Adiposity, joint and systemic inflammation: the additional risk of having a metabolic syndrome in rheumatoid arthritis.

Summary Adiposity is a predisposing condition to atherosclerosis, and rheumatoid arthritis (RA) also predisposes to accelerated atherosclerosis. Adiposity is one of the key features of the metabolic syndrome (MetS) and it is well recognised that a metabolic syndrome (and fat tissue) is a major player in this complex network. Endothelial dysfunction and carotid intima-media thickness, early pre-clinical markers of atherosclerosis which are the main determinants of cardiovascular (CV) morbidity and mortality, occur early on in RA. RA patients have an incidence of CV diseases at least two times higher than the general population. MetS and RA have a low and a severe-moderate degree of inflammation in common, respectively. Adipose tissue has emerged as a dynamic organ that releases several inflammatory and immune mediators (adipokines). In addition, fat has been recognised as a producer of B cell activating factor (BAFF) and of chemerin, an inducer at the chondrocyte level of IL1β, TNFα, IL6, IL8 and MMP13, thus possibly contributing to cartilage damage. Since fat produces inflammation, to obtain a full control of the CV risk in RA, data suggest that it is therefore mandatory to have a "tight control" of both RA and MetS-related inflammation, especially if RA presents MetS as a co-morbidity

Statins and Mortality in Connective Tissue Diseases: Should We Resume the Cardio-rheumatology Spirit in Our Clinics?

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Obesity as a Risk and Severity Factor in Rheumatic Diseases (Autoimmune Chronic Inflammatory Diseases)

The growing body of evidence recognizing the adipose tissue as an active endocrine organ secreting bioactive mediators involved in metabolic and inflammatory disorders, together with the global epidemic of overweight and obesity, rise obesity as a hot topic of current research. The chronic state of low grade inflammation present in the obese condition and the multiple pleiotropic effects of adipokines on the immune system has been implicated in the pathogenesis of several inflammatory conditions including rheumatic autoimmune and inflammatory diseases. We will discuss the main relevant evidences on the role of the adipose tissue on immune and inflammatory networks and the more recent evidences regarding the effects of obesity on the incidence and outcomes of the major autoimmune chronic inflammatory diseases

Migraine in SLE: role of antiphospholipid antibodies and Raynaud's phenomenon

Objectives: To determine the role of antiphospholipid antibodies (aPL) and of Raynaud's phenomenon (RP) in the development of migraine in patients with systemic lupus erythematosus (SLE). Methods: 50 unselected SLE patients and 20 rheumatoid arthritis (RA) controls underwent an interview to define the presence of migraine according to the guidelines of the International Headache Society (1988). Serological tests for aPL were performed in all patients. SLE patients were divided according to positivity for RP and/or aPL into 4 subsets: R-/aPL-, R-/aPL+, R+/aPL- and R+/aPL+. Data were analysed using Fisher's exact test, Chi-square test and U Mann-Whitney test. Results: SLE and RA patients were similar for demographic and clinical features; aPL positivity was found in a greater proportion of SLE patients versus RA controls (68% vs 25%, p=0.0036). 31 of the 50 lupic patients (62%) and 7 of the 20 RA controls (35%) suffered from migraine (OR=3, CI:1-8.9). Among SLE and RA patients, migraine was associated with aPL positivity (p=0.027 and p=0.019). Analysing the combined effect of aPL and RP on migraine, in R+/aPL+ patients we detected an higher frequency of migraine (85.7%) with respect to the patients negative for these two features (27%, p=0.0051, OR=16, CI:2.2-118) and to the patients positive only for aPL (65%, p=0.0031, OR=6.2, CI:1.2-32). Conclusions: Migraine in SLE and RA associates with aPL positivity. The simultaneous presence of RP increases by 2,5 times the probability of having migraine, suggesting that cerebral vasospasm might be more common in patients with peripheral vasospasm, given the presence of aPL

Very early rheumatoid arthritis is the major predictor of major outcomes: clinical ACR remission and radiographic non-progression

OBJECTIVES: To identify predictors of clinical remission as well as of no x-ray progression in a cohort of early rheumatoid arthritis (ERA) treated with a tight-control protocol. METHODS: A total of 121 consecutive patients with ERA were treated to reach European League Against Rheumatism (EULAR) and/or American College of Rheumatology (ACR) clinical remission with methotrexate (MTX) for 3 months, then with a combination with anti-tumour necrosis factor if the patient did not achieve a 44-joint Disease Activity Score (DAS44) ≤2.4. At baseline and after 12 months all the patients had hand and foot joint radiographs. Very early rheumatoid arthritis (VERA) was defined as a disease with symptoms of less than 12 weeks. RESULTS: In all, 46.3% of the patients reached DAS remission and 24.8% achieved ACR remission. More than 60% of patients reached remission with MTX. Male sex and an erythrocyte sedimentation rate <35 mm/h at onset arose as significant predictors of EULAR remission, while VERA disease was the only predictor of ACR remission. At baseline, 28.1% of the patients were erosive. Multivariate analysis demonstrated that the only independent predictor of erosiveness was 'not having VERA disease'. After 12 months, VERA was the only factor predicting a lack of new erosions. CONCLUSIONS: VERA represents the best therapeutic opportunity in clinical practice to achieve a complete remission and to stop the erosive course of rheumatoid arthritis

MicroRNA-155—at the critical interface of innate and adaptive immunity in arthritis

MicroRNAs (miRNAs) are small non-coding RNAs that fine-tune the cell response to a changing environment by modulating the cell transcriptome. MiR-155 is a multifunctional miRNA enriched in cells of the immune system and is indispensable for the immune response. However, when deregulated, miR-155 contributes to the development of chronic inflammation, autoimmunity, cancer and fibrosis. Herein, we review the evidence for the pathogenic role of miR-155 in driving aberrant activation of the immune system in Rheumatoid Arthritis, and its potential as a disease biomarker and therapeutic target

ZAP-70+ B Cell Subset Influences Response to B Cell Depletion Therapy and Early Repopulation in Rheumatoid Arthritis

Objective.To define the role of ZAP-70+ B cells (CD19+/ZAP-70+) as a biomarker of response to B cell depletion therapy (BCDT), their relationship with clinical outcome, and their behavior during repopulation of peripheral blood in patients with rheumatoid arthritis (RA).Methods.Thirty-one patients with RA underwent BCDT and were followed for 12 months. Disease activity was assessed with the European League Against Rheumatism (EULAR) criteria. Cytofluorimetric analysis of peripheral blood B cell subsets at baseline and at 6- and 12-month intervals after BCDT was performed using surface markers (CD45, CD3, CD56, CD19, IgD, CD38, CD27) and intracellular ZAP-70.Results.A moderate/good EULAR response was achieved in 66.6% of the RA cohort. The baseline percentage of CD19+/ZAP-70+ cells was lower in good responder patients (1.8% ± 1.7%) compared to poor responders (5.6% ± 4.9%; p = 0.02). A decrease of plasmablasts (IgD-CD27+CD38+) and pre-switch memory (IgD+CD27+) B cells occurred after BCDT. Recovery of B cells in peripheral blood after the first course of BCDT was characterized by the reappearance of B cell subtypes that showed a naive, activated phenotype, coupled with a decrease in memory cells. B cells carrying intracytoplasmic ZAP-70 increased significantly from the baseline value of 4.4% ± 4.5% to 12.4% ± 9.2% (p = 0.001) at the 6-month and to 9.4% ± 6.4% (p = 0.002) at the 12-month followup.Conclusion.Baseline percentage of CD19+/ZAP-70+ cells is associated with the clinical outcome after BCDT in patients with RA. Depletion of plasmablasts and pre-switch memory B cells and increase of CD19+/ZAP-70+ cells are features of the recovery of the B cell pool after BCDT

Memory B cell subsets and plasmablasts are lower in early than in long-standing Rheumatoid Arthritis

Alterations of B cell subset distribution have been described in the peripheral blood (PB) of rheumatoid arthritis (RA) patients, but no data are available on differences between the onset and the established phases of the disease. The purpose of the study was to clarify whether a peculiar distribution of B cell subsets characterizes RA onset, thus leading to a more favorable clinical response to treatment, and to evaluate the possible association of a particular B cell subpopulation with response to therapy

B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial

INTRODUCTION: An over-expression of CD19 has been shown in B cells of systemic sclerosis (SSc) and B cells are thought to contribute to the induction of skin fibrosis in the tight skin mouse model. The aim was to define the outcome on safety and the change in skin score after rituximab therapy in SSc patients and to correlate the clinical characteristics with the levels of interleukin (IL)-6 and with the immune cell infiltrate detected by immunohistochemistry. METHODS: Nine patients with SSc with mean age 40.9 +/- 11.1 years were treated with anti-CD20, 1 g at time 0 and after 14 days. Skin biopsy was performed at baseline and during the follow-up. B-cell activating factor (BAFF) and IL-6 levels were also determined at the follow-up times. RESULTS: After 6 months patients presented a median decrease of the skin score of 43.3% (range 21.1-64.0%), and a decrease in disease activity index and disease severity index. IL-6 levels decreased permanently during the follow up. After treatment, a complete depletion of peripheral blood B cells was observed in all but 2 patients. Only 3 patients presented CD20 positive cells in the biopsy of the involved skin at baseline. CONCLUSIONS: Anti-CD20 treatment has been well tolerated and SSc patients experienced an improvement of the skin score and of clinical symptoms. The clear fall in IL-6 levels could contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the outcome after B cell depletion