Intra-articular injection of biologic anti-rheumatic drugs enhances local exposure to the joint-draining lymphatics.

Recent reports have highlighted the role of the lymphatic system and its resident immune cells in the development of inflammatory arthritis. Directing therapeutics to the joint-draining lymphatics could improve access to lymphatic-resident pro-inflammatory immune cells, improve local treatment efficacy and enable the administration of lower drug doses to achieve the same or a better effect. Here, we assessed the delivery of disease modifying anti-rheumatic drugs (DMARDs) to the joint-draining lymphatics as a function of therapeutic size and route of administration (intravenous (IV), subcutaneous (SC) and intra-articular (IA) injection). The model drugs included the low molecular weight conventional DMARD methotrexate and the larger biologic DMARDs etanercept and rituximab. Plasma pharmacokinetics, thoracic lymph fluid concentrations and lymph node deposition of the DMARDS were assessed in male Sprague-Dawley rats after IV, IA or SC injection at or near the knee joint. Administration by IA injection resulted in rapid and higher absorption of all drugs into the systemic circulation, compared to SC administration. The large DMARDs etanercept and rituximab were preferentially transported from the IA and SC injection sites via the lymphatics, but a greater percentage of the absorbed dose was recovered in lymph after IA (49-58%) compared to SC administration (17-20%). Methotrexate was almost exclusively transported from the injection site via the blood after IA injection, consistent with its small size which presents minimal barriers to diffusion across the synovium into blood vessels. Importantly, IA but not SC administration resulted in biologic DMARD access to the knee joint-draining iliac lymph fluid and iliac lymph node that is dysfunctional in inflammatory knee arthritis. Overall, IA injection of biologic DMARDs may provide a simple strategy to improve lymph and lymph node access and thus the treatment of inflammatory arthritis.