Smoking Raises Person’s Risk of AAV, Large US Study Suggests

Being a former or current cigarette smoker significantly increases the risk of developing ANCA-associated vasculitis (AAV), data from a large U.S. study show.

This association was particularly  strong in patients with antibodies against myeloperoxidase (MPO).

The abstract with the findings, titled “Cigarette Smoking Is a Risk Factor for ANCA-Associated Vasculitis,” was presented at the recent 2019 American College of Rheumatology and the Association of Rheumatology Professionals Annual Meeting in Atlanta.

AAV is a group of autoimmune diseases caused by the production of anti-neutrophil cytoplasmic autoantibodies (ANCAs), which mainly target one of two proteins  — proteinase 3 (PR3) and MPO — in neutrophils, a type of immune cell.

Neutrophils are wrongly activated and start destroying blood vessels, leading to swelling in different tissues and organs.

Smoking is known to raise a person’s risk of death, with especially strong links to cancer and heart disease. Several studies have shown that smoking is also associated with an exacerbated immune response, potentially through an overactivation of neutrophils.  Likewise, it is associated with several inflammatory and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.

While previous studies and case reports suggest a potential link between smoking and an increased risk of AAV relapse and the production of ANCAs, these findings are based on a small number of patients.

Researchers at Massachusetts General Hospital — one of the founders of Partners HealthCare, a not-for-profit health care system — set out to evaluate whether smoking is a risk factor of AAV by analyzing data of two large Partners HealthCare databases.

These comprised the Partners AAV (PAAV) Cohort — AAV patients registered at Partners HealthCare — and the Partners Biobank database, which includes data of all patients seen at Partners HealthCare hospitals.

They compared the data of 473 AAV patients with that of 1,419 gender-, race-, and age-matched people without the disease (control group), whose data on smoking status were available. Smoking status was divided into three categories: never smoked, former smoker, or current smoker.

All AAV patients were positive for PR3 or MPO. Those with eosinophilic granulomatosis with polyangiitis (EGPA), one of the three major AAV subtypes, were excluded from the analysis.

Participants’ mean age was 59, 84% of them were white, and 59% were women. Most AAV patients (65%) were positive for MPO-autoantibodies, and 64% of them had kidney problems at the time of the analysis.

Results showed that there was a significantly higher proportion of former and current smokers among AAV patients than in the control group, which translated to a 72% increased risk of developing AAV among former and current smokers.

Particularly, being a former smoker increased the likelihood of developing AAV by 58%, while being a current smoker more than doubled the chances of developing the disease, compared with those who never smoked.

Additional analyses divided by gender, ANCA type, organ involvement, as well as educational level led to similar, significant associations between smoking and AAV, supporting the robustness of this association.

However, the association of smoking with a higher risk for AAV with PR3-autoantibodies did not reach statistical significance, meaning that smoking may be more associated with an increased risk of developing autoantibodies against MPO than against PR3.

“In this large case-control study, being a current or former smoker was strongly associated with an increased risk of AAV, especially [AAV with MPO-autoantibodies],” the researchers wrote, adding that “cigarette smoking may be a modifiable risk factor for AAV.”

While the underlying mechanism for an association between smoking and AAV remains unclear, the team suggest it may be due to smoking-induced cell death and/or oxidative stress in the cells of the blood vessels walls. (Oxidative stress is an imbalance between the production of potentially harmful free radicals and the cells’ anti-oxidant defenses, which can lead to cellular damage.)

Future studies are required to confirm these findings, and better understand the mechanisms behind this association and the potential link between smoking and the specific production of MPO-autoantibodies.