Personal cigarette smoking has been shown in multiple studies to be a major risk factor for rheumatoid arthritis (RA). However, the associations between RA and other inhalants have not yet been explored extensively due to the complexity of isolating air particle components, the difficulties of identifying inhalants in patients, and confounding due to the presence of multiple inhalants in patients’ environments.

We interviewed Jeffrey Sparks, MD, MMSc, of Harvard Medical School’s Brigham and Women’s Hospital, about his team’s recent research.1 Their retrospective study explored the associations between RA and passive cigarette smoking, air pollution, inhalant-related occupations, silica, pesticides, household environments, allergic inhalants, and other inhalants.

What are the largest risk factors for rheumatoid arthritis?


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Dr Sparks: The strongest lifestyle risk factor for RA has been established to be cigarette smoking and, interestingly, it has been shown in several different studies that people who have the shared epitope and who smoke are at an even higher risk for developing RA. There seems to be a biologic explanation related to how the immune system could be triggered by smoking in genetically susceptible people. Many nonsmokers get RA, so certainly, smoking is not the only lifestyle risk factor for it.

Is RA less common than other types of arthritis?

Dr Sparks: Osteoarthritis, which is not inflammatory and nonsystemic, is by far more common, but RA, among the inflammatory arthritis causes, is one of the more prevalent.

What was the impetus for conducting this particular study?

Dr Sparks: There’s been more of an interest in how inhalants might trigger lung inflammation that could go on to be associated with events that lead toward RA, so this paper was really trying to catalog all of the other inhalants that have been studied for RA risk, besides cigarette smoking, since that one has been so well established.

Why is it so difficult to identify the specific environmental factors that cause RA?

Dr Sparks: To really set up the ideal study, it would take a huge budget and a long time to follow people prospectively, so for those reasons, almost all the studies are retrospective. That often means that you’re starting with patients who already have RA and trying to work things backwards. But a lot of the studies don’t have the capabilities of looking backwards, so they’re really cross sectional: we’re looking at RA patients, comparing them to others and their data sets and looking to see what kind of occupational exposures vary. However, maybe they didn’t even have the exposure when they were at risk for RA. These could be things that happen well after the disease actually started, so those are limitations. And it’s an uncommon disease in the general population.

Why were autoantibodies as well as pulmonary and mucosal inflammation the most common measures of association between inhalants and RA?

Dr Sparks: I think lung inflammation is the biologic underpinning of what is going on. The smoke is irritating some mucosa in the lungs and airways, which is triggering a breakdown of autoimmunity and auto-antibody production in the immune system. You can measure someone’s inhalants, but it’s really hard. You’d really have to get lung tissue to really understand what’s going on locally. Another proxy would be to just get blood to see whether they have antibodies, and another is to see if they go on to develop RA. However, that’s relatively uncommon and would need lengthy follow-up and a large sample size.

Why is testing lung tissue less common to identify the components of inhalants?

Dr Sparks: Getting a piece of lung is relatively invasive. That’s not to say it’s not done clinically, or even for research, but certainly it has a risk for complications. There’s a lot of hesitancy for people who are healthy to agree to do that.

There is also a lot of intersectionalityfor example, the study mentions that many miners are also smokers, and so forth.

Dr Sparks: It’s hard to disentangle a lot of these factors that are confounding each other or co-linear. A lot of them might look statistically associated, but it’s hard to really understand which was the one driving the association. With smoking being the most established risk for RA, it really needs to be integrated into studies that are trying to understand inhalants because it might all be related to their underlying smoking predisposition.

How difficult is it to identify specific, dangerous inhalants within pollutants such as wood smoke or auto emissions?

Dr Sparks: Trying to understand the specific particulate that is of biological relevance is really difficult because, for example, emissions are a mix of many different things. Certainly, there’s been a lot of research to try to understand what the components of different pollutants are, but it’s always a mixture of different things. Whether it’s cadmium or nitrous oxide, a lot of them have biologic plausibility, but trying to understand which one is related to the association is really tough to do outside of an experimental setting.

It seems like there’s a lot that could still be studied in the way of inhalants and RA.

Dr Sparks: Some things that haven’t been studied are things like cigar smoking, marijuana smoking, and vaping. Those inhalants have nicotine and other substances. The example of smoking and its relationship to RA and other autoimmune diseases has really taught us a lot, but there’s a lot more to be done.

Reference

Prisco LC, Martin LW, Sparks JA. Inhalants other than personal cigarette smoking and risk for developing rheumatoid arthritis. Curr Opin Rheumatol. 2020 May;32(3):279-288. https://doi.org/10.1097/BOR.0000000000000705.