Biomarker explosion

Traces in tears and tissues improve disease diagnosis, prognosis and management

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Rohit Shetty DNB,FRCS,PhD
New chemical and biological markers constantly being identified are proving to be powerful clinical tools for ophthalmologists. Found in tears, ocular tissues and other fluids, these biomarkers are essential to understand the evolving causes of long-known diseases so they can be more accurately diagnosed, and more effectively managed and treated, Rohit Shetty DNB, FRCS, PhD, of Maastricht University, The Netherlands, and GROW Research Laboratories, Bangalore, India, told the 37th Congress of the ESCRS in Paris, France. For example, keratoconus has often been considered a non-inflammatory disease because it does not follow the classic progression of heat, redness, swelling and pain followed by loss of function. Biomarker analysis tells a different story, Dr Shetty said. Tear sample analysis showed elevated expression of matrix metalloproteinase-9 (MMP9) and other inflammatory cytokines in eyes with keratoconus. This suggested treatment with cyclosporin A – which led to reduced MMP9 and cytokine levels, and slowed progression in 20 previously progressing patients (Shetty R et al. IOVS 2015 Feb 3;56(2):738-50). Moreover, following patients over time revealed that progressing patients showed a higher level of MMP9 and cytokines such as IL-4 and IL-8 than non-progressing patients did. “If you see these markers it could mean progression, and help decide on treatment, with cyclosporine to manage ocular surface inflammation,” Dr Shetty said. Conversely, lower levels of lysyl oxidase (LOX) and collagen have been found in the cone of keratoconus patients. Higher levels of LOX correlate with better outcomes in crosslinking, and lower levels of LOX in tears correlates with progression, Dr Shetty noted. Reduced LOX and collagen levels may predispose clinically healthy eyes to ectasia after corneal refractive surgery, making it a good biomarker for screening patients before surgery (Shetty R et al. J Refract Surg. 2019;35(1):6-14). Other markers may help predict post-surgery corneal haze. Recently discovered tear film biomarkers for other ocular diseases include TNFα, IL-6, IL-8, IL-17, MMP9 for dry eye; fibrotic markers for pterygium; inflammatory mediators for blepharitis; IgE for allergies; VEGF, lipocalin 1, lactotransferrin, lacritin, lysosome C and lipophilin A for diabetic retinopathy; and IL-1β, IL-6, IL-12, TNFα, S100As and MMPs for glaucoma. Tear biomarkers also exist for metabolic diseases, autoimmune and neurological disorders, including multiple sclerosis and Alzheimer’s, and for various cancers. Tear film biomarkers are also associated with gut microbiome as well, Dr Shetty added. Tools for using biomarkers are entering the clinical realm, and will include chips that can detect multiple markers, said Dr Shetty, who is developing such a device. Noting that biomarkers may be present in any tissue or fluid that is discarded during surgery, Dr Shetty recommended saving these samples from surgery for future analysis, as it has helped him in his research. “Anything that you throw in the bin may hold biomarkers,” he said.