Background/Purpose: Smoking is an important epidemiological factor for development of rheumatoid arthritis (RA). However, the mechanism of proarthritic role of smoking is not well understood. The purpose of this study is to precisely explore the arthritic role of smoking in two experimental arthritis models including collagen induced arthritis (CIA) and IL-1 receptor antagonist (Ra) knockout (KO) mice. Cigarette smoking was challenged by two routes of inhalation and drinking.

Methods: To deliver elaborate dosage of smoking, we utilized good laboratory product (GLP)-grade closed inhalation chamber system which is equipped in Korea Institute of Toxicology. Smoke was generated by routine analytic cigarette-smoking machine (ISO standard 3308). Tobacco produce-3R4F cigarette (9.4mg tar/0.7mg nicotine) was chosen by ISO standard 3402 for atmosphere conditioning and testing. This study was strictly followed by OECD guidelines for the testing of chemicals section 4 health effects test No.412 Subacute inhalation toxicity. CIA was induced in a total of 60 mice (negative control (n=10), CIA control (n=10), smoke control (n=10), and cigarette smoke (n=30)). After 1^st collagen immunization, three different doses (T1~T3) of smoke were delivered to collagen induced mice (T1 dose 150 ug/L (n=10), T2 dose 300 ug/L (n=10), T3 dose 600 ug/L (n=10)). It is known that concentration of smoke exposure possibly ranges from 50 to 800 ug/L in real world. Cigarette smoke delivery was done 1 hour once a day, 5 days/week, for 4 weeks in close ventilation system. As a second smoking study, cigarette smoke extract (CSE) was delivered per oral to IL-1RaKO mice arthritis model.

Results: Cigarette smoking facilitated the onset arthritis. Twenty percent of mice in cigarette smoke group developed arthritis less than a week after 1^st immunization, while control CIA mice showed 20% incidence of arthritis on four weeks after immunization. Time points of 60% arthritis incidence was on 3 weeks after 1^st immunization, 4 weeks, and 6 weeks in high dose (T3), low dose (T1) and control CIA group, respectively (p<0.05). Higher dose of smoke challenge induced more lymphocyte infiltration in subpleural area of lung. Citrullination was dose dependently increased in smoking inhaled groups. Splenic Th17 popluation increased dose dependently in smoking groups. In contrary to smoking experiment, CSE drinking did not affect the arthritis development in experimental arthritis model. However, interestingly CSE aggravated arthritis score in female group as a subgroup analysis.

Conclusion: In this study, we revealed cigarette smoking facilitated the onset of arthritis and aggravated arthritis score in a dose-dependent manner. Smoking may play a role in advancing the onset of arthritis in those who are at risk of cigarette smoke exposure and contribute to developing RA. Female also can be more vulnerable to cigarette challenge. More precise, large scale epidemiological study may help to verify these observations.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cigarette-smoking-dose-dependently-facilitates-the-onset-of-arthritis-and-aggravates-arthritis-in-female-experimental-arthritis-mice/