Introduction

Rheumatoid arthritis (RA) is a systemic, autoimmune inflammatory disease that primarily affects the joints. While the exact prevalence rate across the entire population is unknown, available data suggest that it affects ∼1% of the population, making it one of the most common autoimmune rheumatic diseases . Furthermore, it leads to >30 billion dollars in health-related costs annually in the United States alone . While as discussed below there are emerging data which show that early treatment of RA can lead to increased rates of drug-free remission, , f or the vast majority of patients with RA who are managed in routine clinical practices, once it becomes clinically apparent, it is a disease that requires prolonged if not lifelong therapy . Based on these figures, means to prevent RA could lead to substantial improvements in public health.

Patients with RA typically present to health care once the signs and symptoms of arthritis (joint pain, stiffness and swelling) develop; however, established and emerging data from multiple studies support that the initial immune dysregulation of RA, as measured by RA-related autoantibodies (e.g. rheumatoid factor (RF) and antibodies to citrullinated protein antigens (ACPAs)) and other inflammatory markers, occurs long prior to the first joint symptoms. While the terminology to describe the autoimmunity of RA prior to the onset of clinically apparent synovitis is still being established (and how to classify clinically apparent disease is also difficult, evidenced by two classification criteria ), currently, a workable label to describe the period of detectable RA-related autoimmunity prior to the onset of the clinically apparent signs and symptoms of joint disease of RA is the ‘preclinical’ phase of RA development ( Fig. 1 ).

Phases of development of rheumatoid arthritis (RA) . In this model of RA development, disease begins with genetic and environmental risks ( Phase 1 ), followed by asymptomatic inflammation and autoimmunity (e.g. autoantibodies, cytokines and chemokines; Phase 2 ), with progression to symptoms that may be present in absence of inflammatory arthritis (IA) on physical examination (Phase 3), and eventual development of undifferentiated IA ( Phase 4 ) that may progress to classifiable RA ( Phase 5 ). Phase 6 is defined as evolution of disease (e.g. exacerbations, remissions, and response to therapy) after clinically apparent articular disease has developed. Although Phase 1 could also be included, ‘Preclinical’ RA is most readily defined as Phases 2 and 3 as they are identifiable by biomarker testing and prior to IA that is identifiable by joint examination. This developmental process is characterized by expanding autoimmunity and inflammation, detectable through assessment of circulating biomarkers. The double-headed arrows indicate that progression of RA may be halted, or reversed, perhaps through immunomodulatory pharmacologic intervention(s), especially if initiated prior to the onset of clinically apparent IA (Phase 4).

Importantly, abnormalities of RA-related biomarkers during preclinical RA are highly predictive of future onset of clinically apparent RA. In addition, a growing number of studies of preclinical RA are identifying mechanisms of RA development as well as risk factors that are likely truly related to disease pathogenesis. When these factors are taken as a whole, they suggest that RA may be preventable, and there is hope that we may soon be able to approach the management of RA much like the medical community approaches cardiovascular disease (CVD) today where risk factors are identified and modified to prevent the future occurrence of clinically apparent disease.

Herein will be reviewed some of the current understanding of the natural history, risk factors and mechanisms of RA development, with discussion on these issues being focussed on potential strategies that could be employed to prevent disease as well as some challenges to be addressed in order to make the prevention of RA a reality in the near future.

The ‘preclinical’ phase of RA development

Multiple studies now demonstrate that there is a ‘preclinical’ phase of RA development during which there are abnormalities of autoantibodies and inflammatory markers prior to the onset of appearance of the signs and symptoms of joint disease that characterize the clinically apparent RA ( Fig. 1 ) . Some of these studies have been prospectively conducted; however, most have utilized biospecimens fortuitously collected prior to the onset of RA. As such, the exact timing of appearance of biomarkers prior to the onset of signs and symptoms of RA has been difficult to identify, but overall RA-related biomarkers, and especially autoantibodies, seem to appear in the circulation on average 3–5 years prior to the onset of clinically apparent RA.

Initial studies of preclinical RA focussed largely on the autoantibodies RF as well as ACPAs, the most commonly tested version of which is the anti-cyclic citrullinated peptide (anti-CCP) antibody, and a range of inflammatory markers including C-reactive protein and a variety of cytokines and chemokines . More recent studies have evaluated a wider range of immunologic factors in preclinical RA that include factors such as additional ACPA tests , autoantibodies to peptidylarginine deiminase (PAD, the human enzyme that is responsible for tissue citrullination) , alterations of glycosylation of antibodies , an increasing array of cytokines and chemokines as well as gene expression profiles , immunoglobulin isotypes and avidity , and autoantibodies to specific citrullinated peptides and proteins . Furthermore, multiple studies have shown that the levels of autoantibodies increase in preclinical RA as the time of clinically apparent disease approaches .

In particular, the studies detailing autoantibodies to specific citrullinated peptides and proteins in preclinical RA have provided important insights into the pathophysiology of RA development. As background, while the antigen structure for the first commercially available anti-CCP is publically available , the later generation of anti-CCP assays test for autoantibodies to proprietary citrullinated antigens; therefore, it is unclear if the test is positive what specific citrullinated protein is being recognized by a particular patient. Several research groups have developed autoantibody assays for specific citrullinated peptides and proteins and applied these tests to preclinical RA. Using a bead-based array to test autoantibodies to multiple individual citrullinated proteins/peptides in preclinical RA samples from subjects from the United States military, Sokolove and colleagues demonstrated that there is epitope spreading to citrullinated targets in the preclinical RA period, and the number of autoantibodies to citrullinated proteins increased in preclinical RA as the time to diagnosis approached . Interestingly, they also identified that the expansion of autoantibodies to citrullinated targets appeared to stop after the diagnosis of RA, suggesting that once clinically apparent RA developed, epitope spreading halted although the reasons for this finding, such as medication effect or other factors, are not known. Brink and colleagues used a Swedish cohort to also evaluate the individual ACPAs in preclinical RA samples, and demonstrated that an increased number of positive ACPAs had a higher specificity for future RA . Similar to what was seen in the Sokolove study, Brink and colleagues also found that systemic autoimmunity in RA was initially restricted to a small number of ACPAs that expanded as time to RA diagnosis approached. Of interest, in the Brink study, the ACPAs detected earliest in the preclinical period were found to often disappear over time suggesting that early in the development of RA autoimmunity may be initiated by a break in tolerance to certain citrullinated proteins, and over time the development of autoantibodies to other citrullinated proteins may be important in the propagation of autoimmunity and transition to clinically apparent disease.

Of note, the prolonged period of preclinical autoimmunity in RA has raised the hypothesis that RA does not start in the joint but rather at some extra-articular site, with this hypothesis supported by several joint examination and imaging studies, as well as a synovial biopsy study, that have found that the majority of subjects with circulating RA-related autoantibodies do not have clear evidence of synovitis . The finding of immunoglobulin A (IgA)-related autoantibodies in preclinical RA , associations between preclinical RA autoantibody positivity and lung disease as well as associations between RA and organisms that cause periodontal disease, gut disease or genitourinary disease suggest that the site of initiation of RA may be a mucosal surface. Investigations into these aspects of RA development are rapidly expanding but, as will be discussed below, they raise an important issue regarding RA prevention: should extra-articular sites be targets for preventive interventions? ( Table 1 )

The ‘preclinical’ phase of RA development

Multiple studies now demonstrate that there is a ‘preclinical’ phase of RA development during which there are abnormalities of autoantibodies and inflammatory markers prior to the onset of appearance of the signs and symptoms of joint disease that characterize the clinically apparent RA ( Fig. 1 ) . Some of these studies have been prospectively conducted; however, most have utilized biospecimens fortuitously collected prior to the onset of RA. As such, the exact timing of appearance of biomarkers prior to the onset of signs and symptoms of RA has been difficult to identify, but overall RA-related biomarkers, and especially autoantibodies, seem to appear in the circulation on average 3–5 years prior to the onset of clinically apparent RA.

Initial studies of preclinical RA focussed largely on the autoantibodies RF as well as ACPAs, the most commonly tested version of which is the anti-cyclic citrullinated peptide (anti-CCP) antibody, and a range of inflammatory markers including C-reactive protein and a variety of cytokines and chemokines . More recent studies have evaluated a wider range of immunologic factors in preclinical RA that include factors such as additional ACPA tests , autoantibodies to peptidylarginine deiminase (PAD, the human enzyme that is responsible for tissue citrullination) , alterations of glycosylation of antibodies , an increasing array of cytokines and chemokines as well as gene expression profiles , immunoglobulin isotypes and avidity , and autoantibodies to specific citrullinated peptides and proteins . Furthermore, multiple studies have shown that the levels of autoantibodies increase in preclinical RA as the time of clinically apparent disease approaches .

In particular, the studies detailing autoantibodies to specific citrullinated peptides and proteins in preclinical RA have provided important insights into the pathophysiology of RA development. As background, while the antigen structure for the first commercially available anti-CCP is publically available , the later generation of anti-CCP assays test for autoantibodies to proprietary citrullinated antigens; therefore, it is unclear if the test is positive what specific citrullinated protein is being recognized by a particular patient. Several research groups have developed autoantibody assays for specific citrullinated peptides and proteins and applied these tests to preclinical RA. Using a bead-based array to test autoantibodies to multiple individual citrullinated proteins/peptides in preclinical RA samples from subjects from the United States military, Sokolove and colleagues demonstrated that there is epitope spreading to citrullinated targets in the preclinical RA period, and the number of autoantibodies to citrullinated proteins increased in preclinical RA as the time to diagnosis approached . Interestingly, they also identified that the expansion of autoantibodies to citrullinated targets appeared to stop after the diagnosis of RA, suggesting that once clinically apparent RA developed, epitope spreading halted although the reasons for this finding, such as medication effect or other factors, are not known. Brink and colleagues used a Swedish cohort to also evaluate the individual ACPAs in preclinical RA samples, and demonstrated that an increased number of positive ACPAs had a higher specificity for future RA . Similar to what was seen in the Sokolove study, Brink and colleagues also found that systemic autoimmunity in RA was initially restricted to a small number of ACPAs that expanded as time to RA diagnosis approached. Of interest, in the Brink study, the ACPAs detected earliest in the preclinical period were found to often disappear over time suggesting that early in the development of RA autoimmunity may be initiated by a break in tolerance to certain citrullinated proteins, and over time the development of autoantibodies to other citrullinated proteins may be important in the propagation of autoimmunity and transition to clinically apparent disease.

Of note, the prolonged period of preclinical autoimmunity in RA has raised the hypothesis that RA does not start in the joint but rather at some extra-articular site, with this hypothesis supported by several joint examination and imaging studies, as well as a synovial biopsy study, that have found that the majority of subjects with circulating RA-related autoantibodies do not have clear evidence of synovitis . The finding of immunoglobulin A (IgA)-related autoantibodies in preclinical RA , associations between preclinical RA autoantibody positivity and lung disease as well as associations between RA and organisms that cause periodontal disease, gut disease or genitourinary disease suggest that the site of initiation of RA may be a mucosal surface. Investigations into these aspects of RA development are rapidly expanding but, as will be discussed below, they raise an important issue regarding RA prevention: should extra-articular sites be targets for preventive interventions? ( Table 1 )

Risk factors for RA development

Preventive strategies that target risk factor modification would ideally be based on a sound understanding of the modifiable exposures that influence the development of RA. There are numerous factors that have been associated with increased risk for RA. Some of these risk factors are presented in Table 2 . Several of the strongest risk factors are certain genetic factors including the presence of human leukocyte antigen (HLA) alleles containing the ‘shared epitope’, female sex, family history of RA and exposure to cigarette smoke . In particular, smoking is the strongest known environmental risk factor, especially for ACPA-positive RA, and is thought to explain up to 35% of ACPA-positive RA . There is also emerging understanding of other factors that may influence RA risk including the protective effect of factors such as alcohol use and intake of certain fatty acids . Furthermore, as mentioned above, there is growing evidence suggesting that certain infections and/or inflammatory processes such as periodontal disease and infections with Porphyromonas gingivalis may be triggers for RA ( Table 3 .

However, a caveat to these risk factors and their association with RA is that most of these associations were identified in subjects who had established RA, and there may be many biases associated with such findings including recall bias, or effects of immunomodulatory therapy on a variety of biomarkers of risk (e.g. associations of infections may be influenced by immunosuppression). It is also not clear in the majority of studies if the risk factors for RA that have been identified are related to the initiation of RA, which likely occurred years prior to the clinically apparent onset of their disease. Furthermore, even if a risk factor is truly associated with RA, the reasons behind why they are related to RA are not wholly clear, although there are emerging data to explain how certain risk factors may influence RA. For example, smoking can lead to citrullination of human tissue likely through a variety of means including up-regulation of PAD enzymes . Moreover, HLA molecules that contain the shared epitope may preferentially present citrullinated peptides to the immune system . Smoking and the shared epitope may therefore act in concert to drive the development of ACPAs and ultimately RA . In addition, P. gingivalis produces an enzyme that can citrullinate human enolase, and autoantibodies to citrullinated enolase are found in strong association with RA ; therefore, this organism may drive some aspects of autoimmunity in RA.

An overall model of RA development

Based on available data it is likely that RA develops as described in Fig. 1 , where initially genetic, environmental and perhaps stochastic factors combine to initiate autoimmunity. Once an initial break in tolerance has occurred, over time, and influenced by ongoing factors that include the same or perhaps additional genetic and environmental factors, autoimmunity evolves to a more pathogenic stage. This state is manifested by expansion of autoreactive T and B cells, epitope spreading, increases in inflammation, up-regulation of signalling molecules, increases in autoantibody levels and alterations of autoantibodies pathogenicity such as changes in glycosylation rendering them more capable of inducing disease. Ultimately, tissue injury occurs to a sufficient degree that the clinical symptoms and signs of RA develop.

Notably, while most studies suggest that abnormalities of RA-related autoantibodies are highly specific for future RA, some individuals with elevations of these autoantibodies may never progress to RA. However, such individuals may still be valuable to study to learn mechanisms of development of RA-related autoimmunity, and perhaps identify key factors that are responsible for the initiation as well as propagation of autoimmunity. Furthermore, emerging data suggest that asymptomatic autoimmunity is not as benign as once thought. In particular, studies demonstrating that the presence of autoantibodies including antinuclear antibodies (ANAs) and RF is associated with CVD even in the absence of a classifiable rheumatic disease may lead to a shift in our understanding of the pathogenic role of autoimmunity in a broad range of illnesses , and we may soon classify autoimmunity as a pathogenic condition that requires intervention even in the absence of a classifiable disease.

How accurate are prediction models for future RA (and how accurate do they need to be)?

An important step in ultimately preventing RA is accurate identification of subjects who are at future risk of disease (i.e., to prevent, we must first accurately predict). Importantly, prediction includes identifying the likelihood of ever-developing disease, as well as identifying the time period in which clinically apparent disease will appear. This is because if clinical trials are developed for RA prevention, they will need to be designed around a clear understanding of the number of subjects expected to develop RA within the temporal confines of the clinical trial.

In terms of identifying the likelihood of developing future RA, elevations of combinations of ACPAs alone and in combination with RF have been shown to be highly predictive of future disease, with some estimates of 100% positive predictive values (PPVs) for future RA in case–control studies , although these PPVs are lower when the prevalence rates of disease in the general population are considered. For example, in the groundbreaking work by Rantapaa-Dahlqvist and colleagues that identified elevations of anti-CCP and RF prior to the onset of RA using samples available from a Swedish cohort study, within the case–control confines of the study, the PPV of anti-CCP and RF-IgM positivity for future RA was 100%; however, when the same sensitivity and specificity derived from this case–control study was applied to a general population where an expected prevalence of RA is ∼1%, the PPV of these autoantibodies fell to 16% . Based on this, even seemingly robust prediction models developed in case–control studies may have lesser predictive capabilities when applied to more general populations.

However, a prospective study of individuals with positivity for ACPAs and/or RF suggests that elevations of these autoantibodies are truly highly predictive of the future onset of RA. Specifically, a long-running Dutch study has used an extensive health-care network to identify and recruit ACPA- and/or RF-positive individuals with arthralgia but no clinically detectable synovitis, and then followed these subjects to investigate the natural history and mechanisms of RA development. An early publication from this project demonstrated that risk for RA is associated with being positive for both ACPA and RF, showing that up to 40% of these individuals would have developed RA within approximately 2 years, with higher rates of progression and quicker onset of disease in subjects with high-titre ACPA positivity . Furthermore, as of a publication in 2012, this project has followed up 374 individuals for several years, and combined other predictors of RA including having RA in a first degree family member, alcohol non-use, duration, severity and location of joint symptoms (including morning stiffness) and a history of swollen joints as reported by the patient ; in this model, patients with the highest risk scores had the highest incident rates of RA development (80% with RA within 60 months), and furthermore had the quickest onset of RA (60% had developed RA within 24 months). Certainly these individuals were identified through a specific clinical pathway based on medical evaluations for musculoskeletal complaints and therefore this risk prediction model may not be directly applicable to all individuals; however, the findings do suggest that elevations of RA-related autoantibodies are highly predictive of future RA.

The findings from this Dutch ‘arthralgia’ cohorts address both the likelihood and timing of RA development. Other studies have indirectly assessed this as well, with the findings that elevations of ACPAs and RF appear on average 3–5 years prior to the appearance of clinical RA, although some individuals have been noted to have elevations of autoantibodies >10 years prior to a diagnosis of RA . In addition, multiple studies have noted that higher levels of autoantibodies, and combinations of ACPAs and RFs, are most likely to be present in a 3-year window prior to a diagnosis of RA .

Several studies have also addressed the likelihood and timing of future RA more directly. In particular, Deane and colleagues used preclinical samples from military subjects who developed RA to develop a two-step approach to predicting the likelihood and timing of future RA. They initially identified that elevations of anti-CCP and/or 2 or more RF isotypes were highly specific for future RA (>95%). In the second step, they identified that within individuals who exhibited that autoantibody profile prior to a diagnosis of RA, an increased number of elevated cytokines and chemokines were associated with a shorter time to onset of RA . Solokolve and colleagues used the same military sample set further to identify that elevations of a set of specific ACPAs along with elevations of certain cytokines and chemokines had fair sensitivity (58.2%) and specificity (87.0%) for a diagnosis of RA within 2 years .

Furthermore, as some studies have suggested that a combination of genetic factors and autoantibody positivity is highly predictive of future RA , an approach that combines autoantibody tests with markers of inflammation, as well as potential inclusion of genetic and environmental risk factors and symptoms may be a reasonable approach to identify individuals at high risk of development of future RA, and also be able to determine in what time frame they will develop clinically apparent disease. Supporting this, Karlson and colleagues have developed a prediction model for future RA in the Nurses’ Health Cohort that incorporates both genetic and environmental factors to develop a predictive model for RA with an area under the curve of ∼0.7 , although it remains to be seen how this approach can identify the timing of development of future RA, and incorporate additional factors such as autoantibodies and symptoms.

In terms of designing an actionable clinical trial that will ultimately have widespread applicability, predictive models will need to balance accuracy with feasibility; therefore, models that utilize primarily biomarkers may have the most utility in the design of clinical prevention trials and ultimately to develop readily attained ‘personalized medicine’ approaches where a specific individual’s risk for the likelihood and timing of onset of a future RA can be determined in a manner similar to CVD where individuals are evaluated for risk of a CVD event within a defined period using models such as the Framingham Risk Score , and subsequently these risk factors are targeted with lifestyle modifications or pharmacologic therapy to reduce risk of future disease.

Of note, the timing of onset of clinically apparent RA goes beyond biology. It is also affected by psychosocial factors including individuals’ perceptions of what abnormal health and joint symptoms are, access to health care and the ability of initial health-care providers to establish a correct diagnosis . As such, it may be that within a clinical trial the subjects may be found to develop RA much earlier than would have otherwise been noted. This will need to be taken into account when designing clinical trials. Furthermore, what is considered to be clinically apparent RA is a difficult area. For example, there are now two established classification criteria for RA, the 1987 American College of Rheumatology (ACR) Revised criteria and the 2010 ACR/European League Against Rheumatism (EULAR) criteria . However, while these criteria have use in both clinical and research practices, subjects with a single swollen joint and ACPA positivity may well have RA but fail to meet formal classification criteria of RA. There are other classification criteria for IA such as the Leiden and Norfolk criteria , and perhaps these are important outcomes to consider in RA prevention especially as very limited IA may be highly important in natural history studies and clinical prevention trials.

Prevention of RA

Based on the above discussion, there is hope that RA-related biomarkers can be used to identify subjects who are at sufficiently high risk of future RA that they would be candidates to receive interventions to prevent disease while they are still in early phase of disease development prior to substantial joint injury. These interventions could take many forms and include risk factor modification (e.g. smoking cessation, and perhaps increased intake of fish and alcohol). Furthermore, based on numerous studies (see Table 4 ) that suggest that early pharmacologic treatment in RA leads to improved long-term outcomes, pharmacologic therapy in preclinical RA may lead to abrogation of RA-related autoimmunity and prevention of future RA. In particular, pharmacologic intervention(s) that target specific or more general aspects of the initiation and propagation of RA may halt the progression of RA. For example, if a dominant inflammatory pathway or process (i.e., a certain organism that appears to drive the initiation of RA, or a certain cytokine-driven process) could be clearly identified as important to the initiation and/or propagation of autoimmunity in preclinical RA, it could then be targeted for prevention. In addition, given the emerging data that RA may be initiated outside of the joint, perhaps preventive interventions should target the mucosal or other sites where RA may be initiated, or seek to block the transition circulating autoimmunity from initiating joint disease, if indeed that is what occurs in the pathogenesis of RA. Furthermore, prevention may be reached by induction of tolerance to antigens that are important to the initiation and propagation of RA at key time points in the natural history of RA. For example, tolerising regimens could be introduced to subjects at risk of future RA who are identified after an initial break in tolerance to citrullinated proteins but prior to substantial expansion of autoimmunity to citrullinated (or other) antigens that are crucial to a transition from preclinical autoimmunity to clinically apparent disease.

Table 4

Potential approaches to prevention of RA.

Potential approaches to prevention of RA
Approach	Examples
Risk factor modification prior to the development of autoimmunity (primary prevention)	Smoking cessation, perhaps targeted in subjects at high genetic risk for a specific ARD (e.g. family history of RA) Antimicrobial therapy targeted causative organisms (e.g. Porphyromonas ?) Risk factor modifications may be difficult to study efficacy because intervention may take years to show clinical benefit, although biomarkers of immunity and inflammation may be used as surrogate markers. Immunomodulatory therapy may used at this point in the natural history of RA may be used as well; however, targeting individuals who do not yet have biomarkers of autoimmunity would be problematic in terms of estimating risk-benefit of pharmacologic therapy.
Risk factor modification or pharmacologic intervention after the development of autoimmunity, but prior to autoimmune disease (secondary prevention)	Smoking cessation (if this is indeed a propagating factor) Immunomodulatory therapy that can abrogate autoimmunityand inflammation. To implement, requires accurate prediction of risk for future RA, and selection of agent with sufficient balance of efficacy, safety, tolerability, and subject willingness to take.
Tolerance induction in preclinical disease – may be applied at several time points in the natural history of RA	Tolerance to citrullinated proteins that may be crucial to early initiation and propagation of RA. Several tolerizing approaches to ARDs have been tested, and such approaches may be feasible in preclinical disease

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