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LONDON — Although tobacco use is a well-established driver of systemic inflammation in rheumatoid arthritis, Crohn’s disease, and systemic lupus erythematosus, it has conversely shown protective signals in diseases such as ulcerative colitis, Behçet disease, and Parkinson’s disease. This duality exists because tobacco smoke can trigger both pro-inflammatory and anti-inflammatory pathways, explained Edoardo Simoncelli, MD, a rheumatologist for the local health authority in Novara, Italy, speaking at the European Alliance of Associations for Rheumatology (EULAR) 2026 Annual Meeting. 

The relationship between tobacco and Sjögren disease (SjD) has remained poorly understood, and until now, no in vitro studies had evaluated the direct biological effects of cigarette smoke extract (CSE) on salivary gland epithelial cells (SGECs).

But new research presented by Simoncelli at the meeting shows that smoking is associated with a lower likelihood of a Sjögren disease diagnosis and milder salivary gland tissue inflammation. These clinical observations are supported by laboratory evidence that CSE directly reduces pro-inflammatory cytokine production in SGECs.

SjD most commonly causes mucosal, skin, and ocular dryness; joint and muscle pain; severe fatigue; and less commonly affects internal organs such as the lungs, gastrointestinal tract, kidneys, and nervous system.

Milder Histopathology Seen in Active Smokers

The researchers evaluated data from 257 patients who underwent minor salivary gland biopsy as part of the diagnostic evaluation of sicca symptoms. The cohort comprised 182 patients with SjD and 75 non-SjD sicca controls. Patients were stratified by lifetime smoking history into current smokers, ex-smokers, never smokers, and ever smokers (a combined group pooling both current and ex-smokers).

A significantly higher proportion of current smokers was observed in the non-SjD sicca control group than in the SjD cohort. Logistic regression analysis revealed that current smoking carried an unadjusted odds ratio (OR) of 0.44 (P = .015) for an SjD diagnosis. This inverse association remained robust after adjusting for age (OR, 0.46), indicating that active smokers have less than half the odds of being diagnosed with SjD compared to nonsmokers.

In addition, among patients within the SjD cohort, smoking status closely correlated with milder local tissue inflammation. Current smokers had the least amount of inflammation and disease activity, whereas people who had never smoked had the highest scores. A history of any exposure (ever smokers) was also associated with significantly lower inflammation and less disease activity compared with lifetime nonsmokers. No significant differences were found between ex-smokers and current smokers.

When inflammation in the salivary glands becomes chronic and highly organized, the immune cells form structures called germinal centers. These are specialized training camps where B cells mature and learn to produce autoantibodies (the proteins that attack the body's own tissues).

The presence of germinal centers is a sign of advanced, highly active disease and is often linked to a higher risk of complications. Current smokers had the lowest rates of germinal center positivity, meaning their immune systems were less successful at forming these advanced inflammatory structures in the salivary tissue.

Smoke Extract Dampens Epithelial Cytokine Secretion 

To investigate a potential biological mechanism underlying these clinical observations, researchers established primary cell cultures of SGECs from salivary gland biopsies of three patients with SjD and three sicca controls. The cultured cells were subjected to five distinct experimental media conditions utilizing standardized CSE and a potent pro-inflammatory agent (polyinosinic:polycytidylic acid or poly I:C).

Under baseline, unstimulated conditions, exposure to CSE drove a selective reduction in interleukin-6 (IL-6) secretion, while TNF-alpha levels remained unaffected.

However, when cells were stimulated into an active inflammatory state with poly I:C, CSE exposure led to a pronounced, broad anti-inflammatory response. Concomitant treatment (poly I:C plus CSE for 24 hours) and sequential treatment (12 hours of poly I:C followed by 12 hours of CSE) each resulted in significantly decreased production of both IL-6 and TNF-alpha.

Clinical Implications

The study provides the first direct in vitro evidence that cigarette smoke can exert an anti-inflammatory effect on the target epithelial tissues of SjD. These findings strengthen the hypothesis that tobacco exposure may be protective against the pathogenesis and structural severity of SjD, Simoncelli said. 

“[Understanding] the effect on levels of tissue inflammation [is] helpful as this has been ambiguous in the past, and there has been little or no mechanistic work to explain this, so that is a first,” Benjamin A. Fisher, MD, professor of clinical rheumatology at the University of Birmingham, UK, who was not involved in the study, told Medscape Medical News. 

“Obviously, no one would advocate that people with SjD start smoking, but if we can understand the mechanisms, then we may be able to harness those to help treat the disease. Awareness of the potential for smoking to alter phenotype may also prevent misclassification,” he said.

A patient's smoking status may artificially lower focus scores and disguise tissue-level disease activity, Simoncelli agreed. “Smoking [status of a patient] should be considered in the interpretation of [salivary gland biopsy] focus scores because it’s a factor that might influence them.”

Simoncelli and Fisher have reported no relevant financial relationships. 

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.