Myositis-Specific Antibodies and Myositis-Associated Antibodies in Patients With Idiopathic Inflammatory Myopathies From the PANLAR Myositis Study Group.

BACKGROUND: Dermatomyositis (DM) and polymyositis (PM) are forms of idiopathic inflammatory myopathies (IIMs), which are associated with the production of autoantibodies that are useful in the diagnosis and prognosis of the disease. OBJECTIVE: The aim of this study was to determine the frequency of antinuclear autoantibodies (ANAs), myositis-specific autoantibodies (MSAs), and myositis-associated autoantibodies (MAAs) in 6 Latin American countries. METHODS: Two hundred ten patients with IIM were included in this cross-sectional study from 2014 to 2017: 112 from Mexico, 46 from Colombia, 20 from Peru, 16 from the Dominican Republic, 10 from Argentina, and 6 from Guatemala. Antinuclear autoantibodies were detected by indirect immunofluorescence on HEp-2 cells. MSAs and MAAs were tested by a line immunoassay method. Mann-Whitney U and χ2 tests were used for statistical analysis. RESULTS: Of the 210 IIM patients, 139 (66.2%) had DM, 59 (28%) PM, and 12 (5.7%) juvenile DM. The mean age was 43.5 (6-79 years); 158 (75.2%) were female, and 52 (24.8%) were male. The overall frequency of ANA was 60%. The most frequent patterns were fine speckled (AC-4) (78.3%) and cytoplasmic (AC-19) (6.45%). The most frequent MSA were anti-Mi-2 (38.5%) and anti-Jo-1 (11.9%). Anti-Mi-2 was more frequent in patients from Colombia (40.1%). The MAA more frequent were anti-Ro-52/TRIM21 (17.6%) and anti-PM-Scl75 (7.5%). CONCLUSIONS: This is the first study of ANA, MSA, and MAA in patients from 6 countries from the Panamerican League against Rheumatism myositis study group. We observed a general prevalence of 60% of ANA. In relation to MSA and MAA, anti-Mi-2 was the more frequent (38.5%).

MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients.

BACKGROUND: Dimerization of the myeloid differentiation primary response 88 protein (MyD88) plays a pivotal role in the exacerbated response to innate immunity-dependent signaling in rheumatoid arthritis (RA). ST2825 is a highly specific inhibitor of MyD88 dimerization, previously shown to inhibit the pro-inflammatory gene expression in peripheral blood mononuclear cells from RA patients (RA PBMC). In this study, we elucidated the effect of disrupting MyD88 dimerization by ST2825 on the pathological properties of synovial fibroblasts from RA patients (RA SFs). METHODS: RA SFs were treated with varying concentrations of ST2825 in the presence or absence of bacterial lipopolysaccharides (LPS) to activate innate immunity-dependent TLR signaling. The DNA content of the RA SFs was quantified by imaging cytometry to investigate the effect of ST2825 on different phases of the cell cycle and apoptosis. RNA-seq was used to assess the global response of the RA SF toward ST2825. The invasiveness of RA SFs in Matrigel matrices was measured in organoid cultures. SFs from osteoarthritis (OA SFs) patients and healthy dermal fibroblasts were used as controls. RESULTS: ST2825 reduced the proliferation of SFs by arresting the cells in the G0/G1 phase of the cell cycle. In support of this finding, transcriptomic analysis by RNA-seq showed that ST2825 may have induced cell cycle arrest by primarily inhibiting the expression of critical cell cycle regulators Cyclin E2 and members of the E2F family transcription factors. Concurrently, ST2825 also downregulated the genes encoding for pain, inflammation, and joint catabolism mediators while upregulating the genes required for the translocation of nuclear proteins into the mitochondria and members of the mitochondrial respiratory complex 1. Finally, we demonstrated that ST2825 inhibited the invasiveness of RA SFs, by showing decreased migration of LPS-treated RA SFs in spheroid cultures. CONCLUSIONS: The pathological properties of the RA SFs, in terms of their aberrant proliferation, increased invasiveness, upregulation of pain and inflammation mediators, and disruption of mitochondrial homeostasis, were attenuated by ST2825 treatment. Taken together with the previously reported anti-inflammatory effects of ST2825 in RA PBMC, this study strongly suggests that targeting MyD88 dimerization could mitigate both systemic and synovial pathologies in a variety of inflammatory arthritic diseases.

IL-21 (rs2055979 and rs2221903)/IL-21R (rs3093301) Polymorphism and High Levels of IL-21 Are Associated with Rheumatoid Arthritis in Mexican Patients.

Rheumatoid Arthritis (RA) is characterized by joint destruction, chronic inflammation, and autoantibody production. IL-21/IL-21R plays an essential role in the immunopathology of RA. Elevated IL-21 serum levels have been associated with RA and disease activity. Here, we evaluated the association of IL-21/IL-21R polymorphisms and IL-21 serum levels with RA. The study included 275 RA patients and 280 Control subjects (CSs). Single nucleotide polymorphisms IL-21 (rs2055979 and rs2221903) and IL-21R (rs3093301) were genotyped using PCR-RFLP. Clinical activity was evaluated by DAS28-ESR; IL-21 and anti-CCP serum levels were quantified by ELISA. The IL-21 rs2055979 AA genotype was higher in RA patients than in the CS group (p = 0.0216, OR = 1.761, 95% CI = 1.085-2.859); furthermore, RA patients showed anti-CCP elevated levels compared to the CA genotype (p = 0.0296). The IL21R rs3093301 AA genotype was also higher in RA patients than in the CS group (p = 0.0122, OR = 1.965, 95% CI = 1.153-3.348). The AT haplotypes of IL-21 rs2055979 and rs2221903 were more frequent (49%) in the RA group (p = 0.006). IL-21 serum levels were significantly elevated in the RA group, but without an association with IL-21 polymorphisms. In conclusion, IL-21 rs2255979 and IL-21R rs3093301 are associated with a higher risk of RA, and could be a genetic marker. Moreover, the elevated IL-21 levels in RA suggest that IL-21/IL-21R could be a therapeutic target in RA.

Targeting inflammasome-dependent mechanisms as an emerging pharmacological approach for osteoarthritis therapy.

Arthritic diseases have attracted enormous scientific interest because of increased worldwide prevalence and represent a significant socioeconomic burden. Osteoarthritis (OA) is the most prevalent form of arthritis. It is a disorder of the diarthrodial joints, characterized by degeneration and loss of articular cartilage associated with adjacent subchondral bone changes. Chronic and unresolving inflammation has been identified as a critical factor driving joint degeneration and pain in OA. Despite numerous attempts at therapeutic intervention, no effective disease-modifying agents targeting OA inflammation are available to the patients. Inflammasomes are protein complexes known to play a critical role in the inflammatory pathology of several diseases, and their roles in OA pathogenesis have become evident over the last decade. In this sense, it is relevant to evaluate the vital role of inflammasomes as potential modulators of pathogenic features in OA. This review will provide an overview and perspectives on why understanding inflammasome activation is critical for identifying effective OA therapies. We elaborate on the contribution of extracellular mediators from the circulatory system and synovial fluid as well as intracellular activators within the synovial fibroblasts and articular chondrocytes toward invoking the inflammasome in OA. We further discuss the merits of emerging inflammasome targeting therapies and speculate on the potential strategies for inflammasome blockade for OA therapy.

Impact of Pharmaceutical Education on Medication Adherence and Its Clinical Efficacy in Patients with Type 2 Diabetes and Systemic Arterial Hypertension.

Purpose: To evaluate the impact of pharmaceutical education on medication adherence in patients with Type 2 Diabetes and Systemic Arterial Hypertension. Patients and Methods: This randomized clinical trial enrolled patients with a diagnosis of Type 2 Diabetes Mellitus and Systemic Arterial Hypertension treated in an internal medicine outpatient clinic of a teaching hospital. One hundred and three patients were randomly assigned to the study groups; 51 to the control group and 52 to the intervention group with a 6 months follow-up. Medication adherence was assessed using the Morisky 8-item medication adherence scale. To improve patient adherence to treatment, a wallet card was provided with an up-to-date list of prescribed medications along with recommendations for follow-up care. Results: One hundred and seventy-nine patients were screened for eligibility, of which 103 (57.5%) participated in the study. The intervention group showed a statistically significant decrease in capillary glucose levels, glycated hemoglobin, systolic and diastolic blood pressure, total cholesterol and triglycerides compared to the control group. The frequencies on medication adherence levels at 3 and 6 months in the control group remained similar to baseline, while in the intervention group the frequency of high adherence increased significantly at 6 months (8.7% to 43.5%). Conclusion: A high percentage of patients are not achieving optimal control of their diabetes. Medication adherence rates were between 45-50% in patients at the baseline of the study, but after receiving education and support from a pharmacist, the intervened group showed a significant increase in their adherence.

Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients.

MyD88-dependent intracellular signalling cascades and subsequently NF-kappaB-mediated transcription lead to the dynamic inflammatory processes underlying the pathogenesis of rheumatoid arthritis (RA) and related autoimmune diseases. This study aimed to identify the effect of the MyD88 dimerization inhibitor, ST2825, as a modulator of pathogenic gene expression signatures and systemic inflammation in disease-modifying antirheumatic drugs (DMARDs)-naïve RA patients. We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients after stimulation with LPS and IL-1ß. The transcriptional profiles of ST2825-treated PBMC were analyzed to identify its therapeutic potential. Ingenuity Pathway Analysis was implemented to identify downregulated pathogenic processes. Our analysis revealed 631 differentially expressed genes between DMARDs-naïve RA patients before and after ST2825 treatment. ST2825-treated RA PBMC exhibited a gene expression signature similar to that of healthy controls PBMC by downregulating the expression of proinflammatory cytokines, chemokines and matrix metalloproteases. In addition, B cell receptor, IL-17 and IL-15 signalling were critically downregulated pathways by ST2825. Furthermore, we identified eight genes (MMP9, CXCL9, MZB1, FUT7, TGM2, IGLV1-51, LINC01010, and CDK1) involved in pathogenic processes that ST2825 can potentially inhibit in distinct cell types within the RA synovium. Overall, our findings indicate that targeting MyD88 effectively downregulates systemic inflammatory mediators and modulates the pathogenic processes in PBMC from DMARDs-naïve RA patients. ST2825 could also potentially inhibit upregulated genes in the RA synovium, preventing synovitis and joint degeneration.

Cytokines (IL-15, IL-21, and IFN-γ) in rheumatoid arthritis: association with positivity to autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) and clinical activity.

INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial membrane damage and autoantibody production. RA is a heterogeneous disease, where cytokines such as IL-15, IL-21, and IFN-γ have been associated. However, their association with the autoantibodies has not been clearly described. The aim of this study was to evaluate the relationship between the cytokines IL-15, IL-21, and IFN-γ with the autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) in RA and disease activity. METHODOLOGY: This study included 153 RA patients and 80 control subjects (CS). The levels of IL-15, IL-21, IFN-γ, anti-CCP, anti-MCV, and anti-PADI4 were quantified by ELISA, whereas RF was quantified by turbidimetry. The disease activity was evaluated by the indices disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), clinical disease activity index (CDAI), and simple disease activity index (SDAI). RESULTS: The serum levels of IL-15, IL-21, and IFN-γ, and autoantibodies were increased in RA patients, compared with CS (p < 0.05). A correlation was found between IL-21 and anti-CCP and anti-MCV (p < 0.05). According to RA evolution, RF, anti-CCP, and anti-MCV had higher levels in early RA. In addition, increased levels of IL-21 were observed in RA seropositive patients (RF/anti-CCP/anti-MCV). The higher levels of both cytokines and autoantibodies were observed in moderate activity, evaluated by the three indices. CONCLUSIONS: Our results suggest that the increased soluble levels of IL-15, IL-21, and IFN-γ are involved in the inflammatory network in RA. However, IL-21 serum levels are associated with higher titers of autoantibodies (RF, anti-CCP, and anti-MCV) and IL-15 with moderate activity. Key Points • IL-15, IL-21, and IFN-y are associated with the immunopathology of RA, but not significantly with the evolution of the disease. • RF, anti-CCP, and anti-MCV had higher levels in early than established RA. • IL-21 has an association with RF, anti-CCP, and anti-MCVand, for this reason, could be proposed as a disease biomarker. • Patients with activity moderate of disease showed higher levels of RF, anti-CCP, anti-MCV, and IL-15.