Although early RA treatment improves results, the ultimate objective of RA management should be disease prevention. The rising body of research showing that the emergence of RA-specific biomarkers occurs before the onset of clinically evident RA [1] makes the idea of RA prevention more alluring and doable. These discoveries have produced the RA development model. In this concept, initial genetic and environmental risk factors for RA (phase 1) "trigger" a stage of asymptomatic RA-related autoimmunity (phase 2) in which aberrant levels of biomarkers, such as rheumatoid factor and Antibodies to Citrullinated Protein Antigens (ACPAs), are present. A period known as arthralgia in absence of IA by several European investigative groups [2] follows this phase, which is followed by clinically apparent IA that may initially be undifferentiated and later evolve into fully classifiable RA (phase 4). This phase is followed by a period in which a subject develops symptoms of inflammatory joint disease without overt clinical findings of IA (phase 3). Importantly, it appears that abnormalities of RA-related autoantibodies and in particular, the highly RA-specific ACPAs in patients without obvious IA, are strongly predictive of future disease onset [3]. This is significant in terms of RA prediction and possibly prevention. On the basis of this, it is hoped that these biomarkers will be able to identify individuals who are sufficiently at risk for developing RA in the future to qualify for disease-prevention interventions while the disease is still in its early stages and before significant joint damage.

However, what is meant by RA prevention will vary depending on the investigator. It might entail stopping the transition from an undifferentiated IA phase to a classifiable RA phase. It might entail identifying those who have developed RA-related autoimmunity without overt IA and putting medicines into place to stop the disease from progressing. Lastly, it can entail modifying RA-related risk factors at the individual or population level to stop the disease from developing in the future. Importantly, the latter method is most similar to primary disease prevention, that is, changing risk factors for disease so that RA-related tissue injury never occurs, because, as was described above, tissue injury may occur even very soon after the clinical onset of RA. 

Prevention of Progression from Undifferentiated IA to 

Classifiable RA

The transition of undifferentiated IA to classifiable RA is largely influenced by the illness classifications that are applied. If the 1987 ACR classification criteria are applied, for instance, it could take a person many months to advance from undifferentiated IA to classifiable RA [4]. With the 2010 ACR/EULAR criteria, however, the transition from IA to classifiable RA may only require the occurrence of three swollen small joints evolving into four swollen small joints in a patient with IA and high-titer RA-related autoantibody positive [5]. According to these definitions of RA, it may be very simple to prevent advancement to RA as defined by the 1987 criteria in a patient with undifferentiated IA, but challenging to prevent progression to RA as described by the 2010 criteria.

Numerous studies have assessed the effectiveness of therapies in halting the transition of undifferentiated IA to classifiable RA with these problems in mind. About 110 patients with undifferentiated IA of 2 years' duration were randomised to receive MTX or placebo in the PRObable Rheumatoid Arthritis: Methotrexate Versus Placebo Treatment (PROMPT) study and they were followed for 18 months for the primary outcome of meeting the 1987 ACR RA classification criteria [6]. While it's crucial to note that the majority of the effect of MTX in postponing or preventing the development of classifiable RA was shown in the anti-CCP positive subset of patients, 40% of the MTX-treated patients developed RA, compared to 53% in the placebo group. Additionally, the radiographic joint damage was lower and the development of classifiable RA was delayed in the MTX-treated group.

Patients with IA of less than 16 weeks' duration were randomised to receive a single intramuscular (IM) dose of 120 mg of methylprednisolone or a placebo and they were then monitored for 12 months for the emergence of RA in accordance with the 1987 criteria [7]. There was no difference in the study groups' development to RA as a result of this intervention. Patients with early IA (4- to 10-week duration) received three weekly 80 mg methylprednisolone IM injections as opposed to a placebo in the STIVEA study and they were monitored for 12 months [8]. One of every ten participants treated as a result of this intervention had the prescription for DMARDs delayed and did not develop RA according to the 1987 criteria. 50 individuals with undifferentiated IA (two or more swollen joints not meeting 1987 RA criteria) were randomised to receive abatacept or a placebo for 6 months in the ADJUST study, with the development of RA (1987 criteria) at 12 months being the primary outcome assessed. Although no statistical comparison was offered for these findings, 12/26 (46%) of the abatacept-treated individuals had progressed to RA, as opposed to 16/24 (67%) of the placebo-treated subjects.

Overall, if the SAVE trial is eliminated, it appears that a sustained intervention with an immunomodulatory drug appears to attenuate part of the progression of RA. The outcomes of these studies in preventing the transition from undifferentiated IA to classifiable RA are mixed. It is necessary to conduct additional research on therapies made during this extremely early stage of arthritis development in order to determine the best course of action for these patients. Since it is likely that many of the participants in these trials met the 2010 ACR/EULAR criteria at baseline, it is crucial to assess whether or not these criteria were met.

Prevention of Initial Onset of IA in Subjects Who Have Developed RA-Related Autoimmunity

Further back in the history of RA, it could be able to stop the development of RA in those who have anomalies of disease-specific auto-antibodies without overt IA. Bos and colleagues made an effort at this strategy by administering two doses of IM 100 mg dexamethasone versus placebo to 83 anti-CCP positive participants who had "arthralgias" but no IA according on assessment by two rheumatologists (baseline and six weeks) [9]. Dexamethasone decreased the levels of autoantibody titers (including rheumatoid factor and ACPAs), but it did not stop the progression of IA from becoming clinically apparent. Although this study did not reduce the outcomes of IA, it is tempting to consider that such an approach might be used to identify people who are at a high risk for developing RA and then intervene to stop the disease from progressing. Maybe instead of using pharmaceuticals, this solution would focus on eliminating environmental risk factors? Tobacco smoke exposure, for instance, has a substantial correlation with RA; according to some estimations, it accounts for about 30% of the risk for seropositive RA [10]. On the basis of this, some have hypothesised that widely adopted programmes for quitting smoking might lead to a marked decrease in RA. Additionally, Porphyromonas gingivals infection and periodontal inflammation may play a role in the development of RA, according to recent research [11]. If this connection is causal, possibly treating periodontal disease or infection will lower the likelihood of developing RA in the future.

Although autoantibodies appear to accurately predict future RA in published case-control studies, our knowledge of the diagnostic accuracy of these antibodies for future RA if testing is carried out in large, healthy populations with low overall RA risk is limited. Furthermore, our knowledge of the mechanisms underlying the early onset of RA is limited and it is currently unclear which of these mechanisms would be most amenable to being targeted with targeted interventions in order to stop the development of RA-related autoimmunity before the onset of IA. In order to create precise illness prediction models for the future and to pinpoint particular mechanisms of disease development so that these elements can be used in RA prevention strategies, we will need to conduct in-depth investigations of the natural history of RA development in the future.

A growing body of research indicates that treating RA as soon as it is discovered improves results, including rates of drug-free remission. The ideal time to diagnose and treat RA is unknown, however DMARD therapy should be started within 3-6 months after the onset of IA symptoms. This objective may be challenging to meet because of the many variables that can influence early RA diagnosis. Although further research is required to determine whether the 2010 ACR/EULAR classification criteria are indeed more effective at identifying RA than the 1987 criteria were, they do appear to do so earlier. Additionally, the ideal drug therapy in early RA is unknown. However, at this  time,  reasonable  therapeutic  approaches  include the early use of DMARD monotherapy with rapid escalation to combination therapy, which may include biologics if disease activity is not controlled and, possibly, initial combination therapy in patients with severe disease. However, more research is required to determine the best treatment plans for specific early RA patients. In the near future, screening programmes to identify subjects at high risk for future RA and the implementation of preventive strategies for RA that may target particular pathogenic mechanisms of disease development may be in use. This is due to the growing understanding of the early natural history of RA and the ability of biomarkers to predict those at future risk for RA.

1. Aho, K. et al. “Antifilaggrin antibodies within ‘normal’ range predict rheumatoid arthritis in a linear fashion.” Journal of Rheumatology, vol. 27, 2000, pp. 2743–2746.

2. Bos, W.H. et al. “Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: A prospective cohort study.” Annals of the Rheumatic Diseases, vol. 69, 2010, pp. 490–494.

3. Deane, K.D. et al. “The number of elevated cytokines/chemokines in pre-clinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner.” Arthritis and Rheumatism, 2010.

4. Aletaha, D. et al. “The need for new classification criteria for rheumatoid arthritis.” Arthritis and Rheumatism, vol. 52, 2005, pp. 3333–3336.

5. Aletaha, D. et al. “2010 Rheumatoid arthritis classification criteria: An American college of rheumatology/European league against rheumatism collaborative initiative.” Arthritis and Rheumatism, vol. 62, 2010, pp. 2569–2581.

6. van Dongen, H. et al. “Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double-blind, randomized, placebo-controlled trial.” Arthritis and Rheumatism, vol. 56, 2007, pp. 1424–1432.

7. Machold, K.P. et al. “The Stop Arthritis Very Early (SAVE) Trial: An International multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis.” Annals of the Rheumatic Diseases, vol. 69, 2010, pp. 495–502.

8. Verstappen, S.M. et al. “Beneficial effects of a three-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: Results of the STIVEA trial.” Annals of the Rheumatic Diseases, vol. 69, 2010, pp. 503–509.

9. Bos, W.H. et al. “Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: A randomised trial.” Annals of the Rheumatic Diseases, vol. 69, 2010, pp. 571–574.

10. Klareskog, L. et al. “Prevention of autoimmune rheumatic disease: state of the art and future perspectives.” Annals of the Rheumatic Diseases, vol. 69, 2010, pp. 2062–2066.

11. Lundberg, K. et al. “Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase.” Arthritis and Rheumatism, vol. 58, 2008, pp. 3009–3019.