Conaghan, Philip

Osteoarthritis (OA) is a major global health problem with no disease-modifying therapies. Interleukin-1 (IL-1) is a critical cytokine associated with the pathophysiology of OA and can be inhibited by IL-1 receptor antagonist (IL-1Ra). Here, we tested the delivery of a gene therapeutic encoding the human IL-1Ra to the knee in a phase 1, open-label clinical trial that enrolled nine patients with radiographic knee OA. The IL-1Ra gene was delivered by a self-complementary (sc)–recombinant adeno-associated virus (rAAV) serotype 2.5 (sc-rAAV2.5IL-1Ra) by intra-articular injection into an index knee at one of three doses: low [1 × 10 11 viral genomes (vg)], mid (1 × 10 12 vg), or high (1 × 10 13 vg). The primary outcome was safety. There were no serious adverse events (AEs) related to sc-rAAV2.5IL-1Ra. Two AEs occurred that were possibly related to the vector. Both were effusions with increased pain and resolved with conservative treatment. sc-rAAV2.5IL-1Ra did not cause changes in vital signs, physical findings, or clinical laboratory measures. Less than 1% of the injected dose of sc-rAAV2.5IL-1Ra vg was detected in circulation after 1 day and was cleared within a week. Titers of neutralizing antibodies to AAV2.5 rose in serum and synovial fluid. In all cases, IL-1Ra concentration increased in the synovial fluid, and IL-1Ra concentrations remained elevated after 1 year. Baseline pain and function scores improved during the study. Therefore, we found that intra-articular gene therapy with sc-rAAV2.5IL-1Ra was safe. The sustained increase in local IL-1Ra in human knee joints supports the further clinical examination of this therapy to provide therapeutic benefit in OA.

AbstractAlthough pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.