Background Cryotherapy is widely used in rheumatic diseases, with a low level of evidence. Tissue mild hypothermia was reported to inhibit pivotal pro-inflammatory enzyme pathways such as COX-2/PG-E21 and NF-kB.2
Objectives We hypothesised that local cryotherapy (LC) might reduce joint inflammation through PG-E2 and NF-kB repression.
Methods 47 patients suffering from non-septic knee arthritis were included (17 gouts, 11 calcium pyrophosphate dehydrate crystal deposition diseases, 6 spondyloarthritides, 13 rheumatoid arthritides), taking no concurrent anti-inflammatory drug/DMARD. They were first randomised to receive local ice (30 min-N=16) or cold pulsed CO2 (2 min – Cryo+ Cryonic-N=16) at 9 A.M and 5 P.M. Synovial fluid was collected just before the first cold application then 24 hours later (9 A.M). Synovial fluid IL-6, IL-1β, TNF-α, IL-17A, VEGF (Multiplex flow cytometry), NF-kB P65 (total/phosphorylated) and PG-E2 (ELISA) were measured and compared before and after 2 LC applications. Contralateral non-treated knees were then used as paired controls (in 16 other ice-treated patients).
Results Synovial IL-6 significantly decreased after 2 LC applications (n=43 paired Wilcoxon:p=0.00015). This decrease was also significant in ice-treated subgroup (n=16 p<0.005) but not in CO2-treated patients (n=14;p=0.1). IL-1β and VEGF levels also decreased after treatment (n=44-p=0.02 and n=47-p=0.03) but not significantly in treatment subgroups. By contrast, IL-6 (n=13), IL-1β (n=15) and VEGF (n=15) didn’t change in contralateral non-treated knees. LC had no significant effect on IL-17A nor TNF-α synovial levels. LC significantly reduced synovial NF-kB (n=38-p=0.04) and NF-kB-P levels (n=38-p=0.004). These levels were also significantly decreased in ice-treated patients (n=26-p=0.03 and 0.003) but not in CO2-treated patients (n=13). We observed no effect on the NF-kB levels in contralateral non-treated knees (n=12). NF-kB variations correlated significantly with IL-6 (Pearson’s r=0.48-N=32 p<0.01) and VEGF (r=0.34-N=36-p=0.038) variations, and with the maximal skin temperature drop induced by LC (r=0.32-N=36-p=0.047). LC significantly reduced synovial PG-E2 (n=38-p=0.04), which was also significantly decreased in ice-treated patients (n=26-p=0.02) but not in CO2-treated patients (n=13). Conversely, we observed a significant increase in PG-E2 levels in contralateral non-treated knees (n=12-p=0.04), with a significant inter-class effect-size (weighted mean difference −1329 [−2232;−426] pg/mL-in 12 bi-arthritic patients).
Conclusions Local ice cryotherapy applied twice during one day showed superior anti-inflammatory effects compared to local CO2, notably by reducing synovial IL-6 levels in arthritic knees. We also showed for the first time that this inhibitory effect on cytokine levels might be PG-E2 and NF-kB dependent, notably through significant inhibitory effects on the PG-E2 and (to a lesser extent) NF-kB pathways.
References  Diestel. Cryobiology2008.
 Yenari. Neurochem Int2006.
Disclosure of Interest None declared
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