MATTERS ARISING EVects of methotrexate on cartilage metabolism

We read with interest the report by Neidal et al on the eVects of methotrexate (MTX) on articular cartilage in vitro and in vivo. The relevance of these findings to patients with rheumatoid arthritis (RA) and other diseases who are receiving MTX is of considerable interest. In a previous study we reported that treatment of RA patients with MTX resulted in reduced numbers of leucocytes and reduced concentrations of interleukin 1â (IL1â) in the synovial fluid (SF) relative to placebo control patients. Sequential specimens of SF were available in four control patients and in eight patients treated with MTX who participated in that study. The SF keratan sulphate concentrations at baseline and at days 7, 28, and 56 were determined as previously described and are shown in figure 1. A progressive and statistically significant reduction in SF keratan sulphate was observed in the MTX group (mean (SEM) 206 (76) μg/ml at baseline versus 108 (15) μg/ml at eight weeks (p<0.02, Wilcoxon matched pairs signed rank test), but not in the controls. Reductions in concentration of keratan sulphate in the SF were observed in all of the eight patients treated with MTX. Among the controls, two patients showed an increase and two showed a decrease in the concentrations of keratan sulphate in SF. Comparison of the keratan sulphate concentrations in the MTX and control groups showed no statistically significant diVerence at any time point other than at eight weeks when the SF keratan sulphate concentrations in the MTX group were significantly lower than those in the control group. These data are consistent with reduced cartilage proteoglycan degradation in MTX recipients. Like Neidel et al we were concerned that MTX may have aVected proteoglycan metabolism directly. Accordingly we examined the eVect of MTX on proteoglycan release in pig cartilage explants. The concentrations of MTX tested in these experiments were commensurate with and in excess of those achieved in vivo. MTX had no eVect on either basal proteoglycan release or that stimulated by maximal concentrations of IL1. As MTX was found to have no eVect on proteoglycan release in vitro, it is unlikely that MTX directly inhibits the enzymes responsible for proteoglycan catabolism. EVects of MTX on proteoglycan clearance from the joint cavity have not been studied, but it is unlikely that MTX increases clearance as it has “anti-inflammatory” rather than “proinflammatory” eVects. Overall the findings suggest that with suppression of rheumatoid synovitis, cartilage proteoglycan degradation is attenuated at least temporarily. Reduced production of pro-inflammatory/pro-catabolic cytokines such as IL1 and perhaps tumour necrosis factor á, LIF and OSM may explain the observed eVects of MTX on proteoglycan release. In summary our findings are in accord with and support those of Neidal et al. They are consistent with the view that MTX does not have a toxic eVect on proteoglycan metabolism in human articular cartilage in vivo. Furthermore in RA our collective findings suggest that the favourable eVect of MTX on overall disease control is accompanied by reduced loss of proteoglycan from the articular cartilage during the first two months of treatment.