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)-1ß and other pro-atherogenic cytokines. Interestingly, increased IL-1ß levels were also detected in tertiary lymphoid structures developing in vessel adventitia adjacent to the atherosclerotic plaque, suggesting a direct role of IL-1ß 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.

One year in review 2019: novelties in the treatment of rheumatoid arthritis.

The current treatment approach in rheumatoid arthritis (RA) follows a stepwise management, starting from early introduction of conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs), moving to biological (b) DMARDs and targeted synthetic (ts) DMARDs. In the last few years, new drugs with different mechanisms of action have demonstrated their efficacy in treating such a disabling condition, and their approval, along with other more "experienced" treatments, has established their effectiveness on disease activity, damage accrual prevention, patients' quality of life improvement, confirming their safety profile. Moreover, new molecular pathways are under investigation as potential targets of new advanced therapies. Clinicians' capability of stratifying treatment strategies and decisions has improved, with several new tools for the optimisation of long-term management of RA; however, a high proportion of patients are refractory to the available drugs. Finally, as RA is a systemic disease, the knowledge in multi-systemic complications of the disease has grown, as well as the possibility in improving extra-articular manifestations of the disease, although certain drugs have potentially relevant non-articular effects, which need to be monitored. This narrative review summarises the most relevant studies published over the last year in the field of treatment of RA, with the major aim to let clinicians and researchers reflect on "what is new", "what is effective" and "what is safe".

Discrepancy between subjective symptoms, objective measures and disease activity indexes: the lesson of primary Sjögren's syndrome.

Mucosal dryness is a key clinical feature in primary Sjögren's syndrome (pSS) and its assessment relies on both objective measurement of residual secretion and subjective symptoms reported by patients. However, while the objective assessment and grading of glandular dysfunction can be easily performed, the spectrum of clinical symptoms encompassed by the terms 'dry eye' and 'dry mouth' is wide and heterogeneous. Therefore, patient reported outcomes (PROs) for dryness in pSS poorly correlate with the amount of glandular secretion. In addition, subjective dryness is not correlated with the severity of systemic disease and severely affects the patient quality of life even in presence of active extraglandular manifestations. The purpose of this review article is to provide an overview of glandular dysfunction in pSS as well as the impact of discrepancy between objective assessment, subjective symptom and extraglandular disease activity on disease management.

The prevalence and relevance of traditional cardiovascular risk factors in primary Sjögren's syndrome.

Accelerated atherosclerosis is a distinct feature of some inflammatory and autoimmune disorders and several specific autoimmune mechanisms and persistent inflammation have been identified to exert a pivotal role in precocious atherosclerotic damage in these disorders. Although increased atherosclerotic risk has been well established in some rheumatic autoimmune systemic diseases, such as systemic lupus erythematosus and rheumatoid arthritis, reliable data regarding the prevalence and pathogenetic mechanisms associated with increased atherosclerotic damage in primary Sjögren's syndrome are scarse. Indeed, primary Sjögren's syndrome is an autoimmune disorder characterised by chronic inflammation and autoimmune dysregulation that shares many pathogenic mechanisms and clinical features with systemic lupus erythematosus and rheumatoid arthitis. Higher prevalence of subclinical atherosclerosis has been observed in primary Sjögren's syndrome patients and recent population-based studies demonstrated an increased risk of cardiovascular events in these patients in comparison to general population. Among mechanisms associated with atherosclerotic damage, the prevalence and the role of traditional cardiovascular risk factors have been poorly investigated. In particular, the issue of whether the presence of these cardiovascular risk factors is associated with an increased risk of cardiovascular events needs to be further explored.

One year in review 2018: pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects joints. The several mechanisms involved in the development of the disease are not completely understood. It has been proposed that different environmental factors, such as cigarette smoking, occupational and atmospheric agents act as trigger stimuli for the development of RA in genetically predisposed individuals, leading to synovial hyperplasia and bone destruction. The initial disease stage of RA is associated with alteration of innate and adaptive immune system with consequent production of autoantibodies, targeting various molecules including modified self-epitopes. In the following stages of the disease, both the innate (e.g. dendritic cells, macrophages and neutrophils) and adaptive immune cells (e.g. B and T lymphocytes) contribute to the amplification and perpetuation of the chronic inflammatory state. The recognition of key cells, mediators and mechanisms implicated in the pathogenesis of RA could provide the basis for the development of new and precise disease-modifying anti-rheumatic drugs. Therefore, we reviewed the literature of the last year in order to find the new insights in RA pathogenesis.