Pilot and Feasibility Study of Intra-articular Anti-CD14 for the Treatment of Knee Osteoarthritis

In recent years, pain in osteoarthritis has been tied to inflammation in the joint. For example, Philpott et al. found that, among 258 patients with KOA, moderate to severe synovitis on ultrasound was associated with a 2- to 4-fold increase in the risk of constant and intermittent pain. A prior study in 535 patients from the Multicenter Osteoarthritis Study (MOST) cohort found that the presence of synovitis on contrast-enhanced magnetic resonance imaging (MRI) was associated with a 9-fold increase in the risk of pain. Supporting these cross-sectional associations is the observation that corticosteroid injections, the use of which aims to reduce inflammation, have been a mainstay of treatment for years, though studies estimating these benefits are heterogeneous and suggest only modest effects. In addition to contributing to pain, synovitis is likely to contribute to the deterioration in joint structures including the progression of cartilage loss. For example, a recent study from the Osteoarthritis Initiative demonstrated that sustained synovitis on MRI was associated with more rapid structural progression over 4 years.

Despite evidence that synovitis plays a role in the symptoms and progression of the disease, to date, highly effective therapies to reduce pain in osteoarthritis by reducing synovitis have not been developed. This may be, in part, due to the complex nature of osteoarthritis pain as well as the lack of strong pathophysiologic rationale for prior therapies. For example, a number of trials evaluated the benefit of blocking Interleukin(IL)-1, with heterogeneous results suggesting small benefits.

CD14 is a pattern-recognition co-receptor of the innate immune response that plays a critical role in mediating inflammatory responses to damage-associated molecular patterns (DAMPs) present in osteoarthritic joints. In KOA, receptors like CD14 contribute to DAMP-activation of synovial macrophages which drive chronic low-grade inflammation through the release of pro-inflammatory cytokines, such as IL-1 and TNF- . These cytokines in turn sensitize nociceptors contributing to pain, and promote chondrocyte production of degradative enzymes accelerating joint degeneration. By blocking CD14, it may be possible to reduce macrophage activation and downstream inflammatory cascades within the knee, thus reducing symptoms and potentially affecting structural progression. Indeed, the investigators' published data in the murine destabilization of the medial meniscus (DMM) OA model suggests that deficiency of CD14 leads to reduced synovial cytokine expression after injury, mitigates development of pain-related behavior, and reduces cartilage loss. Thus, targeting CD14 represents a novel, mechanism-based approach to modulate synovial inflammation, potentially offering symptom relief with fewer side effects compared to traditional therapies. Fortunately, a neutralizing mAb against human CD14 (IC14) already exists and has extensive pre-clinical and in-human safety data from prior work in other conditions.

This trial would represent the first human study of this novel injectable therapeutic agent. The goal of this 2-year study is to establish feasibility and initial safety with the goal of informing the design of a Merit-funded multi-site Phase II study to establish biologic efficacy and evaluate safety within the VA network.

The central study team includes experts in clinical epidemiology and clinical trials, rehabilitation medicine, osteoarthritis, and rheumatology at the VA. Joshua Baker is an Associate Professor of Medicine and Epidemiology at the Hospital of the University of Pennsylvania and the CMCVAMC. He is a VA-funded investigator with an interest in obesity, muscle loss, physical functioning, and long-term outcomes in patients with common forms of arthritis. He is the Clinical Core 3 Co-Leader of the CReATE Motion Center, the Co-Director of the local Network of Dedicated Enrollment Sites (NODES) program, and Director of the Clinical Research Center at the CMCVAMC. He has served as the national PI for 2 RDT-funded trials including the MOVE-OK trial and the ongoing ReAKTIV trial. He has also served as a local site investigator (LSI) for several VA-funded clinical trials.