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Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis
  1. Fenne Wouters1,
  2. Marc P Maurits1,
  3. Laurette van Boheemen2,
  4. Marloes Verstappen1,
  5. Kulveer Mankia3,4,
  6. Xanthe M E Matthijssen1,
  7. Annemarie L Dorjée1,
  8. Paul Emery3,4,
  9. Rachel Knevel1,
  10. Dirkjan van Schaardenburg2,
  11. René E M Toes1,
  12. Annette H M van der Helm-van Mil1,5
  1. 1 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands
  3. 3 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
  4. 4 NIHR Leeds Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  5. 5 Department of Rheumatology, Erasmus Medical Center, Rotterdam, The Netherlands
  1. Correspondence to Fenne Wouters, Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; f.wouters{at}


Objectives The human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis.

Methods We performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA).

Results Meta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not.

Conclusions HLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.

  • arthritis
  • rheumatoid
  • anti-citrullinated protein antibodies
  • autoantibodies
  • smoking

Data availability statement

Data can be requested from the corresponding author.

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Data availability statement

Data can be requested from the corresponding author.

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  • Handling editor Josef S Smolen

  • Contributors FW and AvdH-vM were involved in study conception and design. FW, MPM, RK, LvB and ALD contributed to collection of the data. FW and MV performed the data analyses. FW, AvdH-vM and REMT interpreted the results and wrote the first version of the manuscript. All authors critically revised the manuscript and approved the final version.

  • Funding This work was supported by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (starting grant, agreement no. 714312) and the Dutch Arthritis Society.

  • Competing interests None declared.

  • Patient and public involvement statement Patient partners were involved in the design of the clinically suspect arthralgia cohort.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.