Background/Purpose: Cryotherapy is widely and empirically used in an adjuvant and symptomatic setting in inflammatory rheumatic diseases, with a low level of evidence [1]. The aim of this work was to evaluate local and systemic anti-inflammatory effects of local cryotherapy (LC) in adjuvant-induced arthritis (AIA), comparing 2 techniques (ice and cold gas spray). We considered clinical (arthritis score and ankle diameter) and biological effects on IL-6, IL-17A, IL-1β, TNF-α local and systemic levels.

Methods: Arthritis was induced by a single Mycobacterium butyricum injection in male Lewis rat tails (day 0). At the onset of arthritis (day 11), rats were treated either by 30 minute-ice applications on hind paws (in cages lined with ice pops – n=10) or by 2 minute-cold gas pulverizations on both hind paws (n=9) twice a day for 14 consecutive days. Ten non-treated AIA rats were used as controls. At day 24 (the day after the last cold application), hind paws were grinded in order to measure cytokine gene expression levels by Q-RT-PCR. Plasmatic levels of the same cytokines were also measured in plasma by cytometry (Multiplex Magpix® ebioscience). IL-6 plasma levels were measured by ELISA (rat IL6 platinum ELISA, BMS625®, ebioscience).

Results: Ice application significantly reduced the mean arthritis score and ankle diameter from day 6 to day 14 (p<0.001) and globally throughout the 14 day treatment period (2-way ANOVA: p<0.001) compared to non-treated AIA controls. Cold gas first aggravated arthritis at days 11-12 (p<0.01) then improved clinical inflammation at days 21-24 (p<0.001). Skin temperature after LC didn’t differ between treatment groups. Both techniques significantly reduced IL-6, IL-1β, IL-17A gene expression levels in hind paws at day 24 compared to non-treated AIA (by 60%, 87% and 50% respectively, p<0.001,p<0.001 and p<0.05). Cytokine gene expression levels correlated positively with hind paw arthritis score and ankle diameter. Conversely, LC had no effect on TNF-α gene expression in hind paws. LC also significantly reduced IL-17A plasmatic protein levels at day 24 (Ice : 47+/-3pg/ml versus 132+/-15pg/ml;n=9;p<00001 – cold gas : 89+/-12pg/ml versus 132+/-15pg/ml;p<0.02) and IL-17A plasmatic levels correlated positively with arthritis score, ankle diameter and negatively with weight gain. Ice also reduced IL-6 plasmatic levels (118+/-20pg/ml versus 197+/-60pg/ml;p<0.05) and IL-6 plasmatic levels correlated positively with ankle diameter. By contrast, LC had no effect on TNF-α nor IL-1β plasmatic levels.

Conclusion: These results demonstrate in vivo previously unknown therapeutic and anti-inflammatory effects of 14 day-LC in AIA. We observed both local (at the gene level in treated hind paws) and systemic (at the protein level in plasma) down-regulation of key cytokine pathways critically involved in the pathogenesis and severity of inflammatory rheumatic diseases. LC local and systemic anti-inflammatory effects were mainly IL-6 / IL-17A-driven and TNF-α-independent in this model. [1] Guillot X, et al. Cryotherapy in inflammatory rheumatic diseases: a systematic review. Expert Rev Clin Immunol. 2014;10(2):281-94.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/local-cryotherapy-down-regulates-local-and-systemic-il-6il-17-pathway-with-no-effect-on-tnf-%ce%b1-in-adjuvant-induced-arthritis/