Colchicine for Symptom and Inflammation in Knee Osteoarthritis

Overview

Uric acid may be involved in the activation of the innate immune response in osteoarthritis (OA) pathology and progression. This suggests that traditional gout therapy may be beneficial for OA. Our goal therefore is to assess colchicine, an existing commercially available agent for gout, for a new therapeutic indication-knee OA. The investigators propose a randomized clinical trial (RCT) of 16 weeks' therapy with standard daily dose oral colchicine or placebo for knee OA. The investigators hypothesize that colchicine will block inflammasome mediated inflammation, thereby improve the signs and symptoms of OA, and reduce synovial fluid, serum and urine inflammatory and biochemical joint degradation biomarkers. This trial will potentially provide data to support a new treatment option for knee OA.

In a knee OA cohort with no clinical evidence or self-report of gout, The investigators recently found a significant correlation of synovial fluid uric acid with radiographic and scintigraphic measures of OA severity \[1\]. The investigators also observed strong correlations of OA severity (radiographically and scintigraphically determined) and synovial fluid uric acid with synovial fluid Interleukin (IL)-18 and IL-1β; these two cytokines are classically produced during gout attacks by innate immune system activation mediated by uric acid crystal-induced inflammasome assembly in macrophages. These results strongly support the involvement of uric acid and the innate immune system in OA pathology and progression. Whereas in gout flares, uric acid in a crystal form is what triggers the innate immune response, we suspect that in OA, uric acid in a microcrystalline or particulate form is the pathogenic agent -- able to trigger an innate immune response; this leads to release of inflammatory cytokines like IL-18, IL-1β and subsequently tumor necrosis factor - α which perpetuates further cartilage degradation. This new conception of the pathogenesis of OA has very important treatment implications; it suggests that existing therapies for gout may be of benefit in OA. Colchicine may be an effective treatment for OA due to its capacity in suppressing the innate immune response at various levels. At micromolar concentrations colchicine suppresses activation of the crystal-induced (NACHT), (LRR) and (PYD) domains containing protein-3 (NALP3) inflammasome; IL-1β processing and release; and L-selectin expression on neutrophils \[2\]. At nanomolar concentrations colchicine has blocks the release of a crystal-derived chemotactic factor from neutrophil lysosomes; it blocks neutrophil adhesion to endothelium by modulating the distribution of adhesion molecules on the endothelial cells; and it inhibits urate crystal-induced production of superoxide anions from neutrophils and macrophages. The pain and symptom relieving effects of colchicine for knee OA have been demonstrated in three small but well-performed human randomized controlled trials \[3-5\]; however, the mechanism of action of colchicine in OA has never been evaluated. The investigators therefore propose a RCT of colchicine to examine the effects on signs and symptoms of knee OA and to evaluate the mechanism of action through analysis of synovial fluid and systemic biomarker profiles. Hypothesis: The investigators hypothesize that colchicine will block inflammasome mediated inflammation, thereby improve the signs and symptoms of OA, and reduce synovial fluid serum and urine inflammatory and biochemical joint degradation biomarkers. Aim 1. To determine whether daily oral colchicine at standard clinical doses (0.5 mg two times daily), compared to placebo, can decrease the pain of symptomatic OA knee and improve function when used as adjunctive daily therapy in addition to background therapy with the patient's current stable analgesic regimen. Aim 2. To evaluate the mechanism of action of colchicine for reducing knee OA signs and symptoms through analyses of synovial fluid, serum, and urine biomarker profiles - these will interrogate and characterize the state of activation of joint metabolism (joint degradation and synthesis markers), inflammatory mediators, the innate immune system and the NALP3 inflammasome components specifically both before (at baseline) and after 16 weeks therapy (at study end) with oral colchicine versus placebo treatment. This pilot phase II study uses a double-blinded, randomized, placebo, controlled design. Patients with symptomatic and radiographic knee OA (n=120) will be randomized to colchicine (SIN 12490P) 0.5 mg bid (n=60) or placebo (n=60) daily for 16 weeks. Patients will be permitted to remain on their baseline adjunctive therapy, including non-steroidal anti-inflammatory drugs (NSAIDs) without changes for the duration of the study. They will also be allowed the use of paracetamol not more than 2 g/day as rescue analgesia and pill counting at the end of the study will be conducted to determine the amount of rescue medicine utilized over the course of the 16-week study.