Exosomal Osteoclast-Derived miRNA in Rheumatoid Arthritis: From Their Pathogenesis in Bone Erosion to New Therapeutic Approaches.

Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation, pain, and ultimately, bone erosion of the joints. The causes of this disease are multifactorial, including genetic factors, such as the presence of the human leukocyte antigen (HLA)-DRB1*04 variant, alterations in the microbiota, or immune factors including increased cytotoxic T lymphocytes (CTLs), neutrophils, or elevated M1 macrophages which, taken together, produce high levels of pro-inflammatory cytokines. In this review, we focused on the function exerted by osteoclasts on osteoblasts and other osteoclasts by means of the release of exosomal microRNAs (miRNAs). Based on a thorough revision, we classified these molecules into three categories according to their function: osteoclast inhibitors (miR-23a, miR-29b, and miR-214), osteoblast inhibitors (miR-22-3p, miR-26a, miR-27a, miR-29a, miR-125b, and miR-146a), and osteoblast enhancers (miR-20a, miR-34a, miR-96, miR-106a, miR-142, miR-199a, miR-324, and miR-486b). Finally, we analyzed potential therapeutic targets of these exosomal miRNAs, such as the use of antagomiRs, blockmiRs, agomiRs and competitive endogenous RNAs (ceRNAs), which are already being tested in murine and ex vivo models of RA. These strategies might have an important role in reestablishing the regulation of osteoclast and osteoblast differentiation making progress in the development of personalized medicine.

Analysis of Novel Immunological Biomarkers Related to Rheumatoid Arthritis Disease Severity.

Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the most frequently used rheumatoid arthritis (RA) diagnostic markers, but they are unable to anticipate the patient's evolution or response to treatment. The aim of this study was to identify possible severity biomarkers to predict an upcoming flare-up or remission period. To address this objective, sera and anticoagulated blood samples were collected from healthy controls (HCs; n = 39) and from early RA (n = 10), flare-up (n = 5), and remission (n = 16) patients. We analyzed leukocyte phenotype markers, regulatory T cells, cell proliferation, and cytokine profiles. Flare-up patients showed increased percentages of cluster of differentiation (CD)3+CD4- lymphocytes (p < 0.01) and granulocytes (p < 0.05) but a decreased natural killer (NK)/T lymphocyte ratio (p < 0.05). Analysis of leukocyte markers by principal component analysis (PCA) and receiver operating characteristic (ROC) curves showed that CD45RO+ (p < 0.0001) and CD45RA+ (p < 0.0001) B lymphocyte expression can discriminate between HCs and early RA patients, while CD3+CD4- lymphocyte percentage (p < 0.0424) and CD45RA+ (p < 0.0424), CD62L+ (p < 0.0284), and CD11a+ (p < 0.0185) B lymphocyte expression can differentiate between flare-up and RA remission subjects. Thus, the combined study of these leukocyte surface markers could have potential as disease severity biomarkers for RA, whose fluctuations could be related to the development of the characteristic pro-inflammatory environment.

Negative effect of immunosuppressive therapy in the performance of the QuantiFERON gold in-tube test in patients with immune-mediated inflammatory diseases.

To compare the tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube test (QFG) for the detection of latent tuberculosis infection among patients with immune-mediated inflammatory diseases before antitumor necrosis factor-α therapy. A prospective study including 153 consecutive patients with rheumatoid arthritis (n = 53), psoriasis (n = 45), inflammatory bowel disease (n = 25), and spondyloarthropathy (n = 22) were included. QFG and TST were performed simultaneously. TST was positive in 43/153 (28.1 %) patients. QFG (cutoff ≥ 0.35 IU/ml) was positive in 15/153 (9.8 %) patients, and indeterminate in one (0.7 %). QFG (cutoff ≥ 0.10 IU/ml) was positive in 25/153 (16.3 %). 59.5 % of the patients were on immunosuppressive therapy at the time of testing. There was a significant difference in the rate of positive QFG between patients with and without immunosuppressive therapy after adjustment for age and gender (cutoff ≥ 0.35 IU/ml, 4.6 vs. 17.4 %; adjusted odds ratio [AOR], 0.2; 95 % confidence interval [CI], 0.06-0.8; p = 0.03 and cutoff ≥ 0.10 IU/ml, 11.2 vs. 24.2 %; AOR, 0.3; 95 % CI, 0.1-0.93; p = 0.04). Agreement between TST and QFG was 'fair' (κ = 0.354 and κ = 0.365, for cutoffs ≥ 0.35 and ≥0.10 IU/ml, respectively). Among patients without immunosuppressive therapy, the concordance between TST and QFG was 'moderate-substantial' (κ = 0.593 and κ = 0.690, for cutoffs ≥ 0.35 IU/ml and ≥0.10 IU/ml, respectively). By contrast, among patients on immunosuppressive therapy the concordance was 'poor' (κ = 0.085; κ = 0.041, respectively). Immunosuppressive therapy affects negatively QFG performance. In patients with immune-mediated inflammatory diseases, QFG may have a limited role for screening of latent tuberculosis infection.