Subclinical inflammation in the preclinical phase of rheumatoid arthritis might contribute to articular joint damage.

The first degree relatives of rheumatoid arthritis (RA) patients have a higher risk of developing RA, which is related to the expression of autoantibodies against citrullinated proteins (ACPA). Remarkably, prior to the onset of RA, cartilage damage is already initiated, whereas ACPA autoantibodies are already expressed. Here we show that both TNF-α and IL-6 are also increased prior to the onset of RA. Furthermore, when the levels of DKK1 and Sclerostin were evaluated in first degree relatives of RA patients, we found that the serum levels of TNF- α correlate with the expression levels of both DKK1 and Sclerostin. Interestingly, when the disease is already established, the correlation of TNF- α with DKK1 is lost in RA patients, whereas the correlation of Sclerostin with both TNF- α and IL-6 is further increased. Our data suggest a subclinical inflammation in patients at high risk of developing RA, which might lead to an increase in the levels of both DKK1 and Sclerostin, contributing to joint damage in the preclinical phase of the disease linked to the expression of ACPA autoantibodies.

Expression and activity of AIM2-inflammasome in rheumatoid arthritis patients.

INTRODUCTION: AIM2 inflammasome activation leads to the release of IL-ß, which plays an important role in rheumatoid arthritis pathogenesis. In this work, we evaluated AIM2 expression and activity in RA patients and healthy controls. METHODS: AIM2 and RANKL expression were evaluated by flow cytometry. Inflammasome activity was determined in monocyte cultures stimulated with synthetic DNA by measuring IL-1ß levels in supernatants using an ELISA assay. The caspase-1 expression in monocytes was measured by western blot, the POP3 expression was analysed by qPCR, and serum levels of IFN-γ were evaluated using ELISA assay. RESULTS: We observed a diminution of CD14+AIM2+ cells in RA patients, associated with disease activity and evolution. Likewise, the levels of IL-1ß were increased in monocyte cultures un-stimulated and stimulated with LPS from RA patients with DAS28 ≥ 4. The Caspase-1 activity and RANKL + monocytes in RA patients were slightly increased. Finally, augmented POP3 expression and diminished IFN-γ serum levels were detected in RA patients. CONCLUSION: Our results showed that the monocytes from RA patients were prone to release IL-1ß in the absence of the AIM2 inflammasome signal. The down-regulation of AIM2 to a systemic level in RA patients might be a consequence of augmented POP3 expression and might imply the survival of pro-inflammatory cells contributing to the inflammation process.

Subcutaneous administration of polymerized-type I collagen for the treatment of patients with rheumatoid arthritis. An open-label pilot trial.

OBJECTIVE: To determine the efficacy, tolerance and safety of subcutaneous injections of porcine type I collagen-polyvinylpyrrolidone (PVP) in patients with rheumatoid arthritis (RA). METHODS: Eleven patients with active RA on stable therapy with methotrexate (MTX) were enrolled in a 3 month prospective and longitudinal study. Patients were treated weekly with subcutaneous injections of 0.2 ml of collagen-PVP (1.7 mg of collagen) in the 8 most painful joints. The primary endpoints included the Ritchie index (RI), swollen joint count, disease activity score (DAS), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The secondary endpoints included morning stiffness, pain intensity on a visual analog scale (VAS), and the Spanish-Health Assessment Questionnaire Disability Index (HAQ-DI). Improvement was determined using American College of Rheumatology (ACR) response criteria. RESULTS: Collagen-PVP was safe and well-tolerated and there were no adverse events. Patients had a statistically significant improvement (p < 0.05) in basal versus 3 month's treatment in morning stiffness (Delta -32.3, -68.6%), RI (Delta -10.2, -46.4%), swollen joint count (Delta -10.7, -71.8%), VAS (Delta -39.9, -63.8%), HAQ-DI (Delta -0.5, -48.5%), DAS (Delta -1.35, -70.5%) and ACR20, 50, and 70 (80.0%; 60.0% and 20.0% respectively). We found no differences in serologic or hematologic variables. CONCLUSION: Collagen-PVP was a safe and well-tolerated drug for the short term treatment of RA. The combination of collagen-PVP plus MTX was more efficacious than MTX alone. However, double-blind placebo-controlled phase II and III clinical trials are necessary to determine whether this drug could be useful in the longterm treatment of RA.