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I read with great interest Dr Jawad's letter and the authors' reply about the EULAR recommendations for the management of knee osteoarthritis (OA).1 ,2
As a member of the ESCISIT task force I feel free to discuss some of the issues raised by Dr Jawad and to give further arguments for the accuracy of the recommendations developed by the group of European experts.3
Although most points of criticism were answered by M Dougados and M Doherty it seems to me that treatment of knee OA with symptomatic slow acting drugs in osteoarthritis (SYSADOA) and cyclo-oxygenase-2 (COX-2) inhibitors needs to be discussed in a different way in the light of recent publications.
With respect to SYSADOA, the statement that these substances may modify structure has been strengthened by the publication of Reginsteret al, in which glucosamine sulphate (GS) treatment was proved to exert a significant decrease in joint space narrowing compared with placebo during a three year period, indicating the disease modifying effect of GS for the first time.4Moreover, symptomatic efficacy was shown using the WOMAC index as an outcome measure.
Other publications dealing with possible disease modifying properties of hyaluronic acid are well known,5 and trials investigating the same issue for chondroitin sulphate (CS) are currently underway. Two meta-analyses6 ,7 as well as controlled trials have provided evidence for the symptomatic efficacy of GS and CS and proved their overall excellent tolerability, when compared with treatment with non-steroidal antirheumatic drugs (NSAIDs).
With respect to COX-2 inhibitors, to my knowledge no publication exists to show that COX-2 inhibitors, such as Rofecoxib and Celecoxib, are more efficacious than classical NSAIDs. On the other hand, all the studies indicate better gastrointestinal tolerability of both these new compounds, but some severe gastrointestinal toxicity and dyspepsia, comparable with classical NSAIDs, has been noticed.8 ,9When dyspepsia occurs it is not possible to predict erosions or an ulcer and, therefore, endoscopy has to be performed if epigastralgia occurs. This reduces the potential for cost saving with the new compounds and is inconvenient for patients. Thus the advantages of COX-2 inhibitors remain doubtful, taking into account the costs of these compounds, but should be considered carefully in the future.
It is obviously necessary to develop and adapt treatment recommendations according to upcoming knowledge all the time. The EULAR recommendations for the treatment of knee OA, however, at the time they were written seemed to summarise all the therapeutic options, including non-pharmacological and surgical options, accurately, even in the light of publications appearing after the end of the literature search in December 1998.
Acknowledgments
Dr Leeb is currently taking part in a trial focused on the disease modifying ability of CS, sponsored by IBSA.
References
Author's reply
I thank Dr Leeb for his interest in my recent letter about the EULAR recommendations.1-1 The recent large, randomised, placebo controlled, double blind, prospective trial had shown that glucosamine sulphate (GS) treatment resulted in significantly less medial joint space narrowing of the knee, in addition to significant improvements in pain and disability, which were sustained for the three year duration of the study. However, the general correlation between symptoms and structural changes was poor.1-2 The symptoms of patients with severe joint space narrowing receiving GS did improve, but this was not associated with slowing down of radiographic structure impairment. Further studies with longer follow up are needed to assess whether these changes are predictive of further clinical progression of osteoarthritis.
The year 2000 meta-analysis of the six best designed trials of GS for osteoarthritis reported two possible limitations among the analysed studies. Firstly, only one study had adequately assured randomised allocation.1-3 The second limitation was that authors were often affiliated with the manufacturers of the product tested. Among the six studies analysed, the one assigned the highest quality score reported the smallest effect.1-4
A meta-analysis of seven randomised controlled trials of chondroitin sulphate (CS) in osteoarthritis had shown better pain relief with CS than with placebo at six months; however, no dose effect was noted (for example, 2000 and 800 mg/day were similarly effective).1-5 A large long term, double blind, randomised controlled trial is needed to confirm the symptomatic benefit of CS in osteoarthritis .
The main advantage of GS and CS is their safety, and they are certainly more safe than non-selective, non-steroidal anti-inflammatory drugs (NSAIDs), especially in their effect on the gastrointestinal tract.
With regards to COX-1 sparing NSAIDs, I agree with Dr Leeb, that there is no evidence for any important differences in efficacy between them and non-selective NSAIDs.1-6 1-7 Systematic reviews have also found no important differences in efficacy between different NSAIDs, but found differences in side effects related to increased doses of NSAIDs and the nature of the NSAID itself.1-8 The principal benefit of COX-1 sparing NSAIDs is that they produce analgesia and anti-inflammatory effects comparable with those of the non-selective NSAIDs but cause fewer symptomatic gastric and duodenal ulcers and fewer gastrointestinal symptoms.1-6 1-7 The EULAR recommendations need to be revised in the near future.