Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis

Abstract

ObjectivesThe 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.MethodsWe 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).ResultsMeta-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.ConclusionsHLA-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.

Added value of multiple autoantibody testing for predicting progression to inflammatory arthritis in at-risk individuals

“…Currently, many biomarker have been proposed in individual at-risk of RA. From a single blood test, our study has confirmed the previously reported better individual predictive value of ACPA (using second or third generation tests,37 38 while still demonstrating that combinations of autoantibodies are more informative that each autoantibody alone. In addition to serological testing, other biomarkers such as high resolution imaging (ultrasound and MRI)39–41 or T-cell subsets23 24 or the combination of some, may still provide increased predictive value.…”

Rheumatoid arthritis sera antibodies to citrullinated collagen type II bind to joint cartilage

“…It has been known for a long time that autoantibodies, both RF and ACPA, occur years before the onset of RA [2], but their function or relation to the later joint inflammatory attack and their role for RA development have still not been clarified. Interestingly, the tipping point for arthritis development may not be when ACPA first appear [40] but rather at a stage with quality shift, such as glycosylation [41,42], or specificity changes occurring predominantly in individuals with certain MHC class II alleles [43]. It has widely been assumed that most autoantibodies are pathogenic since they are associated with disease development and because depletion of B cells is therapeutic [44].…”

Sulfonylureas or biguanides is associated with a lower risk of rheumatoid arthritis in patients with diabetes: A nationwide cohort study

“…The pathogenesis of rheumatoid arthritis (RA) involves genetic background, obesity ( 12 ), chronic infection ( 13 ), and environmental factors such as oral hygiene ( 14 ), smoking ( 15 ), and diet ( 16 ), which can influence oral ( 17 ) and gut microbiota ( 18 ) and thus indirectly impact the development of RA. Take obesity as an example, as shown in a US study ( 12 ) and other studies ( 19 , 20 ), it accounts for 4.8 cases per 100,000 (52%) of the increased incidence of female RA patients between 1985 and 2007.…”