ENVI-RA: Impact of ENVIronmental factors and gene-environment interaction in the development of Rheumatoid Arthritis


Rheumatoid arthritis (RA) is a complex di- sease in which environmental agents are thought to interact with genetic factors to trigger auto-immunity.

The contribution of genetic factors to RA susceptibility is well recognized. The heritability of anticitrullinated protein auto- antibody (ACPA)-positive and ACPA-negative RA implicates different genes [2]. To date, the main known genetic factoris HLA, in particular the HLA-DRB1-shared epitope (SE) alleles, that predispose much more strongly to ACPA. However, the concordance for RA between monozygotic twins is only 15.6%. Thus, environment plays a crucial role in the development of the disease as well.

Facts and figures

Project lead
R Seror
Université Paris Sud
FOREUM research grant: € 100.000

Meet the team

R Seror
Université Paris Sud
D van der Woude
UMC Leiden
C Boutron
Gustave Roussy Institute
D Alpízar-Rodríguez
Hôpitaux Universitaires de Genève
P Preiss
Association France Polyarthrite


This project aims to investigate the role of new environmental factors and of potential interactions between the genetic background and specific environmental factors in the development of RA and/or preclinical phases of RA.

Patient voice

Patients will be involved at each step: For case validation, for interpreting/discuss results of research, and they will help providing key message derived from research results to other patients. Patients from dif- ferent countries will be involved to input different view and perspectives.

Interim results

RA cases validation

In the French prospective general population cohort (E3N). Among the 98,995 included women, we identified and validated self-reported RA cases 3 methods including a specific validation questionnaire, a medical chart review (where available) and the use of the reimbursement database. Among the 3,192 identified potential cases, 964 RA cases were validated, including 698 incident cases and 266 prevalent cases. Of them, 314 (32.6%) were seropositive cases, 23 (2.4%) seronegative and 627 (65.0%) had unknown antibody status. Mean age at diagnosis was 57.4 ± 13.9 years (40.9 ± 10.4 years for prevalent cases, and 63.8 ± 9.0 for incident cases).


Chronic Diarrhoea and Risk of Rheumatoid Arthritis

In the E3N cohort, we assessed the relationship between gastrointestinal disorders and the risk of further development of RA. We observed that chronic diarrhea was associated with an increased risk of subsequent RA development (HR 1.70, 95% CI: 1.13–2.58), particularly among ever-smokers (HR 2.21, 95% CI: 1.32–3.70), independently of dysthyroidism or dietary habits. These data fit with the mucosal origin hypothesis of RA, where interaction between intestinal dysbiosis and smoking could occur at an early stage to promote emergence of autoimmunity, followed years later by clinical disease. 


Adherence to the Mediterranean diet and risk of RA

In the E3N cohort, we assessed the relationship between adherence to the Mediterranean diet and risk of RA. We observed that, among ever-smokers, MD score was associated with a decreased risk of RA (HR for 1-point increase of MD score: 0.91; 95% CI: 0.84 to 0.99, P = 0.03).


Hormonal exposure and risk of RA

In the E3N cohort, we assessed the relationships between hormonal exposures and the risk of RA in women. We observed that Early age at menopause (<45 yrs) was associated with an increased risk of RA, particularily in women exposed to tobacco. By contrast, exogenous hormonal exposures were not.


  • Nguyen Y, Salliot C, Gusto G, Descamps E, Mariette X, Boutron-Ruault MC, Seror R. Improving accuracy of self-reported diagnoses of rheumatoid arthritis in the French prospective E3N-EPIC cohort: a validation study. BMJ Open. 2019 Dec 16;9(12):e033536.
  • Nguyen Y, Mariette X, Salliot C, Gusto G, Boutron-Ruault MC, Seror R. Chronic Diarrhoea and Risk of Rheumatoid Arthritis: Findings from the French E3N-EPIC Cohort Study. Rheumatology (oxford), 2020 (in press)