MicroRNAs in Rheumatoid Arthritis: From Pathogenesis to Clinical Utility

Emerging evidence suggests that microRNAs (miRNAs) play a key role in the regulation of immunological functions including innate and adaptive immune responses, development and differentiation of immune cells, and the prevention of autoimmunity. The current state of our knowledge in this area is far from being complete, and continued investigations will be needed to reveal a better understanding of the miRNA network that is involved in the pathogenesis of rheumatoid arthritis (RA). In RA, miRNA plays an important role in many different cellular processes. It has been shown that they modulate inflammatory responses, proliferation of synoviocytes, and production of metalloproteinases in rheumatoid joins and affect the development, differentiation, effector, and regulatory functions of T and B cells and cytokine production. The specific circulating miRNA species may also be useful for the diagnosis, classification, and prognosis of diseases and prediction of the therapeutic response

Replication Study Of Polymorphisms Associated With Response To Methotrexate In Patients With Rheumatoid Arthritis

About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as.DAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to.DAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response

Review papers U1-RNP and Toll-like receptors in the pathogenesis of mixed connective tissue disease Part II. Endosomal TLRs and their biological significance in the pathogenesis of mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a chronic autoimmune immunopathological disease of unknown etiology, which is characterized by the presence of various clinical symptoms and the presence of autoantibodies against U1-RNP particles. The U1-RNP component engages immune cells and their receptors in a complex network of interactions that ultimately lead to autoimmunity, inflammation, and tissue injury. The anti-U1-RNP autoantibodies form an immune complex with self-RNA, present in MCTD serum, which can act as endosomal Toll-like receptor (TLR) ligands. Inhibition of TLRs by nucleic acids is a promising area of research for the development of novel therapeutic strategies against pathogenic infection, tumorigenesis and autoimmunity. In this review we summarize current knowledge of endogenous TLRs and discuss their biological significance in the pathogenesis of MCTD. In part I we described the structure, biological function and significance of the U1-RNP complex in MCTD

Review paper U1-RNP and TLR receptors in the pathogenesis of mixed connective tissue disease. Part I. The U1-RNP complex and its biological significance in the pathogenesis of mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a rare autoimmune syndrome, signified by complex interactions between disease-related phenomena, including inflammation, proliferative vascular arteriopathy, thrombotic events and humoral autoimmune processes. It is still controversial whether MCTD is a distinct clinical entity among systemic connective tissue diseases, although several authors consider that it is distinct and underline characteristic, distinct clinical, serological and immunogenetic features. The putative target of autoimmunity in MCTD is U1-RNP, which is a complex of U1-RNA and small nuclear RNP. Both the U1-RNA component and the specific proteins, particularly U1-70K, engage immune cells and their receptors in a complex network of interactions that ultimately lead to autoimmunity, inflammation, and tissue injury. U1-RNA is capable of inducing manifestations consistent with TLR activation. Stimulation of innate immunity by native RNA molecules with a double-stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins

Pharmacogenomics of Anti-TNF Treatment Response Marks a New Era of Tailored Rheumatoid Arthritis Therapy

Rheumatoid arthritis (RA) is the most commonly occurring chronic inflammatory arthritis, the exact mechanism of which is not fully understood. Tumor Necrosis Factor (TNF)-targeting drugs has been shown to exert high effectiveness for RA, which indicates the key importance of this cytokine in this disease. Nevertheless, the response to TNF inhibitors varies, and approximately one third of RA patients are non-responders, which is explained by the influence of genetic factors. Knowledge in the field of pharmacogenomics of anti-TNF drugs is growing, but has not been applied in the clinical practice so far. Different genome-wide association studies identified a few single nucleotide polymorphisms associated with anti-TNF treatment response, which largely map genes involved in T cell function. Studies of the gene expression profile of RA patients have also indicated specific gene signatures that may be useful to develop novel prognostic tools. In this article, we discuss the significance of TNF in RA and present the current knowledge in pharmacogenomics related to anti-TNF treatment response

Cytokines and MicroRNAs as Candidate Biomarkers for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with varied course and symptoms. Its etiology is very complex and not clearly understood. There is growing evidence of the important role of cytokines in SLE pathogenesis, as well as their utility as biomarkers and targets in new therapies. Other potential new SLE biomarkers are microRNAs. Recently, over one hundred different microRNAs have been demonstrated to have a significant impact on the immune system. Various alterations in these microRNAs, associated with disease pathogenesis, have been described. They influence the signaling pathways and functions of immune response cells. Here, we aim to review the emerging new data on SLE etiology and pathogenesis

miRNAs as Biomarkers and Possible Therapeutic Strategies in Rheumatoid Arthritis

Within the past years, more and more attention has been devoted to the epigenetic dysregulation that provides an additional window for understanding the possible mechanisms involved in the pathogenesis of autoimmune rheumatic diseases. Rheumatoid arthritis (RA) is a heterogeneous disease where a specific immunologic and genetic/epigenetic background is responsible for disease manifestations and course. In this field, microRNAs (miRNA; miR) are being identified as key regulators of immune cell development and function. The identification of disease-associated miRNAs will introduce us to the post-genomic era, providing the real probability of manipulating the genetic impact of autoimmune diseases. Thereby, different miRNAs may be good candidates for biomarkers in disease diagnosis, prognosis, treatment and other clinical applications. Here, we outline not only the role of miRNAs in immune and inflammatory responses in RA, but also present miRNAs as diagnostic/prognostic biomarkers. Research into miRNAs is still in its infancy; however, investigation into these novel biomarkers could progress the use of personalized medicine in RA treatment. Finally, we discussed the possibility of miRNA-based therapy in RA patients, which holds promise, given major advances in the therapy of patients with inflammatory arthritis

Personalized medicine in rheumatology

In the era of the 21st century, rheumatoid arthritis (RA) is still poorly characterized. Rheumatoid arthritis is a common but heterogeneous disease, not only in the course and clinical symptoms, but also in the clinical response to treatment. Now it is known that early, correct diagnosis and starting treatment with disease-modifying drugs (DMARDs), of which methotrexate (MTX) remains the gold standard in the treatment of RA, is crucial in order to prevent joint destruction, functional disability and an unfavourable disease outcome. Early diagnosis of rheumatoid arthritis is significant in so much as the primary treatment can be started better. Pharmacogenetic and pharmacogenomic studies, which help determine the genetic profile of individual patients, may bring us closer to personalized medicine. Further studies on RA should allow for the identification of disease-specific genes at the stage when their tolerance by the organism is still preserved (before auto-aggression develops)

VAV1 Gene Polymorphisms in Patients with Rheumatoid Arthritis

Introduction: Rheumatoid arthritis (RA) is an important public health problem because this disease often causes disability. RA is a chronic, destructive autoimmune disease that leads to joint destruction and the development of extraarticular manifestations. VAV1 is an intracellular signal transduction protein that plays a significant role in signal transduction in T cells and affects T cell development, proliferation and activation. The VAV1 gene contains 27 exons and is located on chromosome 19. In this study, we examined the association between VAV1 rs2546133 and rs2617822 polymorphisms and RA. Methods: We examined 422 patients with RA and 338 healthy subjects as the control group. Results: Among RA patients, there was a statistically significant increase in the frequency of VAV1 rs2546133 polymorphism in T allele carriers (TT + CT versus CC, odds ratio: 1.69, 95% confidence interval 1.05–2.73, p = 0.035). There was no statistically significant difference in the distribution of the rs2617822 genotypes and alleles between RA patients and the control group. Additionally, patients who carried the VAV1 rs2546133 T and rs2617822 G allele presented an increased frequency of extraarticular manifestations: vasculitis, amyloidosis and Sjogren syndrome. Conclusions: The results suggest an association between VAV1 gene rs2617822 polymorphism and RA