research. The aim of this paper is to describe the potential role of US in the assessment of PsA and to discuss the current evidence supporting its application in daily clinical practice.