Background/Purpose: Compared with non-obese patients, obese patients with rheumatoid arthritis (RA) reportedly experience worsening of symptoms [Arthritis Care Res (Hoboken). 2013; 65: 78-87] and do not respond as well to TNF inhibitors [Arthritis Rheum. 2011; 63: 359-64, Arthritis Care Res (Hoboken). 2013; 65: 94-100]. However, the efficacy of IL-6 inhibition in the treatment of RA under conditions of obesity has not yet been fully examined. In this study, we investigated the response to IL-6 inhibition in an obese mouse model of collagen-induced arthritis (CIA).

Methods:

1) To prepare a model of obesity, mice were fed a high-fat diet for 5 weeks. The level of mRNA expression of macrophage marker F4/80 in hind limbs of non-collagen-immunized obese and non-obese mice was measured by real-time PCR. CIA was then induced according to a previously described method [Arthritis Rheum. 1998; 41: 2117-21]. We treated CIA mice with anti-IL-6 receptor antibody (anti-IL-6R) and TNF inhibitor TNFR-Fc. Clinical symptoms of arthritis were evaluated by observation and expressed as an arthritis score on a scale of 0–4 for each limb. The level of cyclooxygenase (COX)-2 mRNA expression as a parameter of inflammation was measured by real-time PCR in hind limbs of mice at the peak of arthritis. 2) The mouse macrophage cell line RAW264.7 and synovial cells from non-obese CIA mice were cultured with IL-6 or TNF-α for 24 h. After culture, to evaluate the inflammatory response, expression level of COX-2 mRNA was determined by real-time PCR.

Results:

1) We confirmed that obesity was induced by the 5-week high-fat diet (relative body weight: 125%). At this time the expression of F4/80 mRNA was higher in obese mice than in non-obese mice. Moreover, arthritis scores were relatively higher (but not significantly) in obese mice than in non-obese mice at the peak of arthritis (Day 33). Anti-IL-6R significantly inhibited the arthritis scores on Day 33 in both obese (87% inhibition) and non-obese mice (62% inhibition). On the other hand, TNFR-Fc significantly inhibited the arthritis scores on Day 33 in non-obese mice (64% inhibition) but not obese mice (54% inhibition). The expression level of COX-2 mRNA correlated well with arthritis score and was higher in obese mice than in non-obese mice on day 33. 2) Expression of COX-2 mRNA was dramatically increased by IL-6 in RAW cells and by TNF-α in synovial cells.

Conclusion: We demonstrated that there is the potential for inflammation to be increased by obesity and that the anti-arthritis effect of TNFR-Fc was reduced in obese mice, as has been shown in clinical reports. We also demonstrated that anti-IL-6R was effective in this mouse model regardless of whether the mice were obese. One reason might be that obesity promotes macrophage infiltration, and IL-6 is prominently involved in the inflammatory response of macrophages in mice. It goes without saying that it is essential for every patient to reduce excess weight not only because of its risk of exacerbating inflammation but also because of its association with risk of developing other diseases such as cardiovascular disease and diabetes. However, anti-IL-6R has the potential to be useful in the treatment of all RA patients, even those who are obese.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-il-6-receptor-antibody-is-effective-in-arthritis-regardless-of-obesity-in-mouse-model/