Background/Purpose: ANCA-associated vasculitis (AAV) is a systemic small vessel vasculitis of unclear etiology associated with excess morbidity and mortality compared to the general population. Environmental exposures (e.g. asbestos) have been associated with AAV but the effect of cigarette smoking on disease risk is unclear. Previous studies suggest that smoking is associated with an increased risk of AAV relapse and its effect may vary according to age and disease manifestation. However, these findings were based on studies with relatively small sample size.  We performed a large case-control study to examine the association of cigarette smoking, a potentially modifiable factor, with the risk of AAV.

Methods: The Partners AAV (PAAV) Cohort is a consecutive inception cohort established at Partners HealthCare, a large hospital system in New England. All cases are PR3- or MPO-ANCA+.  Eosinophilic granulomatosis with polyangiitis cases were excluded.  For each AAV case, we randomly selected 3 controls from participants in the Partners HealthCare Biobank who completed a smoking questionnaire (N=30,536) and with no diagnosis of AAV and matched by sex, race, and age (± 2 years) at the index date (i.e., treatment initiation).  Smoking status at the index date was extracted from the electronic medical record and categorized into three groups: never, former, current. We examined the association between cigarette smoking and the odds of AAV using conditional logistic regression.  We performed stratified analyses to verify the robustness of the findings.

Results: We identified 473 AAV cases and 1,419 controls whose data on smoking status were available (mean age: 59 (±16) years; women: 59%, white: 84%). The majority (65%) of cases were MPO-ANCA+ and 64% had any baseline renal involvement. There was a greater proportion of current and former smokers among AAV cases (Current=43 [9%], Former=211 [45%]) than in the control group (Current=63 [4%], Former=533 [38%]). The multivariable adjusted odds ratios for AAV were 1.58 (95% CI:  1.25-2.00) for former cigarette smoking and 2.70 (95% CI 1.76-4.14) for current cigarette smoking as compared with non-smoking (Table 1).  When the proportion of ever-smokers was compared with that of never smokers, we found a similar association (1.72 [95% CI: 1.37-2.15]).  These associations persisted in stratified analyses by sex, ANCA type, and organ involvement though they did not reach statistical significance in the PR3-ANCA+ subgroup.  When we further matched cases and controls by education level, our findings were unchanged.  When we stratified by index date and whether or not a case had established care in Partners ≥ 1 year prior to the index date, our findings were unchanged.

Conclusion: In this large case-control study, being a current or former smoker was strongly associated with an increased risk of AAV, especially MPO-ANCA+ AAV. The precise biological mechanism underlying this association remains to be elucidated but may be related to cell apoptosis and necrosis, and/or oxidative endothelial stress. These findings suggest that cigarette smoking may be a modifiable risk factor for AAV. Additional studies are warranted to confirm these findings.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cigarette-smoking-is-a-risk-factor-for-anca-associated-vasculitis/