Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Abstract

Smoking is now well recognised not only as a risk factor for rheumatoid arthritis (RA), but also as a determinant of disease activity, severity, response to therapy, and possibly mortality. Recent studies have provided significant insights into the molecular and cellular mechanisms which underpin the pathogenesis of smokingrelated RA. These involve release of the enzymes, peptidylarginine deiminases (PADs) 2 and 4 from smoke-activated, resident and infiltrating pulmonary phagocytes. PADs, in turn, mediate the conversion of various endogenous proteins to putative citrullinated autoantigens. In genetically susceptible individuals, these autoantigens trigger the production of anti-citrullinated peptide/protein pathogenic autoantibodies (ACPA), an event which precedes the development of RA. This review is focused primarily on smoking-mediated harmful chronic inflammatory responses, both local and systemic, which promote the formation of ACPA, as well as the possible involvement of other types of outdoor and indoor pollution in the pathogenesis of RA. This is preceded by a brief overview of the evidence implicating smoking as a risk factor for development of ACPA-positive RA.Keywords: Anti-citrullinated peptide/protein antibodies; airway microbiota; atmospheric pollution; heavy metals; peptidylarginine deiminases; smoking cessation strategies. ImplicationsChronic inflammatory mechanisms operative in the lungs of smokers lead to the production of anti-citrullinated protein antibodies which, in turn, drive the development of rheumatoid arthritis. These mechanistic insights not only reinforce the association between smoking and risk for rheumatoid arthritis, but also the necessity to increase the level of awareness in those at highest risk.

Combined Collagen-Induced Arthritis and Organic Dust-Induced Airway Inflammation to Model Inflammatory Lung Disease in Rheumatoid Arthritis

“…Several inhalant environmental factors are implicated in the development of RA with cigarette smoking being the most well‐established risk factor . Occupational inhalant exposures have been increasingly associated with the risk of disease development, particularly among males .…”

Asthma and the Risk of Rheumatoid Arthritis: An Insight into the Heterogeneity and Phenotypes of Asthma

“…For example, studies have suggested that smokers are at increased risk of developing asthma69 and RA70 independently. Furthermore, recent studies have reported insights into the molecular and cellular mechanisms which establish the pathogenesis of smoking-related RA7172. Possible mechanisms are as follows: smoking commences chronic inflammatory process in the lungs, which induces the release of the enzymes, namely peptidylarginine deiminases 2 and 4 from smoke-activated, resident, and infiltrating pulmonary phagocytes.…”

“…Peptidylarginine deiminases mediate conversion of diverse endogenous proteins to presumed citrullinated autoantigens. In genetically susceptible subjects who have the shared epitope (SE)-containing HLA-DRB1 alleles71, this SE might provoke the generation of anti–cyclic citrullinated peptide (CCP) and pathogenic autoantibodies (anti-CCP antibodies), which play a critical role in initiating inflammatory responses in RA72. Accordingly, genetic studies have reported that the HLA-DRB1 SE alleles are particularly associated with anti-CCP–positive RA73 and also influence the magnitude of the anti-CCP antibody production74.…”

Avaliação da influência de fatores ambientais sobre o diagnóstico de artrite idiopática juvenil em crianças e adolescentes

“…O tabagismo materno e seus efeitos têm sido atribuídos a alterações teciduais e vasculares (vasoconstricção) sofridas pela placenta e à transferência placentária direta de alguns dos 9.600 produtos químicos presentes na fumaça do tabaco, como nicotina, CO, benzeno e alcatrão. 29,59 Outros estudos também demostraram uma associação entre o tabagismo materno durante a gestação e a metilação do DNA. [60][61][62][63] No entanto, estudos anteriores que evidenciaram a associação entre o início da AIJ e a exposição ao tabaco durante a gravidez permanecem controversos.…”

“…29,35,36,39 O tabagismo e outros agentes pró-inflamatórios inaláveis podem ter um papel na estimulação da citrulinação de proteínas nas células pulmonares, mediada pela enzima peptidilarginina desiminase e, provavelmente, podem induzir a formação de autoanticorpos. 29 Em indivíduos geneticamente predispostos, a citrulinação de proteína pode apresentar um risco potencial de produção de anti-ccp, 29 destacou-se como um importante fator de risco para a AIJ. Além disso, a exposição ao ozonio no segundo ano de vida e a exposição ocupacional materna também foram fatores de risco relevantes, podendo-se inferir que a AIJ é mais uma doença a ser incluída entre os problemas de saúde pública gerados pela exposição aos poluentes inalatórios.…”