Intra-articular Corticosteroids and Knee Osteoarthritis: Interpreting Different Meta-analyses.

Osteoarthritis, the most common form of arthritis, affects approximately 27 million individuals in the United States.1 With the aging of the population and rising rates of obesity, the prevalence of osteoarthritis is increasing.2 Roughly 25% of adults aged 55 years or older have knee pain on most days, and most of these people have osteoarthritis.3 According to studies of the global burden of diseases,4 the effect of osteoarthritis on adverse health outcomes is increasing rapidly, especially in developed countries where people have extended life spans. Osteoarthritis develops after a joint is damaged repeatedly by a combination of mechanical stresses and a suboptimal repair response to the damage. Aging diminishes repair capacity and low-grade inflammation, a common feature of the osteoarthritic joint, probably also impairs healing. Many factors contribute to the inflammatory process in osteoarthritis such as inflammatory cytokines synthesized and released into the joint environment by multiple tissues, including cartilage and synovium. Synovial inflammation, which exists to varying degrees among persons with osteoarthritis, is a major source of cytokines and other inflammatory mediators. In imaging studies, synovial thickening is indicative of synovial inflammation. The amount of synovial thickening correlates with knee pain severity in persons with osteoarthritis,5 and synovial thickening is associated with subsequent radiographic osteoarthritis and cartilage loss.6,7 Given the association of inflammation with pain and structural damage in osteoarthritis, treatments targeting inflammatory processes have potential promise. Corticosteroids are thought to counteract inflammatory processes within the osteoarthritic joint. In support of this concept, a recent study8 documented that patients receiving an intra-articular corticosteroid injection experienced a reduction in synovial volume and the amount of reduction was correlated directly with the reduction in knee pain. Intra-articular corticosteroids are a mainstay of treatment for osteoarthritis. In an animal model of osteoarthritis,9 corticosteroids reduced synovial inflammation, angiogenesis, and pain. Clinical trials and meta-analyses of studies in humans have reported that intra-articular corticosteroids are more effective than placebo in relieving pain from knee osteoarthritis, although this treatment effect lasts only 1 to 4 weeks following an injection, after which the treatment and placebo groups experience asimilarcourse.In2meta-analyses,ArrollandGoodyear-Smith10 and Bellamy et al11 suggested that in the first 1 to 2 weeks after a corticosteroid injection, the treatment effect was large with a number needed to treat range of 1.5 to 4 persons to achieve 1 clinical response, such as a 30% reduction in pain or patientreported improvement. In 2 recent studies, 68% to 79% of patients receiving intra-articular corticosteroids experienced a clinically important reduction in knee pain.8,12 That background precedes a report in this issue of JAMA by da Costa and colleagues13 on use of intra-articular steroids for the treatment of knee osteoarthritis. This article provides a summary of an updated Cochrane meta-analysis14 by these same authors led by Jüni and 4 of their colleagues. Similar to previous studies of this issue, Jüni et al14 reported that corticosteroids are associated with greater benefit in reducing knee pain than placebo, but emphasized the short-term and sometimes inconsistent associations across trials. While acknowledging that intra-articular steroids are associated with benefit, the authors also raised questions about the role of steroids in the treatment of patients with knee osteoarthritis. Treatment guidelines typically recommend intra-articular steroid use for patients with knee osteoarthritis.15 In clinical practice, intra-articular corticosteroids are widely considered as the most acutely effective nonsurgical treatment for osteoarthritis and typically provide substantial pain relief. However, the effect is short-term, a finding corroborated in all meta-analyses, including the report by Jüni et al.14 Also, low doses of corticosteroids (defined as <50 mg of methylprednisolone) are not as effective and do not have comparable durability as higher doses of steroids.16-20 However, most of the studies in the metaanalysis by Jüni et al14 examined low doses of steroids, including some trials that used doses of 20 mg or less. The Cochrane report14 summarized by da Costa et al13 found modestly higher efficacy in trials using higher doses of steroids, but these studies included combined interventions (joint lavage, exercise, or both), rather than steroids vs placebo injection alone. An earlier meta-analysis by Arroll and Goodyear-Smith10 reported a substantially greater benefit associated with high-dose steroid administration (≥50 mg of prednisolone equivalent), with benefit extending for up to 24 weeks after injection compared with placebo. O’Neill et al8 recently reported that 20% of 120 patients who received an intraarticular injection of 80 mg of methylprednisolone did not have a recurrence of knee pain at 6 months and that these selected patients also had persistent synovial shrinkage visible with magnetic resonance imaging, suggesting a persistent structural response to this higher steroid dose. Some patients with knee osteoarthritis do not respond to intra-articular steroids, perhaps because they do not have a substantial inflammatory component to their osteoarthritis Related article page 2671 Opinion