Mucosa-Environment Interactions in the Pathogenesis of Rheumatoid Arthritis

Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa environment interaction

Identification of subclinical lung involvement in ACPA-positive subjects through functional assessment and serum biomarkers

Lung involvement is related to the natural history of anti-citrullinated proteins antibodies (ACPA)-positive rheumatoid arthritis (RA), both during the pathogenesis of the disease and as a site of disease-related injury. Increasing evidence suggests that there is a subclinical, early lung involvement during the course of the disease, even before the onset of articular manifestations, which can potentially progress to a symptomatic interstitial lung disease. To date, reliable, noninvasive markers of subclinical lung involvement are still lacking in clinical practice. The aim of this study is to evaluate the diagnostic potential of functional assessment and serum biomarkers in the identification of subclinical lung involvement in ACPA-positive subjects. Fifty ACPA-positive subjects with or without confirmed diagnosis of RA (2010 ARC-EULAR criteria) were consecutively enrolled. Each subject underwent clinical evaluation, pulmonary function testing (PFT) with assessment of diffusion lung capacity for carbon monoxide (DLCO), cardiopulmonary exercise testing (CPET), surfactant protein D (SPD) serum levels dosage and high-resolution computed tomography (HRCT) of the chest. The cohort was composed of 21 ACPA-positive subjects without arthritis (ND), 10 early (disease duration < 6 months, treatment-naïve) RA (ERA) and 17 longstanding (disease duration < 36 months, on treatment) RA (LSRA). LSRA patients had a significantly higher frequency of overall HRCT abnormalities compared to the other groups (p = 0.001). SPD serum levels were significantly higher in ACPA-positive subjects compared with healthy controls (158.5 ± 132.3 ng/mL vs 61.27 ± 34.11 ng/mL; p < 0.0001) and showed an increasing trend from ND subjects to LSRD patients (p = 0.004). Patients with HRCT abnormalities showed significantly lower values of DLCO (74.19 ± 13.2% pred. vs 131.7 ± 93% pred.; p = 0.009), evidence of ventilatory inefficiency at CPET and significantly higher SPD serum levels compared with subjects with no HRCT abnormalities (213.5 ± 157.2 ng/mL vs 117.7 ± 157.3 ng/mL; p = 0.018). Abnormal CPET responses and higher SPD levels were also associated with specific radiological findings. Impaired DLCO and increased SPD serum levels were independently associated with the presence of HRCT abnormalities. Subclinical lung abnormalities occur early in RA-associated autoimmunity. The presence of subclinical HRCT abnormalities is associated with several functional abnormalities and increased SPD serum levels of SPD. Functional evaluation through PFT and CPET, together with SPD assessment, may have a diagnostic potential in ACPA-positive subjects, contributing to the dentification of those patients to be referred to HRCT scan

Mucosa–Environment Interactions in the Pathogenesis of Rheumatoid Arthritis

Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA—namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa–environment interaction

Capitolo 9.8 Malattia IgG4-correlata

La malattia IgG4-correlata (IgG4-related disease, IgG4-RD) è una patologia infiammatoria cronica sistemica ad eziologia sconosciuta e patogenesi immuno-mediata, caratterizzata dalla presenza di un infiltrato linfoplasmacellulare negli organi coinvolti e dal frequente riscontro di un aumento dei livelli sierici delle immunoglobuline G di sottoclasse 4. La storia naturale della malattia consiste in un’evoluzione fibrotica con conseguente disfunzione dell’organo interessato. La IgG4-RD è stata identificata come entità nosologica a se stante solo nel 2003, quando venne riconosciuta come l’”ombrello”sotto cui includere numerose condizioni cliniche precedentemente considerate patologie d’organo isolate, per le quali non era nota una eziopatogenesi sistemica. La dimostrazione di un infiltrato plasmacellulare IgG4-positivo è un criterio diagnostico indispensabile per considerare una patologia parte dello spettro della IgG4-RD. Il sospetto diagnostico e la successiva conferma istologica sono di fondamentale importanza, in quanto una terapia appropriata e tempestiva previene lo sviluppo della fibrosi e quindi della disfunzione d’organo irreversibile

Mavrilimumab: an evidence based review of its potential in the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) management has greatly improved with the development of biologic disease modifying antirheumatic drugs, but a proportion of patients do not improve despite the biologic drugs currently available. We need new biologic agents with novel mechanisms of action for the treatment of refractory patients. Recent evidence has shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is involved in the pathogenesis of RA. GM-CSF can exacerbate RA and elevated levels of this cytokine have been observed in synovial fluid from RA patients. Antagonism of GM-CSF can strikingly reduce established disease in mouse models of arthritis. Mavrilimumab, a human monoclonal antibody to GM-CSF receptor α, is a competitive antagonist of GM-CSF signaling. Phase I and II studies have shown good clinical response with a good safety profile in patients with mild to moderate RA, suggesting encouraging effects of mavrilimumab for the treatment of RA. This paper reviews the preclinical and clinical data evaluating the safety, tolerability, and efficacy of mavrilimumab in the treatment of RA. © 2014 Di Franco et al

Asymmetric Dimethyl Arginine as a Biomarker of Atherosclerosis in Rheumatoid Arthritis

Cardiovascular disease is the main cause of morbidity and mortality in rheumatoid arthritis (RA). Despite the advent on new drugs targeting the articular manifestations, the burden of cardiovascular disease is still an unmet need in the management of RA. The pathophysiology of accelerated atherosclerosis associated to RA is not yet fully understood, and reliable and specific markers of early cardiovascular involvement are still lacking. Asymmetric dimethylarginine is gaining attention for its implication in the pathogenesis of endothelial dysfunction and as biomarkers of subclinical atherosclerosis. Moreover, the metabolic pathway of methylarginines offers possible targets for therapeutic interventions to decrease the cardiovascular risk. The purpose of this review is to describe the main causes of increased methylarginine levels in RA, their implication in accelerated atherosclerosis, the possible role as biomarkers of cardiovascular risk, and finally the available data on current pharmacological treatment

Reactive arthritis: current treatment challenges and future perspectives

Reactive arthritis is a group of inflammatory joint diseases triggered by a previous infection, often associated with extra-articular features. The clinical course and consequently the treatment are complicated by the variability of the disease evolution in the single patient. In some patients, the disease assumes a chronic and destructing course, requiring the introduction of therapy. However, the role of antibiotic treatment of the triggering infection as well as the role of the currently available disease-modifying anti-rheumatic drugs is still unclear. The better understanding of the infectious agents-host interaction in reactive arthritis pathogenesis opens the possibility of new therapeutic strategies for the disease management. The purpose of this review is to illustrate the recent discoveries about the induction of joint inflammation by the infectious agents, the prognostic factors to better identify patients at risk of chronicity, the current available therapeutic strategies and lastly, the future possibilities of therapeutic approaches to reactive arthritis

Dietary Habits and Nutrition in Rheumatoid Arthritis: Can Diet Influence Disease Development and Clinical Manifestations?

Rheumatoid arthritis (RA) is a systemic, autoimmune disease characterized by joint involvement, with progressive cartilage and bone destruction. Genetic and environmental factors determine RA susceptibility. In recent years, an increasing number of studies suggested that diet has a central role in disease risk and progression. Several nutrients, such as polyunsaturated fatty acids, present anti-inflammatory and antioxidant properties, featuring a protective role for RA development, while others such as red meat and salt have a harmful effect. Gut microbiota alteration and body composition modifications are indirect mechanisms of how diet influences RA onset and progression. Possible protective effects of some dietary patterns and supplements, such as the Mediterranean Diet (MD), vitamin D and probiotics, could be a possible future adjunctive therapy to standard RA treatment. Therefore, a healthy lifestyle and nutrition have to be encouraged in patients with RA