No other group of diseases encompasses a greater pathophysiology than do the rheumatic diseases. Spanning multiple organ systems, clinical decisions often rely on coordinated efforts from primary care providers and rheumatologists to rule in or rule out differential diagnoses when treating inflammatory conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). RA is a symmetric, inflammatory, peripheral polyarthritis leading to deformity of joints via erosion of bone and surrounding cartilage. SLE can affect virtually any organ leading to fatigue, fever, myalgia, weight change and complications associated with renal, central nervous system, and hematologic systems can be life-threatening. RA and SLE are diagnosed through clinical judgment after excluding alternative diagnoses. In the case of both diseases, individual laboratory tests are effective only in a portion of the disease population. In RA, testing for rheumatoid factor and anti-CCP antibodies provide very important information when positive. However, these two analytes remain negative in ~50% of patients and continue to be negative throughout diagnostic follow-up in 20% of patients with RA. Further, erythrocyte sedimentation rates (ESR) and c-reactive protein (CRP) levels are generally strongly correlated with radiographic findings of joint damage. These measurements, however, can be elevated by other infectious and inflammatory processes that are not specific for RA or can be altered, in the case of ESR, by acute phase reactants from malignancy, tissue injury, or trauma. In SLE, exclusion of markers diagnostic for RA coupled with presence of markers measuring antinuclear antibodies (ANA) and followed by assays measuring double stranded DNA (dsDNA), anti-Sm, anti-Ro/SSA, anti-La/SSB, anti-U1 RNP, or antiribosomal P are frequently used. Across these analyses, the sensitivity and specificity for these laboratory measurements vary greatly and many have high specificity to rule in SLE but lack sensitivity as these diagnostic markers can be found in other disorders. For instance, anti-Ro/anti-La are found in Sjogren's syndrome and anti-U1 RNP is frequently associated with mixed connective tissue disease. As a physician colleague pointed out, it is difficult to diagnose a negative. Thus, diagnostic approaches for both RA and SLE often rely on multiple, independent laboratory tests combined with clinical observation. Distinguishing between these diseases is important, as the treatment procedures for these diseases are different. Time is a frequent factor in the diagnosis of these diseases and tools are needed to facilitate earlier diagnosis as treatment for autoimmune diseases are highly effective and early initiation of therapy leads to the best outcomes. Misdiagnosis of these conditions is also not uncommon. Another common disease seen by rheumatologists is fibromyalgia syndrome (FMS). FMS is a common cause of widespread musculoskeletal pain that affects tendons, ligaments, and muscle. FMS is difficult to diagnose and treat and a critical clinical point is that FMS is not explained by another rheumatic or systemic disorder. Thus, FMS is a diagnosis of exclusion once other etiologies have been considered and excluded. RA and SLE are two diseases that must be eliminated from the differential diagnosis. Given the complicated diagnostic process these patients are often forced to endure, recent studies have also suggested that healthcare dollars are saved post-diagnosis and patient outcomes improve. To date, there is no laboratory test that can determine presence or absence of these three conditions from a single blood sample. The question of whether or not disease classifiers capable of providing clinically useful information could be built based upon disease-specific expression levels of mRNAs in whole blood has been a subject of research for greater than ten years. Many disease-specific gene expression signatures have been identified in the research lab. A few of these have even progressed into commercially viable diagnostic tests, notably for systemic sclerosis. Long non-coding RNAs (lncRNA) are recently discovered regulatory RNA molecules that do not code for proteins but influence a vast array of biological processes. In vertebrates, the number of lncRNA genes greatly exceeds the number of protein-coding genes. It is also thought that lncRNAs drive greater biologic complexity between vertebrates and invertebrates. These lncRNAs also show much greater cell-type specific expression patterns than mRNAs. Humans also develop many more complex diseases than other organisms. As such, our data presented in preliminary studies, support the notion that disease-associated lncRNAs exhibit far greater differences in expression than disease-associated mRNAs. In this application, we propose to explore the hypothesis that lncRNAs are better biomarkers of human disease than mRNAs. Here, we will focus on FMS and rheumatic diseases as disease categories and have identified FMS and rheumatic disease- associated differentially expressed lncRNAs. Study of lncRNAs in human autoimmune disease is in its infancy and exploration of lncRNAs as biomarkers of autoimmune disease has not been previously addressed. We propose the following specific aim: To identify annotated and novel lncRNAs differentially expressed among CTRL, FMS, RA, and SLE and assess their function as biomarkers to distinguish FMS, RA, and SLE subjects from healthy subjects and subjects with other rheumatic diseases.
Public Health Relevance Statement: Diagnosis of fibromyalgia syndrome and other rheumatic diseases can be a difficult, long and costly process and misdiagnosis of these diseases is not uncommon. Long non-coding RNAs (lncRNA) are a new class of regulatory RNA molecules that exhibit high degrees of cell-type specific expression. The hypothesis we will test in this application is that measurement of expression of disease-specific lncRNAs in rheumatic diseases and fibromyalgia syndrome will have greater utility to provide meaningful clinical information to health-care providers faced with these diagnostic dilemmas than measurement of disease-specific mRNAs.
Project Terms: Acute-Phase Proteins; Address; Affect; Anti-citrullinated peptide antibody; Antinuclear Antibodies; Autoimmune Diseases; base; Biological Assay; Biological Markers; Biological Process; Blood specimen; body system; Body Weight Changes; bone erosion; Cartilage; Categories; cell type; Clinical; Code; Complex; Coupled; Data; Deformity; Diagnosis; Diagnostic; diagnostic biomarker; Diagnostic tests; Differential Diagnosis; differential expression; Disease; disease diagnosis; Early Diagnosis; Erythrocyte Sedimentation Rate; Etiology; Exclusion; Exhibits; Fatigue; Fever; Fibromyalgia; follow-up; Functional disorder; Gene Expression Profile; Genes; Health Personnel; Healthcare; Human; human disease; improved; Individual; infancy; Inflammatory; Injury; Invertebrates; joint injury; Joints; Judgment; Kidney; Laboratories; Life; Ligaments; Malignant Neoplasms; Measurement; Measures; Messenger RNA; Mixed Connective Tissue Disease; Muscle; Musculoskeletal Pain; Myalgia; Neuraxis; novel; Organ; Organism; Outcome; Patient-Focused Outcomes; Patients; Pattern; Peripheral; Physicians; Polyarthritides; Population; Primary Health Care; Procedures; Process; Proteins; Provider; Research; Research Subjects; Rheumatism; Rheumatoid Arthritis; Rheumatoid Factor; rheumatologist; RNA; Sensitivity and Specificity; Sjogren's Syndrome; Specificity; System; Systemic Lupus Erythematosus; Systemic Scleroderma; Tendon structure; Testing; Time; Tissues; tool; Trauma; Untranslated RNA; Vertebrates; Whole Blood
