Preclinical and early osteoarthritis

The World Health Organization defines chronic diseases as ones of long duration and generally slow progression (http://www.who.int/topics/ chronic_diseases/en). Chronic diseases are characterized by complex causality, multiple risk factors, long latency periods, a prolonged course of illness, and functional impairment or disability (http://www.aihw.gov.au/chronicdiseases). Many conditions can be considered chronic diseases, including coronary heart disease, chronic obstructive pulmonary disease, and osteoporosis. These chronic diseases are viewed as amenable to preventive measures; such perception has led to the development of public health strategies to encourage healthy environments and lifestyles. For instance, it has led to efforts to control blood pressure and cholesterol to reduce the burden of heart disease and stroke. OA well fits this chronic disease paradigm. Such recognition that OA fits this chronic disease paradigm would be expected to broaden the scope of study beyond a focus on diagnosis, monitoring, and treatment of end-stage radiographic disease to include efforts to identify and characterize the preclinical and preradiographic stages to spearhead more effective efforts to reduce the burden of disease. Moreover, the process of disease involves the interaction of cartilage with all other structural elements of the joint and mechanical factors; it is reasonable to assume that a similar holistic process is operational in preclinical and early OA. The strongest evidence for the existence of preclinical OA is provided by the sequence of pathologic stages observed after a major joint injury. Unlike primary idiopathic OA, posttraumatic OA has a known time of onset, making it much more tractable as a method of detecting and monitoring preclinical OA. Based on longitudinal studies, intraarticular pathogenic processes, initiated at the time of injury, result in radiographic OA 10 to 20 years later and preradiographic OA based on MRI much sooner. Longitudinal studies of the aftermath of severe joint injury have convincingly established the existence of a prolonged preclinical molecular phase of disease characterized by protein and microRNA biomarker abnormalities. After knee injury, cartilage degradation is favored over repair, with increased collagen cleavage. Within the first month after joint injury in humans, elevations have been documented in synovial fluid concentrations of cartilage proteoglycan fragments, metalloproteinases (MMP-3/stromelysin-1), tenascin-C, and collagen fragments. Aggrecanase cleavage of aggrecan (at 392Glu-393Ala in the interglobular domain) is one of the early key events in arthritis and joint injuries. Elevations of cartilage components in the serum can persist over decades after joint injury. The sustained increased release of cartilage macromolecular fragments after joint trauma is thought to be a harbinger for the development of posttraumatic radiographic OA in patients with injuries. Many of these fragments are not only biomarkers of early disease pathology but themselves also act as disease-associated molecular proteins (DAMPs) as part of an innate immune response to induce and prolong inflammation after joint injury and therefore represent biomarkers within the causal pathway of disease. Consistent with this paradigm, joint inflammation by MRI predicts incident radiographic knee OA, even in the absence of knee pain. In the course of idiopathic (primary) OA, devoid of a clear inciting severe acute injury, it is difficult to track early events. Nevertheless, a few studies have identified premonitory biomarker alterations that herald the later appearance of idiopathic radiographic OA. In the Chingford cohort, with serial samples and knee radiographs available over the course of 23 years, two serum biomarkers, cartilage oligomeric matrix protein (higher) and aggrecan (lower), predicted in advance, by as much as 10 years, incident radiographic knee OA. In another study, serum cartilage oligomeric matrix protein (COMP) and hyaluronan (HA), predicted the occurrence, 7 years later, of incident knee joint space narrowing (COMP and HA) and osteophyte DEFINITION OF PRECLINICAL AND EARLY OSTEOARTHRITIS