Nicotine dependence is associated with an increased risk of developing chronic, non-communicable inflammatory disease: a large-scale retrospective cohort study

Abstract

Introduction: Chronic, non-communicable inflammatory diseases (CIDs) affect a large portion of the population, imposing a significant morbidity, encompassing a substantial mortality. Thus, they are a major medical burden with a high unmet need. CIDs develop over the span of several years, and the risk of developing CIDs has been linked to genetic and environmental factors. Thus, modification of environmental factors is a promising approach for the prevention of CIDs. Among modifiable environmental factors that have been linked to the CID risk is nicotine dependence. However, for only few CIDs, compelling evidence suggests that nicotine dependence increases (e.g., rheumatoid arthritis and asthma) or decreases (e.g., pemphigus) the CID risk. For most CIDs, there are inconsistent, scant, or no reports on the risk of CID associated with nicotine dependence.

Methods: To address this gap, we leveraged TriNetX, analyzing data from over 120 million electronic health records (EHRs). Using propensity score matching (PSM) to control for age, sex, ethnicity, and other CID risk factors, we contrasted the risk of developing any or any of the 38 CIDs in 881,192 EHRs from individuals with nicotine dependence to PSM-matched unexposed counterparts.

Results: The analytical pipeline was validated by demonstrating an increased risk of individuals exposed to nicotine dependence for subsequent diagnosis of myocardial infarction, malignant neoplasm of the lung, and chronic obstructive pulmonary disease. Overall, 16.8% of individuals with nicotine dependence developed CIDs, compared to 9.6% of individuals not exposed to nicotine dependence (hazard ratio 2.12, confidence interval 2.10-2.14, p < 0.0001). Investigating single CIDs, nicotine dependence imposed increased risks for 23 of the 38 investigated diseases, i.e., dermatomyositis, granulomatosis with polyangiitis, pyoderma gangrenosum, and immune thrombocytopenic purpura. The sex-stratified analysis revealed few sex-specific differences in CID risk.

Discussion: Our study emphasizes the importance of preventive measures targeting nicotine addiction to reduce the global burden of CIDs.

Keywords: COPD; asthma; chronic inflammatory diseases; dermatomyositis; granulomatosis with polyangiitis (GPA); lupus; nicotine dependence; pyoderma gangrenosum.

Figure 1

Study flowchart.

Figure 2

Nicotine dependence increases the risk of developing chronic obstructive pulmonary disease, lung cancer, and acute myocardial infarction. For validation, the risk for chronic obstructive pulmonary disease (COPD), lung cancer, and acute myocardial infarction was compared between cases and controls. As expected, the risk for all three diseases was increased in persons with documented current or past nicotine dependence as opposed to those without.

Figure 3

Nicotine dependence increases the risk of developing chronic, non-communicable inflammatory diseases (CIDs). We compared the risk of persons with documented current or past nicotine dependence (exposed) of developing any or any one of 38 CIDs to that of persons without documented current or past nicotine dependence in the US Collaborative Network of TriNetX. (A) The Nelson–Aalen plot of the risk of developing any of the 38 selected CIDs in persons with current or past nicotine dependence (red) compared to those without (blue). The shaded line indicates standard error. (B) The Nelson–Aalen plot of the risk of developing any of the 38 selected CIDs, except for asthma and COPD in persons with current or past nicotine dependence (red) compared to those without (blue). The shaded line indicates standard error.

Figure 4

Nicotine dependence increases the risk of developing chronic, non-communicable inflammatory diseases (CIDs). We compared the risk of persons with documented current or past nicotine dependence (exposed) of developing any or any one of 38 CIDs to that of persons without documented current or past nicotine dependence in the US Collaborative Network of TriNetX. Exposed individuals (with a history of current or past nicotine dependence) were matched 1:1 to unexposed individuals (without any documentation of current of past nicotine dependence at the index healthcare visit) using age, sex, ethnicity, and risk factors of chronic, non-communicable inflammatory diseases. Non-significant data (after adjustment for multiple testing) is indicated by light gray. Hazard ratios were calculated by univariate Cox regression p-values determined by the Log-rank test. COPD, chronic obstructive pulmonary disease; GPA, granulomatosis with polyangiitis; EGPA, eosinophilic granulomatosis with polyangiitis; PV, pemphigus vulgaris; PF, pemphigus foliaceus.