PREDICT TO PREVENT

Complex diseases such as cancer and autoimmunity develop over several years. 

Development of cancer is preceded by precancerous condition hallmarked by the presence of abnormal cells that are at high risk of turning cancerous. Precancerous conditions are often identified through screenings such as colonoscopy, mammography, pap tests to examine cervical cells or blood tests to identify hematological abnormalities or abnormal levels of circulating proteins (e.g. CEA, CA-125, CA 15-3, CA 19-9, PSA, AFP). These routine medical exams implemented as standard screenings for general population dramatically changed cancer management with early detection and intervention giving best prognosis. In addition, genetic testing has proven very useful of identifying patients at risk with family history of certain cancers, for example screenings for mutations in BRCA1 and BRCA2 to identify individuals at risk for developing breast and ovarian cancer [1].

Screening tests for pre-autoimmune condition are less advanced, however our increasing knowledge about molecular pathways in autoimmunity brings us closer to developing good screening methods. In some autoimmune diseases, presence of autoantibodies precedes development of clinical symptoms years earlier making autoantibodies good candidates as predictive biomarkers. For example, in one study 3/4th of the systemic lupus erythematosus (SLE) patients showed autoantibodies against nuclear antigens, including anti-Ro, anti-La and anti-dsDNA antibodies ±5 years before the onset of symptoms and before clinical diagnosis [2]. Similarly, autoantibodies against Fc portion of Immunoglobulin G, the so-called rheumatoid factor (RF) and antibodies against citrullinated protein antigens (ACPA) are often formed as early as 10 years in the pre-disease stage of rheumatoid arthritis (RA) [3, 4]. However, important to note, presence of autoantibodies does not automatically lead to development of clinical manifestations of an autoimmune disease, neither predicts its future development. Additional events must take place that turn autoantibodies from being non-pathogenic to pathogenic. Exemplified in a large study of several thousand of healthy children without a first-degree family history of diabetes, 155 screened positive for the autoantibodies. 26 of these 155 and 2 of the autoantibody-negative children developed diabetes demonstrating that most of the autoantibody-positive children remained diabetes-free despite the presence of the autoantibodies [5]. In another study, 10% of healthy individuals showed presence of autoantibodies to one or more of the 10 autoantigens tested while not showing inflammatory autoimmune phenotype [6]. Thus, it seems that autoimmune disease develops in two steps: 1) development of non-pathogenic T- and B-cell and autoantibody responses followed by 2) inflammatory onset that could be triggered by external stress-factors altering non-pathogenic responses towards pathogenic ones. 

How can we easily screen for increased inflammation? An interesting candidate biomarker for systemic inflammation and stress is lymphocyte-to-neutrophil ratio (NLR). NLR is influenced by many conditions including age, medication, chronic disease like coronary heart disease, stroke, diabetes, obesity, psychiatric diagnosis, cancer of solid organs, anemia and stress. A normal range of NLR is between 1-2, the values higher than 3.0 and below 0.7 are pathological. NLR between 2.3-3.0 may serve as early warning of pathological process developing such as cancer, atherosclerosis, infection, non-infectious inflammation [7]. NLR has found its utility in many settings and its reaout is easy and cheap. Is it used enough and has its potential been fully explored?