Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches

Abstract

Inflammation plays a central role in the pathogenesis of knee PTOA after knee trauma. While a comprehensive therapy capable of preventing or delaying post-traumatic osteoarthritis (PTOA) progression after knee joint injury does not yet clinically exist, current literature suggests that certain aspects of early post-traumatic pathology of the knee joint may be prevented or delayed by anti-inflammatory therapeutic interventions. We discuss multifaceted therapeutic approaches that may be capable of effectively reducing the continuous cycle of inflammation and concomitant processes that lead to cartilage degradation as well as those that can simultaneously promote intrinsic repair processes. Within this context, we focus on early disease prevention, the optimal timeframe of treatment and possible long-lasting sustained delivery local modes of treatments that could prevent knee joint-associated PTOA symptoms. Specifically, we identify anti-inflammatory candidates that are not only anti-inflammatory but also anti-degenerative, anti-apoptotic and pro-regenerative.

Long-Term Incidence of Total Knee Arthroplasty after Open Reduction and Internal Fixation of Proximal Tibial and Distal Femoral Fractures: A Nationwide Cohort Study

“…The possible reasons for this finding are multifactorial, including working status, early return to work because of economic factors, or poor compliance with physical therapy. Such patients may require more aggressive postoperative management approaches and follow-up protocols, including early detection of the progression of posttraumatic arthritis with serum biomarker levels [ 22 ], radiographic studies [ 23 ], prompt intervention with anti-inflammatory and regeneration therapy [ 24 ], aggressive rehabilitation programs for muscle strength around the knee joint, and adequate protective braces suitable for early return to work after ORIF.…”

Post-traumatic knee osteoarthritis; the role of inflammation and hemarthrosis on disease progression

“…The most studied anti-inflammatory therapies in OA are inhibitors of IL-1, IL-6, and TNF-α. To date only a limited number of clinical trials have tested anti-inflammatory agents in human patients to impede PTOA of the knee ( 157 ). The only published trials are a proof-of-concept RCT using anakinra in 11 patients with an ACL rupture and a RCT using corticosteroid or placebo injection in 49 patients with an ACL injury.…”

“…Both RCT's reported on short-term patient reported outcomes and biomarkers with anakinra showing improvement in patient reported outcomes and corticosteroid injections showing improvements in some chondrodegenartive biomarkers ( 158 , 159 ). Multiple promising targets to counteract post-traumatic inflammation exist, leaving room for future clinical trials ( 157 ).…”

In Vitro Anti-Inflammatory and Regenerative Effects of Autologous Conditioned Serum from Dogs with Osteoarthritis

“…Competitive binding at the IL-1 receptor by IL-1RA is considered the primary action inhibiting the joint’s inflammatory process [ 7 , 9 ]. Studies have shown that IL-1RA prevents IL-1 ligand activation resulting in reduced synthesis of mediators such as metalloproteinases (MMPs), cyclooxygenase-2 (COX2), prostaglandins, and nitrous oxide that propagate OA [ 1 , 9 , 10 , 11 ]. Furthermore, the high concentration of IL-1RA in joints is crucial to maintain joint homeostasis whereas low levels are observed in synovial tissues from the OA patient [ 12 ].…”

“…Using autologous bioactive agents enriched in anti-inflammatory mediators and growth factors for tissue regeneration has become a novel insight for OA management [ 11 , 23 ]. Apart from the IL-1 receptor modulation, several recent studies suggest that T cell-mediated response plays a significant role in the aggravation of OA, including an increase in activated T cells in synovial fluid and synovial membrane [ 24 , 25 ].…”