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  1. Carine Salliot1,2,
  2. Yann Nguyen2,3,
  3. Juliette Gambaretti2,
  4. Amandine Gelot2,
  5. Xavier Mariette4,
  6. Marie-Christine Boutron-Ruault2,
  7. Raphaèle Seror5
  1. 1CHR Orleans, Rheumatology, Orleans, France
  2. 2CESP INSERM 1018, Villejuif, France
  3. 3APHP, Paris, France
  4. 4Université Paris-Sud, IMVA, INSERM U1184, Kremlin Bicetre, France
  5. 5Université Paris-Sud, IMVA, INSERM U1184, Kremlin Bicetre, France


Background: Smoking has been reproducibly reported as associated with an increased risk of ACPA-positive Rheumatoid Arthritis (RA) [1]. The involvement of female hormones in the pathogenesis of RA is supported by numerous observations: a 2-4 female to male ratio before age 50, but below 2 after the age of 60, an increased incidence in the first year post-partum, and a peak of RA incidence around the age of menopause. To date, many studies have evaluated the association between hormonal treatments and other reproductive factors, and RA risk with conflicting results [2, 3].

Objectives: To assess the relationships between endogenous and exogenous female hormonal exposures and the risk of RA in women involved in the E3N cohort.

Methods: E3N is an ongoing French prospective cohort that included 98,995 women aged 40-65 years in 1990. Women completed mailed questionnaires every 2-3 years on lifestyle, reproductive factors, and health-related information. Female endogenous hormonal exposures were assessed using age at menarche, age at menopause, and the duration of reproductive life. Exogenous hormonal exposures included oral contraception and menopausal hormonal treatment (MHT). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident RA were estimated using Cox proportional hazards regression models with age as the time scale, first applied to the overall population, then stratified for smoking exposure.

Results: A total of 698 incident RA cases were validated among and 78,452 women over 1,865,213 women-years. Multivariate models for age at menopause and cumulative duration of MHT appear in Table. After stratification for smoking exposure, early age at menopause was associated with a somewhat stronger RA risk in women exposed to smoking (HR=1.6, 95% CI: 1.1-2.4; plinear trend=0.0270) than in those with no smoking exposure (HR=1.3, 95% CI: 0.8-2.2; plinear trend =0.1811). However when adjusting for cumulative duration of MHT, early age at menopause was no longer associated with incident RA, even in women exposed to smoking (HR=1.3, 95% CI: 0.8-2.2; plinear trend =0.7973), while a cumulative duration of MHT > 4 years was borderline associated with RA in women exposed to smoking [HR=1.3, 95%CI: 1.0-1.7; plinear trend=0.09] in comparison with women who did not received MHT. Age at menopause and duration of THM were strongly correlated: in women with early menopause duration of MHT was significantly longer: 7.01 (7.3) years versus 4.8 (5.0) years (p<0.001). There was no evidence of an association between oral contraception use, age at menarche and duration of reproductive life with the risk of RA.

Conclusion: Early age at menopause and/or duration of MHT > 4 years use may increase the risk of RA. Further studies are requested to disentangle the effect of early menopause to that of long-term MHT.

References: 1. Raphaèle Seror, Julien Henry, Gaelle Gusto, Henri-Jean Aubin, Marie-Christine Boutron-Ruault, Xavier Mariette. Passive Smoking In Childhood Increases The Risk Of Developing Rheumatoid Arthritis. Rheumatology 2018.

2. Merlino LA, Cerhan JR, Criswell LA, et al. Estrogen and other female reproductive risk factors are not strongly associated with the development of rheumatoid arthritis in elderly women. Semin Arthritis Rheum 2003;33:72–82.

[3] Bengtsson C, Malspeis S, Orellana C, Sparks JA, Costenbader KH, Karlson EW.Association Between Menopausal Factors and the Risk of Seronegative and Seropositive Rheumatoid Arthritis: Results From the Nurses’ Health Studies. Arthritis Care Res (Hoboken). 2017;69:1676-1684.

Acknowledgement: FOREUM as supporter of this project.

Disclosure of Interests: Carine Salliot: None declared, Yann Nguyen: None declared, Juliette Gambaretti: None declared, Amandine gelot: None declared, Xavier Mariette Grant/research support from: Servier, Consultant for: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, UCB Pharma, Marie-Christine Boutron-Ruault: None declared, Raphaèle Seror: None declared

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