Background/Purpose :
Patients with rheumatoid arthritis (RA) are predominantly female, smokers and
positive for autoantibodies, rheumatoid factor and antibodies to citrullinated peptides. The oncoprotein
survivin has recently emerged as an early marker for
RA being frequently found in seropositive patients. High levels of survivin may be measured in serum several years before
disease onset. Presence of survivin in serum is also
a risk factor for an aggressive and treatment resistant disease. This study elucidates
associations between smoking and survivin.

Methods : To
study if smoking contributes to higher levels of survivin
in serum we measured survivin in 252 (184 women, 68
men) RA patients and 168 healthy controls (95 women, 73 men). Information about smoking habits was
collected via extended questionnaire. Serum survivin
was analysed with a sandwich ELISA, where the level >0.45ng/ml was
considered positive. Production of survivin isoforms
of wild type, survivin-2B and survivin-deltaExon3 and estrogen
receptor alpha (ERa) by peripheral blood mononuclear
cells (PBMC) was measured by qPCR.

Results: The
prevalence (43% vs 22.8%, p<10^-5) and
the absolute levels of serum survivin were
significantly higher in smokers compared to never smokers (p=0.0024). In women,
the estimated risk to be survivin-positive was significantly
higher for healthy smokers (OR 3.64[1.17-11.35], p=0.025) and for RA patients (OR
1.98[1.03-3.52], p=0.039). In contrast, no significant increase in risk was
found in men.

High serum levels of survivin
were associated with combined expression of all three survivin
isoforms in PBMC. To study gender-dependent effects of smoking, we compared ERa transcription in PBMC of smoking and non-smoking women
RA patients. We observed a smoking-dependent increase of ERa
in young women (age <50 years) compared to the older women (p=0.0056). Also,
young survivin-positive smokers had higher ERa compared to survivin-negative
non-smokers (p=0.0137). Finally, these young survivin-positive
women had higher estimated risk for the combined expression of all three survivin isoforms (p=0.012). Functional studies in mouse
model proved synergistic effect of smoking and ERa on
survivin transcription in leukocytes.

Conclusion:
Smoking significantly increases risk for high serum levels of survivin in healthy women and in women with RA potentially
decreasing the threshold for the disease. ERa has
experimentally been shown as a mediator of survivin
production in leukocytes predisposing to an active and proliferating phenotype of
these cells.