While stem cell therapy may constitute a potential therapy for OA patients in the future, there is need for additional new effective and safe treatment options. Currently available systemic treatments for OA symptoms are commonly associated with gastrointestinal, hepatic, renal, and/or cardiac adverse events, especially in the elderly [8
]. This makes IA and local therapies attractive options, especially for patients with limited OA in the knee or hip joints. The counter-argument is that OA is a systemic disease in many patients with involvement of several joints, and therefore there is also a great need for new systemic therapies. Additionally, IA administration may provide a higher concentration of the medication in the joint macro and micro environment, including the cartilage and synovium, and avoid several systemic adverse events [23
]. The disadvantage of rare infection following IA injection (0.002%) [24
] is far outweighed by its advantages. We discuss a few interesting potential new IA therapies with evidence of early efficacy in human OA. A more complete list is provided in Table .
Emerging intra-articular therapies for osteoarthritis
Interluekin-1 beta (IL-1β), thought to play an important role in OA pathology, was targeted with IL-1 receptor antagonist administered IA (at 2 doses, 50 mg and 150 mg) as a single injection in 170 patients [25
] and an antibody against IL-1 administered subcutaneously every 4 weeks for three months in 149 patients [26
] in one placebo-controlled randomized controlled trial (RCT) each. There were no significant differences in the primary outcome, the Western Ontario McMaster Arthritis Index (WOMAC) scores, at 4-6 weeks follow-up between treatment and placebo groups, in either study. Biochemical and histopathogical changes, including decrease in synovial inflammation and hypertrophy, reduction in highly sensitive C-reactive protein and increase in proteoglycan content, were noted in the patients who received the active treatment. A high placebo response and short half-life of the molecule in the joint may be partially responsible for lack of an effect. It remains to be seen whether modifying the available preparations of IL-1β and/or targeting other cytokine targets in addition to IL-1β, can provide an effective treatment option.
There has been significant recent interest in the use of autologous conditioned serum, which is derived by incubating patient's serum with glass beads to induce the release of several anti-inflammatory cytokines such as IL-1 receptor antagonist, IL-4, IL-10, and IL-13, centrifuged and injected intra-articularly into the joints. However, the early results from two RCTs in humans are contradictory. One RCT of six IA injections showed no significant difference in WOMAC scores (primary outcome) compared to IA saline [27
], while the other RCT reported significantly better outcome in IA autologous conditioned serum group, compared to IA hyaluronic acid or IA saline [28
Another interesting approach is the use of IA botulinum toxin, which is hypothesized to have antinociceptive and possibly anti-inflammatory action. In three RCTs of a single IA injection of botulinum toxin in to 43-60 painful joints each (with painful OA or painful arthroplasty with OA as the underlying condition), clinically and statistically significant improvements in primary outcome of pain as well as extremity function (on WOMAC and shoulder indices) were noted in IA botulinum toxin group (with or without lidocaine) compared to control treatment (saline or saline plus lidocaine) [29
]. In another RCT, IA botulinum toxin had efficacy similar to IA corticosteroid [32
]. Botulinum toxin is known to inhibit substance P and calcitonin-gene related protein [33
], the main mediators of neurogenic inflammation, a phenomenon of vasodilatation, protein extravasation, and stimulation of inflammatory cells induced by antidromic stimulation of primary afferent fiber [37
Another therapy on the horizon targets bone morphogenetic protein-7 (BMP-7). In a phase I tolerability and safety study, IA recombinant human BMP-7 showed a higher response rate in treatment compared to the placebo group [38
]. Other innovative therapies including human platelet-rich plasma [39
], fibroblast growth factor-18 (FGF-18) [41
], platelet-derived growth factor (PDGF) [43
], and insulin-like growth factor (IGF) [43
] are being tested in early (animal and early human) studies for their potential to repair cartilage (Table ).