Individuals at risk of seropositive rheumatoid arthritis: the evolving story

Abstract

The aetiology of the autoimmune disease rheumatoid arthritis (RA) involves a complex interplay between genetic and environmental factors that initiate many years before the onset of clinical symptoms. These interactions likely include both protective and susceptibility factors which together determine the risk of developing RA. More than 100 susceptibility loci have been linked to RA. The strongest association is with HLA‐DRB1 alleles encoding antigen presenting molecules containing a unique sequence in the peptide‐binding grove called the ‘shared epitope’. Female sex, infections during childhood, lifestyle habits (e.g. smoking and diet) and distinct microbial agents, amongst many others, are interacting risk factors thought to contribute to RA pathogenesis by dysregulating the immune system in individuals with genetic susceptibility. Interestingly, patients with RA develop autoantibodies many years before the clinical onset of disease, providing strong evidence that the lack of tolerance to arthritogenic antigens is amongst the earliest events in the initiation of seropositive RA. Here, we will discuss the clinical and mechanistic evidence surrounding the role of different environmental and genetic factors in the phases leading to the production of autoantibodies and the initiation of symptomatic RA. Understanding this complexity is critical in order to develop tools to identify drivers of disease initiation and propagation and to develop preventive therapeutics.

Patients’ and rheumatologists’ perceptions on preventive intervention in rheumatoid arthritis and axial spondyloarthritis

“…A minority of rheumatologists sometimes advises individuals at risk of RA to stop smoking and lose weight, but the majority requires more evidence as to whether lifestyle changes reduce the risk of developing RA before implementing lifestyle advice into daily practice. Indeed, while some environmental risk factors have been identified, it has not yet been fully clarified how most of these influence autoimmunity [ 26 ] and how changing these factors affect RA-risk. To address this, we are currently performing a randomized controlled trial investigating the effects of a lifestyle intervention program on disease risk in individuals with (an increased risk of) RA.…”

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis

“…In RA, the emergence of RF as well as antibodies to citrullinated perinuclear antigens and filaggrin before onset of joint inflammation was first shown in Finland [152,153] and provided the basis for a still expanding field of studies aiming to understand the gradual evolution of immunity and symptoms associated with RA (see also [7]). The development of this field including the recognition that not only ACPAs but also antibodies to other post-translational modifications (AMPAs) and RF emerge long before onset of RA [154][155][156] and that epitope spreading as well as changes in glycosylation of these antibodies happen during the transition from autoimmunity to autoimmune disease [31][32][156][157][158][159] has been covered in an excellent recent review in Journal of Internal Medicine [160].…”

Insights into the study and origin of the citrullinome in rheumatoid arthritis

“…Since ACPAs are detected years before the onset of joint symptoms in RA, it is uncertain whether the immune response to citrullinated proteins is initiated in the joints. Instead, there is growing support for the hypothesis that breach of immunologic tolerance to citrullinated antigens in preclinical RA initially occurs at mucosal sites such as the oral mucosa, lung, and gastrointestinal tract .…”