OUTCOMES RESEARCH IN REVIEW
Intra-Articular Steroids May Hasten Cartilage Loss in Knee Osteoarthritis
McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA 2017;317:1967–75.
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Objective. To determine the effects of intra-articular triamcinolone acetonide at a dose of 40 mg administered at 3-month intervals on knee pain and progression of knee cartilage loss.
Design. Randomized, double-blind, placebo-controlled trial.
Setting and participants. 140 patients with ultrasonic features of synovitis and symptomatic knee osteoarthritis were selected from the patient pool at Tufts Medical Center in Boston, Massachusetts, between June 2011 and January 2015. Patients selected were age 45 years or older and met American College of Rheumatology osteoarthritis diagnostic criteria. Western Ontario and McMaster Universities (WOMAC) pain scores were between 2 and 8 on weight-bearing questions. Tibiofemoral osteoarthritis on posteroanterior weight bearing semi-flexed radiographs was evident in participants at a Kellegren-Lawrence grade 2 or 3. Eligible patients also had ultra-sonographic evidence of synovitis with an effusion larger than 2 mm in the study knee. Participants were excluded if they had undergone any trauma to the study joint such as osteonecrosis or a poorly controlled systemic illness. If the patient had used antibiotics, hyaluronic acid, glucosamine, chondroitin or had undergone recent intra-articular steroids in 3 months or fewer prior to the enrollment period the patient was excluded from the study. Further, patients were excluded if they were unable to undergo an MRI. Prior to pain assessments, patients were to discontinue any analgesics for 48 hours with the exception of acetaminophen if needed. The mean age of patients in this study was 58 years and the mean body mass index was 30. Half of patients had malalignment of the knee joint.
Intervention. 40 mg of a preparation of 40 mg/mL (total volume 1 mL) was injected into the intervention patients’ affected knees while 1 mL of 0.9% sodium chloride (saline solution) was injected into the control patients’ affected knees. Local anesthetic was not used. If present, synovial fluid was aspirated from the knee prior to injection. Injections were administered every 12 weeks for 2 years. Needle placement by ultrasound was utilized to ensure accurate injections, however, the probe was removed prior to injection. The injecting clinician was not involved in measuring outcomes in the study. Both intervention solutions were in identical syringes and were masked so the patient was blinded to which intervention he or she may have received.
Main outcome measure. Cartilage loss, pain, articular structural damage and physical function were the main outcome measures. Cartilage loss and structural damage were determined by MRI using validated quantitative and semi-quantitative assessments. Pain was measured with WOMAC scores and physical function was assessed using the 20-m walk test and the chair stand test. Patients were assessed during 9 scheduled visits at 3-month intervals when subjective data, blood pressure, and hemoglobin A1c levels were obtained. At 6-month intervals, patients underwent objective measures of function measured by a timed 20-m walk and chair stand testing. Evaluation of quantitative measures of cartilage analysis, semi-quantitative assessment of cartilage damage, bone marrow lesion and effusion volume measurement by MRI were done at time zero, 12 months and 24 months. The 36-Item Short-Form Health Survey was administered at these times as well. Results were computed with intention-to-treat analysis for all outcomes.
Main results. 140 patients were randomized out of 445 patients who were assessed for eligibility. Ten patients in the saline arm and 11 in the glucocorticoid arm were lost to follow-up. Groups were similar in age, BMI, varus or valgus malalignment, ultrasound measures, pain, and function measures. The group injected with triamcinolone had a higher rate of cartilage loss than the group injected with saline (–0.21 mm vs. –0.10 mm, P = 0.01) and had a higher rate of cartilage damage (–133.66 vs –72.41, P = 0.048). Cartilage denudation, bone marrow lesions, trabecular morphology and effusion volumes were not significantly different between groups. WOMAC pain measure differences from baseline in the groups were similar (–1.2 for triamcinolone group vs. –1.9 for the saline group, P = 0.17). There were also no differences between groups for the Visual Analog Scale pain score, stiffness, the 20-m walk test, or the chair stand test. Adverse events were similar between groups. At the end of the study protocol, only 45% of patients were able to correctly identify the group to which they were assigned.
Conclusion. In patients meeting American College of Rheumatology diagnostic criteria for osteoarthritis and evidence of inflammation in the affected joint, 40 mg of triamcinolone administered intra-articularly is no more effective in relieving pain or physical functioning after 2 years of injections every 3 months than normal saline. Injecting 40 mg of triamcinolone may hasten cartilage loss and damage as measured by MRI.
In the current study, the rate of cartilage loss in the saline group was on par with prior studies examining the natural history of cartilage loss, suggesting that intra-articular steroid may actually be hastening the loss of cartilage observed in this study. The effect size was deemed moderate by the authors, though clinically significant minimal change has not been determined. Intra-articular cartilage loss is positively correlated with arthroplasty rates . While this study was not designed to investigate the rate of joint replacement after intra-articular corticosteroid measurement, this may be an area for future study. Interestingly, pain and function scores were not significantly different between the 2 groups, despite the changes in cartilage. Of note, prior studies have shown the largest gains in pain relief occur during the first 4 weeks after an injection and pain measurements in this study were performed 3 months after the injections. While helpful for determining the long-term effects of intra-articular glucocorticoid administration, short-term benefits were not measured.
The Osteoarthritis Research Society International guidelines for the nonpharmacologic management of knee osteoarthritis recommend intra-articular steroids for short-term pain management based on meta-analysis of randomized controlled trials . Guidelines set forth by the American College of Rheumatology in 2012 for management of osteoarthritis of the knee also recommend intra-articular steroids . Intra-articular corticosteroid injections were listed as interchangeable, in the absence of comorbid conditions leading to contraindications, with oral acetaminophen, oral and topical NSAIDs, and tramadol.
Hemoglobin A1c and blood pressure were not negatively affected by intra-articular steroids in this study.
Applications for Clinical Practice
While this study overall showed hastening of cartilage loss/damage without long-term pain relief benefit, there are instances where intra-articular steroid injection may still be appropriate. For example, in patients for whom joint replacement therapy has been scheduled and temporary pain relief is needed prior to surgery, intra-articular steroids may provide the pain relief desired without cartilage loss being a clinical concern. Further, if a patient is in need of temporary pain relief to attend an important event and is at a level of marginal functional status due to pain, the benefit may outweigh the risk of hastening cartilage damage/loss to that particular patient. In light of the knowledge gained by this study, any time an intra-articular steroid injection is offered to a patient it should be made clear that the pain relief gained may be temporary and could result in faster deterioration of the cartilage.
Nonpharmacologic therapies for osteoarthritis, including water-based and land-based physical therapy and weight reduction, should be utilized before offering intra-articular corticosteroid injections. These interventions not only have a positive effect on knee osteoarthritis  but also promote general health and well-being.
—Christina Downey, MD, Geisinger Medical Center, Danville, PA
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