Association Between Environmental Air Pollution and Rheumatoid Arthritis Flares

Giovanni Adami; Ombretta Viapiana; Maurizio Rossini; Giovanni Orsolini; Eugenia Bertoldo; Alessandro Giollo; Davide Gatti; Angelo Fassio


Rheumatology. 2021;60(10):4591-4597. 

In This Article

Abstract and Introduction


Objectives: Environmental air pollution has been linked to the pathogenesis of RA. Nevertheless, evidence linking higher concentrations of air pollutants with the risk of RA reactivations is missing. The objective of the present study was to determine the association between RA flares and air pollution.

Methods: We collected longitudinal data of patients affected by RA and of the daily concentration of air pollutants in the Verona area. We designed a case-crossover study. We compared the exposure to pollutants in the 30-day and 60-day periods preceding an arthritic flare referent to the 30-day and 60-day preceding a low-disease activity visit.

Results: The study included 888 patients with RA with 3396 follow-up visits; 13 636 daily air pollution records were retrieved. We found an exposure–response relationship between the concentration of air pollutants and the risk of having abnormal CRP levels. Patients exposed to greater concentrations of air pollutants were at higher risk of having CRP levels ≥5 mg/l. Concentrations of CO, NO, NO2, NOx, PM10, PM2.5 and O3 were higher in the 60-day period preceding a flare.

Conclusions: We found a striking association between air pollution and RA disease severity and reactivations in a cohort of patients followed over a 5-year period. The exposure to high levels of air pollutants was associated with increased CRP levels and a higher risk of experiencing a flare of arthritis. This excessive risk was evident at very low levels of exposure.


The pathogenesis of RA is multifactorial and involves both genetic and environmental factors.[1] Primary and secondary preventive strategies should address modifiable factors involved in the pathogenesis and should reduce either the beginning or the progression of the disease.[2,3] Cigarette smoking is among the most studied modifiable factors associated to RA risk.[4,5] Many interventions aiming at smoking cessation have achieved remarkable results in reducing RA incidence and progression.[6] The underlying mechanisms linking cigarette smoking to RA has been carefully studied in the past decades.[7,8] There are >4000 chemical substances contained in cigarette smoke, most of which are toxic or carcinogenic, that can induce post-translational protein modification with the development of autoantigens and, eventually, autoantibody production.[9] In addition, cigarette smoking was linked to increased susceptibility to erosive and aggressive subset of RA, even in the absence of specific autoantibodies.[6,10] Indeed, smokers with RA were 2.4 times more likely to show radiographic progression as compared with non-smokers, independently from overall disease activity scores or seropositivity.[6] In addition, tobacco cessation can ameliorate RA activity independently from autoantibody titre.[11] Smoking has been associated with poor response to methotrexate and anti-TNF treatment in RA patients.[12–15] However, the role of cigarette smoking in determining RA flares is still unclear.

The pollutants produced by fossil combustion share several toxic constituents with cigarette smoking. Anthropogenic pollutants contain a mixture of carbon monoxide (CO), nitric oxide (NO), nitric dioxide (NO2), oxides of nitrogen (NOx), particulate matter with a diameter of 10 μm or 2.5 μm (PM10, PM2.5) or less and ozone (O3). The inhalation of these substances can induce the formation of a particular type of lymphoid tissue, known as inducible bronchus-associated lymphoid tissue (iBALT).[16] The iBALT was linked to citrullination of the proteins triggering the development of RA.[17] Indeed, several studies suggested that even traffic pollution, given the similarity to cigarette smoke, may increase the risk of RA and/or the risk of RA reactivation.[18,19] Interestingly, van der Zee and colleagues found that increments of 10 μg/m3 in NO2 concentration corresponded to, on average, 4.0 passively smoked cigarettes per day in relation to the risk of cardiovascular events.[20] Long-term longitudinal cohort studies showed a direct association between exposure to air pollution and the probability of developing RA.[21,22] Unfortunately, the evidence linking air pollutant concentration with disease reactivation is scarce even if the biological rationale is strong.

The prevalence of RA in the general population of the Veneto region is around 1%. This proportion is even higher in individuals aged 65 years or more and in individuals living in the province of Verona.[23] The Po valley is one of most industrialized and polluted area of Europe.[24] The 'Agenzia Regionale per la Prevenzione e Protezione Ambientale del Veneto' (ARPAV) systematically collects data on the concentration of air pollutants in the Veneto region, providing daily and detailed information concerning the quality of air.[24] Unravelling the possible associations between air pollutants and inflammatory arthritis severity and the chances of progression or relapse might help predict treatment response and healthcare utilization of such patients. The primary objective of the present study was to determine the association between the concentration of air pollutants and RA disease relapses.