I congratulate Vannabouathong et al. for the well-performed and relevant systematic review. In Germany, the Association of Scientific Medical Societies (AWMF) just published a guideline on the medical treatment of knee osteoarthritis (see: https://www.awmf.org/uploads/tx_szleitlinien/033-004l_S2k_Gonarthrose_2018-01_1.pdf), which comes to very similar conclusions as those presented in this systematic review.
The new German guideline suggests a four-stage algorithm starting with topical NSAIDs and escalating to oral NSAIDs (according to individual risks), then followed either by glucosamine, hyaluronic acid (HA), or corticosteroids, and ends finally with opioids. It was very useful that Vannabouathong et al. used the AAOS description for clinical significance, and it was elegant of them to include the effect of intra-articular placebo in their analysis of intra-articular treatments. This review compares treatment-group differences (not within-patient improvements) and considers that the placebo effect in osteoarthritis trials is typically large, particularly in the case of intra-articular injections. Consequently, the measured effect size would underestimate the clinical benefits for patients1, 2. It is valuable that this systematic review calculated the intra-articular placebo versus the oral placebo effect and added the resulting difference of 0.29 standard deviation (SD) units to the respective effect sizes of the intra-articular treatments.
This review concludes that the intra-articular injection of HA has the most concise effect estimate and exceeds the defined threshold of clinical importance of 0.5 SD units. Thus the clinical usefulness of HA is boosted from “possibly clinically important” to “clinically important” according to the AAOS definitions. This review also investigates HA formulations in terms of different molecular weights. It illustrates clearly the effect sizes of high-molecular-weight HA formulations between 1,500 kDa and 6,000 kDa, as well as those above 6,000 kDa.
One point requiring further discussion is that many patients have contraindications to NSAIDs due to comorbidities or comedications. Our new German guideline points out that NSAIDs are contraindicated for elderly patients (>60 years old) and those with existing ulcers, GI bleeding, or infections with H. pylori. Additional contraindicated factors are comedications such as corticosteroids, anticoagulants, or aspirin. In addition, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) reasons that oral NSAIDs have a moderate effect on pain relief, but they are associated with a 3- to 5-fold increase in the risk of upper GI complications, including peptic ulcer perforation, obstruction, and bleeding3.
Another analysis from the Coxib and Traditional NSAID Trialists (CNT) Collaboration shows that 2 to 4 out of 1,000 patients face GI complications after the daily intake of 150 mg of diclofenac. The same applies for 6 to 16 out of 1,000 patients taking 1,000 mg of ibuprofen per day4. An announcement of the Medicines Commission of the German Medical Profession also mentions high relative risks for GI complications associated with NSAIDs. The German guideline recommends intra-articular HA injections especially for individuals at risk for adverse NSAID side effects and for those for whom NSAIDs are not sufficiently effective.
The German guideline also discusses potentially beneficial effects of combining corticosteroids with HA. This should be a topic for a future systematic review.
Prof Joerg Jerosch is a professor of orthopaedic surgery at Johanna-Etienne Hospital in Neuss, Germany.
1. Bannuru RR et al., Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis e meta-analysis, Osteoarthritis Cartilage. 2011 Jun;19(6):611-9. doi: 10.1016/j.joca.2010.09.014.
2. Bannuru RR et al., Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis, Ann Intern Med. 2015 Jan 6;162(1):46-54. doi: 10.7326/M14-1231
3. Bruyere O et al. A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis-From evidence-based medicine to the real-life setting. Semin Arthritis Rheum, 2016. 45(4 Suppl): p. S3-11
4. Bhala N et al., Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382(9894): 769-779