Binoy J Paul, Hemanth Illath Kandy, and Vinod Krishnan
Published online 2017 Apr 11
Abstract
Pre-rheumatoid arthritis (pre-RA) is the preclinical period of the disease that precedes the onset of clinically apparent RA. It includes the interaction between genetic and environmental risk factors and development of disease-related autoantibodies and joint symptoms and signs, which may be considered nonspecific or unclassified for RA. A better understanding of the pre-RA stage will be useful in developing screening programs for early detection of RA. Identifying and modifying risk factors such as smoking, periodontitis, obesity, viral infections, and hormonal or dietary factors will be useful in preventing RA in susceptible population.
Keywords: Pre-rheumatoid arthritis, unclassified arthritis, rheumatoid arthritis prevention
Introduction
Pre-rheumatoid arthritis (pre-RA) is used to designate events before the clinical occurrence of RA. This stage is characterized by the presence of abnormalities in immune function and responses in the absence of clinical manifestations of autoimmune tissue injury. There is a preclinical period in the development of RA where the genetic and environmental factors interact, probably sequentially, to initiate and propagate the autoimmune process, resulting in tissue inflammation and injury. Moreover, disease-related autoantibodies such as rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) can develop in the absence of clinical signs and symptoms of tissue injury. At a later stage, minimal symptoms or signs can develop, which may be considered nonspecific or unclassified for any particular rheumatic disease before developing classical RA. Importantly, all patients need not experience each stage of the disease, and the phases can be in a combinational manner. For instance, a patient can have genetic risk factors, ACPA, and joint pain.
In the current medical literature, researchers used different terminologies, such as pre-RA, preclinical RA, autoantibody-positive arthralgia, probable RA, very early RA, and early undifferentiated arthritis progressing to RA, to describe the earlier phases of RA. To avoid confusion in terminologies, different professional associations such as EULAR recommend certain specific terminologies in the past few years.
The different phases of RA development in at-risk individuals from pre-RA to clinically apparent RA has been described in Figure 1. Phase I involves the interaction between genetic and environmental risk factors of RA. Phase II includes the production of RA autoantibodies such as RF and anti-cyclic citrullinated peptide (anti-CCP). Some of these individuals later enter into phase III where they develop arthralgia or joint stiffness without any clinical evidence of arthritis. In phase IV, patients develop arthritis in one or two joints, which is termed as early undifferentiated arthritis. In some cases, the arthritis can be intermittent at this stage and it is termed as palindromic rheumatism. Finally, some of these patients develop classical clinical features of RA, which is described as established RA (Phase V).
The EULAR study group recommends that in prospective studies, individuals at risk of developing RA should be described as having the following five stages.
Individuals with genetic risk factors for RA
Individuals exposed to environmental risk factors for RA
Systemic autoimmunity associated with RA
Symptoms without clinical evidence of arthritis
Unclassified arthritis
The term pre RA is used retrospectevely to describe an earlier phase of the disease, at stage (a) to (e) or any of their combination, in a person who has developed RA. The term pre-RA is used to describe all phases before the development of a disease classifiable as RA, which will be asymptomatic (stages a, b, or c) or symptomatic (stages d or e).
Genetic risk factors of RA
It is well known that 70% of RA patients have genetic association with HLADR4 compared with 30% among controls, increasing the relative risk of developing RA with this gene by 4 to 5 fold. Susceptibility to RA is associated with the third hypervariable region of DRβ1 allele, which is termed as the susceptibility epitope (SE). Other genes discovered later such as protein tyrosine phosphatase 22 and peptidyl arginasedeiminase (PADI-4) also carry approximately 2-fold risk of developing RA. Numerous other genes associated with lower risk are also described.
Twin studies show that 12–15% of identical twins develop RA compared with 4% in non-identical twins. The incidence of disease among first degree family members is 0.8%, when compared to 0.5% in the general population. It is found that the known genetic risk alleles and heredity factors can explain only 16% of the overall disease burden. Many other factors such as epigenetics can further alter the gene expression in favor of developing RA. It is now clear that genes only modestly increase the risk of RA and that the environment is likely to play a stronger role.
