Subclinical Atherosclerosis in Primary Sjögren's Syndrome: Does Inflammation Matter?

Sjögren's syndrome (SS) is a systemic autoimmune disease mainly characterized by inflammatory involvement of exocrine gland. Atherosclerosis is a complex process leading to plaque formation in arterial wall with subsequent cardiovascular (CV) events. Recently, numerous studies demonstrated that SS patients bear an increased CV risk. Since activation of immune system is a key element in atherosclerosis, it is interesting to analyze whether and how the autoimmune and inflammatory events characterizing SS pathogenesis directly or indirectly contribute to atherosclerosis risk in these patients. An increase in circulating endothelial microparticles and integrins, which may be a consequence of endothelial damage and impaired repair mechanisms, has been demonstrated in SS. Increased endothelial expression of adhesion molecules with subsequent infiltration of inflammatory cells into arterial wall is also a critical event in atherosclerosis. The early inflammatory events taking place in the atherosclerotic plaque cause an increase in alarmins, such as S100A8/A9, which seems to be associated with SS disease activity and, in turn, induce up-regulation of interleukin (IL)-1β and other pro-atherogenic cytokines. Interestingly, increased IL-1β levels were also detected in tertiary lymphoid structures developing in vessel adventitia adjacent to the atherosclerotic plaque, suggesting a direct role of IL-1β in this process. Similar to these structures, germinal center-like structures arising in SS exocrine glands are also tertiary lymphoid systems where T-helper (Th) cell subsets govern the adaptive immune response. Th1 cells are the most prevalent subtype and have been shown to be strongly involved in both SS pathogenesis and atherosclerosis. Th17 cells are attracting great interest and few studies showed its importance in SS development. Albeit in low amounts, a Th17 signature was also detected in atherosclerotic plaques and some animal models demonstrated a significant pro-atherogenic role and positive effects of IL-17A blockade. Despite the fact that T cells have a pivotal role in the inflammatory process that ultimately leads to atherosclerosis, B cells have also been detected in atherosclerotic plaques, although their exact role is still mostly unknown with studies showing contrasting results. In this scenario, the role of inflammation in atherosclerosis pathogenesis in patients with SS needs to be further explored

Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease

Objectives: Increasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation. Methods: T cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes. Results: Significant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte–T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio. Conclusions: Interaction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders

Targeting Inflammation to Prevent Cardiovascular Disease in Chronic Rheumatic Diseases: Myth or Reality?

Evidence for increased risk of cardiovascular morbidity and mortality in chronic inflammatory rheumatic diseases has accumulated during the last years. Traditional cardiovascular risk factors contribute in part to the excess of cardiovascular risk in these patients and several mechanisms, including precocious acceleration of subclinical atherosclerotic damage, inflammation, and immune system deregulation factors, have been demonstrated to strictly interplay in the induction and progression of atherosclerosis. In this setting, chronic inflammation is a cornerstone of rheumatic disease pathogenesis and exerts also a pivotal role in all stages of atherosclerotic damage. The strict link between inflammation and atherosclerosis suggests that cardiovascular risk may be reduced by rheumatic disease activity control. There are data to suggest that biologic therapies, in particular TNFα antagonists, may improve surrogate markers of cardiovascular disease and reduce CV adverse outcome. Thus, abrogation of inflammation is considered an important outcome for achieving not only control of rheumatic disease, but also reduction of cardiovascular risk. However, the actual effect of anti-rheumatic therapies on atherosclerosis progression and CV outcome in these patients is rather uncertain due to great literature inconsistency. In this paper, we will summarize some of the main mechanisms linking the inflammatory pathogenic background underlying rheumatic diseases and the vascular damage observed in these patients, with a particular emphasis on the pathways targeted by currently available therapies. Moreover, we will analyze current evidence on the potential atheroprotective effects of these treatments on cardiovascular outcome pointing out still unresolved questions

Salivary Gland Ultrasonography in Sjögren’s Syndrome: A European Multicenter Reliability Exercise for the HarmonicSS Project

Objectives: Salivary gland ultrasonography (SGUS) is increasingly applied for the management of primary Sjögren's syndrome (pSS). This study aims to: (i) compare the reliability between two SGUS scores; (ii) test the reliability among sonographers with different levels of experience. Methods: In the reliability exercise, two four-grade semi-quantitative SGUS scoring systems, namely De Vita et al. and OMERACT, were tested. The sonographers involved in work-package 7 of the HarmonicSS project from nine countries in Europe were invited to participate. Different levels of sonographers were identified on the basis of their SGUS experience and of the knowledge of the tested scores. A dedicated atlas was used as support for SGUS scoring. Results: Twenty sonographers participated in the two rounds of the reliability exercise. The intra-rater reliability for both scores was almost perfect, with a Light's kappa of 0.86 for the De Vita et al. score and 0.87 for the OMERACT score. The inter-rater reliability for the De Vita et al. and the OMERACT score was substantial with Light's Kappa of 0.75 and 0.77, respectively. Furthermore, no significant difference was noticed among sonographers with different levels of experience. Conclusion: The two tested SGUS scores are reliable for the evaluation of major salivary glands in pSS, and even less-expert sonographers could be reliable if adequately instructed.publishedVersio

Potenziali applicazioni della valutazione combinata del complesso unghia-entesi mediante ecotomografia e videocapillaroscopia nei pazienti affetti da malattia psoriasica

Uno degli aspetti peculiari dell’interessamento muscolo-scheletrico nella malattia psoriasica è rappresentato dall’entesite. È stato ipotizzato che tale fenomeno possa rappresentare un importante anello di congiunzione tra gli stimoli ambientali (soprattutto il microtraumatismo cronico sulle entesi) e l’innesco del processo infiammatorio caratteristico della malattia. Nel contesto della flogosi della cute e della sinovia in corso di malattia psoriasica è stato dimostrato un significativo incremento dei processi neoangiogenetici, anche rispetto ad altre malattie infiammatorie articolari, quali l’artrite reumatoide. Una sede ideale per lo studio di questi fenomeni è rappresentata dall’unghia, ove è stata evidenziata una contiguità anatomica tra l’entesi del tendine estensore profondo delle dita, l’articolazione interfalangea distale e la matrice ungueale. È quindi possibile caratterizzare le alterazioni morfologiche e vascolari del complesso unghia-entesi-interfalangea distale mediante una valutazione ecografica in scala di grigi e in color-Doppler e in videocapillaroscopia. Dal nostro studio emerge che i pazienti con malattia psoriasica presentano significative differenze in termini di alterazioni ecostrutturali dell’entesi, del complesso ungueale e dei vasi peri-ungueali rispetto ai soggetti sani e ai pazienti con artrite reumatoide. In futuro tale strumento potrebbe quindi acquisire un ruolo nella valutazione clinica dei pazienti affetti da malattie infiammatorie articolari. One of the most peculiar aspects of musculoskeletal involvement in psoriatic disease is enthesitis. It has been hypothesised that this phenomenon may represent a link between environmental stimulus (mainly chronic entheseal microtraumatism) and the triggering of inflammation in psoriatic disease. It has been demonstrated that the skin and the inflamed synovium of patients with psoriatic disease show a marked increase in neoangiogenesis compared to other inflammatory joint diseases, such as rheumatoid arthritis. An ideal structure to study these phenomena in vivo is the nail, where an anatomical contiguity among the enthesis of the extensor digitorum profundus tendon, the distal interphalangeal joint and the nail matrix has been demonstrated. Thus, it is possible to characterise morphological and vascular changes of the nail-enthesis-interphalangeal joint complex by gray-scale and power-Doppler ultrasound, along with nailfold videocapillaroscopy. In this study we have shown that patients with psoriatic disease display significant differences in the structure and aspect of the enthesis, the nail complex and nailfold capillaries, compared to healthy individuals and patients with rheumatoid arthritis. In the future, this tool may prove useful in the clinical evaluation of patients with inflammatory articular diseases

Psoriatic arthritis: tissue-directed inflammation?

The clinical picture of psoriatic arthritis (PsA) is heterogeneous, potentially involving numerous organs and tissues, such as skin and joint. From a clinical point of view, discrete tissue PsA features develop and respond to treatments apparently independently. The pathogenic events occurring in the various tissues are only partially understood. Although the vast majority of known genetic predisposing factors are shared between patients with skin psoriasis (PSO) and those affected by PsA, some tissue-specific variants have been identified. Furthermore, current data suggest that the TNF pathway and IL-23/Th17 pathways may be differentially activated in distinct tissue sites. In this review, we briefly describe current knowledge on the pathogenesis of PsA in terms of genetic predisposition, environmental factors and immunology, advancing our hypothesis to explain why a common immunologic process can express itself with significant differences in various tissues