Review: Preclinical Rheumatoid Arthritis: Progress Toward Prevention
Authors: Kulveer Mankia, Paul Emery
Journal: Arthritis & Rheumatology (2016)

Starting therapy early leads to better outcomes for rheumatoid arthritis (RA) patients. Early initiation of disease-modifying treatments is associated with less joint damage and increased chances of achieving remission. But what is early disease? Conventionally, this is taken to mean the initial phase after arthritis becomes clinically detectable. However, recent studies have challenged this presumption and have suggested that disease processes become established in the preclinical period, a phase often described as pre-RA. The corollary of this represents a paradigm shift; clinical arthritis is not the beginning of the disease but is, instead, the culmination of a whole series of well-established pathologic events. In this review, we provide an overview of the preclinical phases of RA, with special focus on recent advances in the field. Specifically, we will review evidence suggesting that localized autoimmunity may be an important trigger in preclinical disease, an area attracting growing research interest. Newly characterized immunologic and imaging biomarkers and their significance in prospective cohorts will also be discussed. Finally, the clinical features and management of individuals at-risk of developing RA are also described. Many important pathologic events occur before RA becomes clinically manifest. In order to standardize the terminology for the phases leading up to and including RA, the European League Against Rheumatism Standing Committee on Investigative Rheumatology devised a recommendation for nomenclature 1. Six phases of RA development were agreed upon (Figure 1). The categories are genetic and environmental risk factors for RA (phases A and B, respectively), systemic autoimmunity associated with RA (phase C), symptoms without clinical arthritis (phase D), and both undifferentiated arthritis and RA (phases E and F, respectively). The proposed categories are intended as a broad framework based on the current understanding of the etiology of RA. It is clear that individuals may not necessarily progress through all phases, and that individual phases are not mutually exclusive. Importantly, although individuals are at risk of RA, the terms preclinical RA and pre-RA should only be used retrospectively, as many at-risk individuals will never develop clinical arthritis or RA. This is especially true for individuals in phases A and B who are healthy individuals with risk factors that may never translate into pathologic processes. The 6 phases of rheumatoid arthritis (RA) development, as presented by the European League Against Rheumatism Standing Committee on Investigative Rheumatology. US = ultrasound; MRI = magnetic resonance imaging; UA = undifferentiated arthritis. Considering the various phases of the at-risk continuum, immune dysregulation (phase C) likely reflects the initial pathologic processes that occur in the development of RA. Its onset is influenced by genetic and environmental risk factors (phases A and B), but other events may be necessary to cross the threshold from risk to pathology. Recent work suggests that systemic autoimmunity may be driven by initiating events at mucosal surfaces, such as the lung, periodontium, and gut. Localized pathologic processes in the mucosae may therefore represent an additional important phase in RA development (Figure 1). Further along the at-risk continuum, another important group are those individuals with symptoms and abnormal findings on imaging, in the absence of clinical arthritis. These individuals probably sit between phases D and E in the at-risk continuum (Figure 1). The significance of both of these groups will be further discussed below. In those individuals who go on to develop RA, the presence of genetic and environmental risk factors can be considered to be the earliest phases of preclinical disease. These risk factors have been well described previously, and their detailed discussion is beyond the scope of this review. Genetic risk factors make a significant contribution; heritability is estimated to be ∼50% in those with seropositive RA, and having a first-degree relative (FDR) with RA increases an individual's risk by 3-fold 2. Genome-wide association studies have identified >100 genetic susceptibility loci associated with RA, many of which are commonly present in the general population 3. Although many of these genes lie outside the major histocompatibility complex, the HLA–DRB1 region, in particular the shared epitope (SE) alleles (HLA–SE), demonstrates the strongest association with RA. The HLA–SE alone is associated with a 3-fold increased risk of RA 4. Of the several environmental factors that have been investigated in relation to RA, the evidence implicating cigarette smoking as a risk factor remains by far the most robust. There is a striking association between smoking, the HLA–SE, and anti–citrullinated protein antibody (ACPA)–positive RA; smokers carrying 2 HLA–SE alleles have a 21-fold increased risk of developing ACPA-positive disease 5. In a putative biologic model linking these risk factors, smoking may promote the generation of novel citrullinated epitopes, which are then presented to T cells by HLA–SE alleles, resulting in ACPA production and RA. Other environmental factors, including high birth weight, obesity, and lower socioeconomic status, have also been found to be associated with a higher risk of RA. Similarly, environmental exposures, such as ultraviolet light and silica dust, have also been linked with increased RA risk. In contrast, lifestyle factors, such as longer duration of breastfeeding and moderate alcohol intake, may be protective 6, 7. It is important to recognize that the above-mentioned risk factors are present in many individuals who will never develop RA or, indeed, autoimmunity. Progression beyond this first phase in the at-risk continuum is a significant step, as it represents the translation of a theoretical risk into the first pathologic processes that may lead to RA. It is now accepted that RA-related systemic autoimmunity occurs well before clinical disease. The fact that autoantibodies can be detected prior to clinical, imaging, or histologic evidence of joint involvement 8 suggests that their origin is likely to be distant to the joints. The discovery of well-developed IgA ACPA responses in at-risk individuals and in the stored serum of RA patients obtained at the preclinical phase suggests that immune events at mucosal surfaces occur in the earliest phases of RA and may precede systemic autoimmunity 9-11. As such, events at the oral mucosa, lung, and gut in the earliest phases of RA have come under increasing scrutiny (Table 1). Patients with treatment-naive, new-onset RA had higher prevalence of PD compared to controls. In patients with new-onset RA, PD status rather than RA per se influences oral microbial diversity. Patients with PD have increased expression of citrullinated proteins and the citrullinating enzymes PAD2 and PAD4 at the oral mucosa (diseased periodontium). Patients with PD have increased levels of IgG anti-CCP antibodies in the gingival crevicular fluid compared to those without PD. A putative etiologic link between the oral mucosa and RA is largely based around 2 key observations. First, the prevalence of periodontal disease (PD) is increased in RA 12-14, and the 2 conditions share clinical and histopathologic similarities as well as genetic (HLA–DR SE) and environmental (smoking) risk factors 15, 16. Second, Porphyromonas gingivalis, a bacterium synonymous with PD, is uniquely able to modify arginine residues to citrulline by virtue of the enzyme peptidylarginine deiminase (PPAD) 17. PPAD is thought to citrullinate molecular targets not normally accessible to endogenous human PPADs. P gingivalis expresses arginine-specific gingipains, which expose C-terminal arginine residues for PPAD-mediated citrullination 18. Additionally, there is evidence that PAD autocitrullination may occur 19. In this way, novel citrullinated antigens may be generated at the oral mucosa, potentially breaking immune tolerance and initiating the ACPA response in RA. The observation that patients without RA who have PD have higher serum ACPA levels and anti–P gingivalis levels compared to those who do not have PD 20, 21 lends further support to this hypothesis. This holds true in established RA, where the association between PD and RA appears to be restricted to ACPA-positive patients 22. Localized ACPA responses at the oral mucosa have also been described; IgA anti–cyclic citrullinated peptide (anti-CCP) antibodies have been reported in the saliva of RA patients 23 and IgG anti-CCP antibodies have been reported in the gingival crevicular fluid of patients with PD 24. The long-established association between smoking and RA points toward an etiologic role of the lung 5. In ACPA-positive disease, there is evidence that smoking is associated with citrullination at the lung mucosa 25. Furthermore, shared citrullinated protein targets in the lungs and synovial joints of RA patients have been identified using mass spectrometry–based proteomics 26. These findings suggest that local citrullination at the lung mucosa, which may be promoted by smoking, could generate novel antigens, leading to a localized, and thereafter systemic, ACPA response to these targets as RA develops. Consistent with this notion, lung parenchymal abnormalities evident on high-resolution computed tomography (HRCT) are more frequently seen in ACPA-positive patients with early RA compared to their ACPA-negative counterparts, and this is independent of smoking status 27. In that study, the ACPA-positive group also had local enrichment of IgG and IgA ACPAs in the bronchoalveolar lavage fluid. Structural and immunologic abnormalities have also been reported in the lungs of individuals at-risk for RA 28-30. At-risk individuals without arthritis who were seropositive for ACPAs were found to have a similar prevalence of airway abnormalities on HRCT when compared to matched RA patients 28, and rheumatoid-type lung disease was found in seropositive individuals who later progressed to develop RA 30. Similar to PD, the presence of lung mucosal abnormalities in seropositive individuals raises the possibility that the mucosae could simply precede the joints as a downstream target, rather than providing the initial trigger for autoimmunity. However, some at-risk individuals who are seronegative for autoantibodies have evidence of well-established localized autoimmunity at the lung mucosa 29; the discovery of RA-related autoantibodies in the sputum of these patients supports the role of the lung as a potential initiating site of RA autoimmunity. Rather than promoting mucosal citrullination, the involvement of the gut in the pathogenesis of RA may be related to the influence of its colonizing bacteria on localized gut immune cell responses. Animal studies have shown that the gut microbiome, which refers to the totality of ecologic bacterial communities (symbiotic, commensal, and pathogenic) populating the gut and their genes 31, plays a crucial role in shaping the immune system. Specifically, there is evidence that gut bacteria influence the balance between local pro- and antiinflammatory T cell subsets, thus helping to preserve normal gut immune homeostasis 32-35. As the gut microbiome is altered in many diseases, it is conceivable that this dysbiosis may play a pathogenic role by disrupting local immune homeostasis. Altering the local T cell balance in this way may lead to systemic autoimmunity. Indeed, several studies have demonstrated that gut dysbiosis occurs in RA 36-39 and that specific bacteria, including Lactobacillus 36 and Prevotella copri 37, are more abundant in new, untreated RA patients. What remains to be established is whether gut dysbiosis occurs as a consequence of the systemic inflammatory environment in early RA, or whether dysbiosis itself is the primary trigger for autoimmunity in some individuals. The answer should lie in the prospective study of at-risk cohorts. In any case, the variable link with citrullination at different mucosal sites is interesting, and suggests that different sites may be important in ACPA-positive compared to ACPA-negative individuals. Systemic autoimmunity, possibly triggered at mucosal surfaces, is well developed in the preclinical phase of RA. Most of our knowledge in this area has come from the retrospective examination of stored blood samples from RA patients. These studies, which have been comprehensively reviewed elsewhere 40, have shown that ACPAs and rheumatoid factor (RF) can be found in the serum years before the onset of clinical disease 41, 42. Although the time course of preclinical seropositivity for ACPAs and RF has varied in different cohorts, there is consistent evidence of maturation of the ACPA response as clinical RA approaches 43, 44. In other words, the number of autoantibodies to different citrullinated targets increases in the run-up to clinical disease, an observation likely to be explained by epitope spreading. This increase in ACPA fine specificity is associated with an increase in the serum levels of cytokines and chemokines, suggesting that RA-related inflammation also begins preclinically 43. Prospective studies have corroborated these findings, both in seropositive patients with arthralgia 45 and in FDRs of patients with RA 46. Furthermore, an expanded ACPA repertoire is associated with higher anti-CCP levels and dual seropositivity (ACPAs and RF) and is predictive of arthritis development 45. Is screening for RA-related autoantibodies clinically useful? In a Dutch cohort, despite 40% of RA patients having tested positive for anti-CCP in blood samples obtained prior to the diagnosis of RA, a positive anti-CCP result gave a 5-year positive predictive value (PPV) for RA development of only 5% in the general population 41. Thus, autoantibodies alone do not appear to have enough predictive power to effectively distinguish high-risk individuals from the background population. However, in those with genetic risk factors, the additional presence of RA-related autoantibodies appears to add significant predictive power; in a recent prospective study of healthy relatives of RA patients, anti-CCP positivity was associated with a 5-year PPV of 61%, compared to 0.4% in anti-CCP–negative subjects 47. Likewise, seropositive individuals with joint symptoms appear to have a markedly higher risk of arthritis development 48-50, with absolute risks of up to 50% at 12 months. These studies are not directly comparable, but the striking gains in predictive ability highlight the value of combining autoantibodies with other variables in order to achieve clinically useful risk stratification. Autoantibodies against carbamylated proteins (anti-CarP) have recently been described in RA patients 51. Although homocitrulline, the product of carbamylation, shares structural similarities with citrulline, the role of anti-CarP antibodies in RA pathogenesis is unclear. As with ACPAs, anti-CarP antibodies have been identified in at-risk individuals prior to RA development, both retrospectively in stored serum 52 and in a prospective cohort 53. Shi et al found anti-CarP antibodies in 39% of their cohort of seropositive patients with arthralgia, compared to 6% of controls 53. Anti-CarP antibody–positive patients were more likely to progress to the development of RA, and to do so within a shorter timeframe. Interestingly, although anti-CarP antibodies were associated with anti-CCP antibodies, the positive association between anti-CarP antibodies and RA remained significant in the anti-CCP antibody–positive subgroup, suggesting that anti-CarP antibody is predictive of RA independent of ACPA status. Furthermore, in a retrospective analysis by Gan et al (52), it was reported that RA patients had anti-CarP antibodies detectable 4 years before diagnosis, compared to 10 years for ACPAs. The presence of anti-CarP antibodies had a lower sensitivity (<30%) than did ACPAs and RF, but a comparatively high specificity (>95%), for the future development of RA. Importantly, the potential usefulness of anti-CarP antibody as a predictive biomarker was less convincing in the study by Gan et al. No seronegative patients were anti-CarP antibody positive, and it did not add predictive power to the biomarker of seropositivity for ACPAs and/or RF. Further studies in different cohorts will be needed to validate these findings and improve our understanding of the etiologic role and predictive power of these autoantibodies in RA development. In addition to the presence of autoantibodies, the immune dysregulation that underpins evolving RA may be characterized by other molecular biomarkers. In an explorative study, investigation of gene expression profiles by DNA microarray analysis showed increased expression of genes involved in interferon (IFN)–mediated immunity and cytokine/chemokine activity in seropositive patients with arthralgia compared to controls 54. Furthermore, there was heterogeneity among at-risk patients with arthralgia, with individuals expressing gene signatures associated with type I IFN–mediated immunity and/or cytokine and chemokine–mediated immunity at higher risk of progression to arthritis, independent of ACPA status. The strength of this association was impressive, with logistic regression analysis revealing an odds ratio (OR) of 21 for arthritis development within 12 months. Conversely, genes involved in B cell–mediated immunity were associated with protection against arthritis development. The association between the type I IFN signature and arthritis development has been validated in 2 other cohorts 55. In that study, expression levels of 7 type I IFN response genes were determined, and at-risk individuals were stratified into IFN-high or IFN-low groups based on the findings. An IFN-high signature was predictive of arthritis development within a 2-year follow-up period, and this was independent of autoantibody status. Of note, the combination of ACPAs/RF and IFN-high score was more predictive of arthritis development than was ACPAs/RF alone, suggesting that this biomarker could add value in a predictive model. There is recent evidence to indicate that stratifying the B cell signature in this way (B cell–high versus B cell–low) is similarly predictive, with a B cell–high signature associated with protection against arthritis development 56. Interestingly, combining the IFN and B cell signatures can identify IFN-high/B cell–low individuals who appear at higher risk of arthritis development than those with IFN-high signatures alone. Most rheumatologists would recognize that some RA patients present with symptoms before clinical arthritis is detectable. Recent qualitative research confirms anecdotal experience; a wide range of symptoms are described by patients prior to arthritis development, including pain, stiffness, fatigue, and muscle weakness 57. In addition, burning sensations as well as warmth and redness of the skin were also described by seropositive patients with arthralgia and recounted by RA patients who stated that these features preceded joint swelling and increased in intensity as the disease developed. Symptoms are an important starting point for risk prediction, as this is usually why patients first present. It is therefore useful to know if a particular symptom complex can identify those at higher risk of progression to arthritis, over and above laboratory biomarkers such as serology. Evidence from Dutch and UK cohorts indicates that symptoms add significant predictive power in seropositive individuals 48-50. Bos et al found that 20% of their cohort of ACPA and/or RF–positive patients with arthralgia of any form experienced progression to arthritis after a median follow-up of 28 months 48. Interestingly, of the subgroup with symmetric small joint pain and morning stiffness, 60% progressed to arthritis development, although the absolute numbers of patients were small. When formal risk stratification was later applied to this cohort 49, clinical features, such as symptom duration, intermittent symptoms, symptoms in both the upper and lower extremities, early morning stiffness of ≥1 hour, and self-reported joint swelling, were all found to be independently predictive of progression and were incorporated into their risk-scoring tool. Such scoring allowed high-risk individuals (43% experiencing progression to arthritis at 1 year) to be differentiated from those at intermediate risk and those at low risk (17% and 3% experiencing progression to arthritis at 1 year, respectively). Similarly, in the Leeds cohort, small joint tenderness and early morning stiffness of ≥30 minutes were associated with an increased risk of progression to arthritis. However, other symptoms included in the Dutch model (e.g., symptom duration, intermittent symptoms, symptoms in both the upper and lower extremities) were not found to be predictive. Differences between the baseline characteristics of the cohorts may be one explanation for the discrepancy, as the Leeds cohort appeared to be better enriched for those with imminent RA, since subjects had a 50% rate of progression to arthritis at a median of 8 months, and all were anti-CCP positive 50. While these prospective studies highlight the discriminative ability of symptoms in seropositive individuals, it is important to recognize that in clinical practice, serologic findings are not always known when patients first present. Furthermore, it is important to identify seronegative patients in the preclinical phase. For these reasons, inception cohorts of subjects with "clinically suspect arthralgia" are now being studied prospectively 58. However, whether presenting symptoms alone are specific enough to effectively stratify patients according to the level of risk remains to be determined. It is conceivable that some at-risk individuals, such as those with arthralgia without clinical arthritis, may already have established inflammatory processes in the joints. Although the maturation of these processes results in soft tissue swelling that is palpable as synovitis, imaging techniques may be sensitive enough to identify these evolving inflammatory changes in the subclinical phase. The value of ultrasound (US) as a biomarker in pre-RA has been assessed both in Dutch cohorts 59 and in UK cohorts 50 of seropositive patients with arthralgia. Van de Stadt et al 59 found that abnormalities detected on US imaging (joint effusion, synovitis on gray-scale and power Doppler) were predictive of arthritis development at the joint level but not at the patient level. The combination of gray-scale synovitis and power Doppler abnormalities was the strongest predictor of arthritis (OR 12.9 and PPV 35%). In contrast, in the Leeds cohort, power Doppler signal was independently predictive of arthritis development at the patient level 50. Differences in the US data sets collected may be one reason for the discrepancy between these studies. A prespecified set of 22 hand and wrist joints was imaged in the Leeds study, whereas van de Stadt et al scanned only tender or painful joints, including directly adjacent and contralateral joints only if the symptomatic region was in the fingers or metatarsophalangeal joints (median 8 joints). In this way, asymptomatic joints with US abnormalities may have been missed. Moreover, in the Dutch study, some joints with US abnormalities did not develop arthritis during the follow-up period, raising questions about the specificity of these features as predictive biomarkers on an individual patient level. The significance of this apparent false-positive finding could be overestimated due to the relatively short follow-up period in the Dutch study (median follow-up 11 months), and some patients may well have gone on to develop arthritis in the future. However, given these reservations, one pragmatic strategy to enhance the predictive ability of US findings is to combine it with other relevant biomarkers, as will be discussed below. Magnetic resonance imaging (MRI) biomarkers have also been investigated in autoantibody-positive individuals at risk of arthritis development. In one prospective cohort, no MRI evidence of synovial inflammation was found in the knee joints of seropositive, at-risk individuals 8, 60. However, imaging of the small joints of the hands and feet has yielded different results. Krabben et al 61 showed that inflammation, as measured by a combined synovitis and bone marrow edema score, was present in the painful small joints of ACPA-positive patients with arthralgia. Although the cohort was too small to determine whether MRI-detected abnormalities could be predictive of arthritis development, the authors reported that MRI inflammation scores were greater in the wrists of ACPA-positive patients with arthralgia compared to age-matched, pain-free healthy controls. Similar trends were found in the metacarpophalangeal, proximal interphalangeal, and metatarsophalangeal joints, but differences were not significant in comparison to the background inflammatory changes in the control group. Similarly high sensitivities have been reported in a recent small study by Gent et al 62, who found MRI evidence of abnormalities in the hand small joints of 93% of ACPA-positive patients with arthralgia, although bone marrow edema was present in only 11%. Of note, all healthy controls had MRI evidence of synovitis, and higher MRI scores were seen with increasing age in both groups, suggesting that degenerative changes may be contributory. MRI-detected inflammation has also been described in seronegative patients with arthralgia 63. In the largest MRI study published to date, significant inflammation shown by MRI (over and above the healthy control score) was found in 44% of 93 patients with clinically suspect arthralgia 58. However, no significant correlation with symptoms or other clinical characteristics was found, and MRI biomarkers were unable to differentiate those patients who progressed to arthritis development. Thus, MRI appears to be a highly sensitive tool to identify inflammation in at-risk individuals, but there are questions with regard to its specificity. MRI evidence of synovitis is often seen in healthy persons, and this may be related to degenerative change. For this reason, perhaps symptomatic, rather than pain-free, matched controls may be more appropriate comparators in future pre-RA studies. Other imaging modalities appear to identify joint abnormalities with higher specificity in seropositive patients with arthralgia. An exploratory study showed that macrophage positron emission tomography could discriminate at-risk individuals from controls and could identify with high specificity those who would progress to arthritis development 64. However, the sensitivity of this modality has not been compared to MRI and US, and there are obvious concerns about the radiation dose and cost of serial imaging. Should a seropositive patient with arthralgia who is found to have synovitis on US or MRI be treated as a patient with inflammatory arthritis? When faced with such patients, the pragmatic clinician may argue that imaging identifies subclinical synovitis that clinical examination misses, and that imaging synovitis may therefore be used to confirm a suspected case of clinical arthritis. However, as highlighted above, the significance of imaging abnormalities in at-risk individuals who have not developed clinical synovitis are not clear; it is unlikely that all of these individuals will go on to develop clinical arthritis. Furthermore, whether and how an individual's imaging phenotype changes when arthralgia progresses to arthritis has not yet been addressed in prospective cohorts. For these reasons, we would argue that at-risk patients with arthralgia who have demonstrated imaging abnormalities form an important part of the at-risk continuum and should be considered as a population distinct from patients who have clinical arthritis. Given the demonstrated ability of autoantibodies and other biomarkers to be predictive of arthritis development, it is logical that combinations of these biomarkers may improve predictive power further. To this end, risk stratification tools have been developed to identify those with the highest risk of progression, a subgroup in whom the risk:benefit ratios may favor potential preventive interventions. Thus far, risk-scoring tools have been developed in 2 cohorts of seropositive patients with arthralgia. In the first cohort, combining clinical features and serologic findings to yield a 13-point score enabled identification of a high-risk group of individuals, of whom 63% progressed to arthritis development within 2 years 49. In the Leeds anti-CCP–positive cohort, clinical features and serologic findings were combined with US power Doppler signal in a model able to identify a high-risk group of individuals, of whom 72% progressed to arthritis development within 2 years 50. Incorporating other markers of immune dysfunction may also prove useful. As discussed above, novel autoantibodies 53 and immune gene signatures 55, 56 have independent predictive ability and may improve risk stratification further. The goal of management in at-risk individuals is to prevent these subjects from following their natural trajectory toward clinical disease, in this case, RA. By better characterizing at-risk individuals and quantifying their risk of progression to disease, preventive intervention in RA has become feasible. When considering how best to intervene in individuals at high risk of RA, 2 broad strategies could be employed. First, one may address potentially modifiable risk factors that could increase an individual's risk of progression to disease. For example, smoking status and body mass index have been shown to influence arthritis risk in a cohort of seropositive patients with arthralgia 65, implying that lifestyle adjustment could prevent disease in some at-risk patients. Considering mucosal autoimmunity in this way, treatment of PD and mucosal dysbiosis may also alter disease risk. In RA patients, treatment of PD has been shown to improve disease severity 66, and oral and gut dysbiosis appears to improve following treatment with disease-modifying antirheumatic drugs 39. Whether similar success is achievable in preclinical disease remains to be seen and is certainly an exciting area for future research. The second preventive strategy is to move forward the therapeutic window for established RA therapy. Accepting that the systemic immune dysregulation present in patients with RA is also seen preclinically, it is logical that the immunomodulatory treatments that deliver remission in early arthritis could also be effective in at-risk individuals. Although a glucocorticoid trial in one group of seropositive patients with arthralgia was ineffective 67, larger multicenter randomized, controlled trials assessing the ability of abatacept (the APPIPRA study; International Standard Randomised Controlled Trials Number 46017566) and rituximab (the PRAIRI study; Nederlands Trail Register no. 2442) to prevent arthritis development in this population are now under way. There is now clear evidence to support the notion that immune dysregulation and inflammation occur preclinically in RA. The translation of genetic and environmental risk into these pathologic processes may first occur at mucosal surfaces, far distant to the synovial joints that bear the brunt of established rheumatoid disease. Prospective cohorts of at-risk individuals are now providing valuable insights into the various phases of preclinical disease. In this way, the predictive abilities of clinical, genetic, immunologic, and imaging biomarkers may be assessed and, indeed, combined to enable us to identify those at highest risk of progressing to clinical disease. To intervene and change the course of disease development in these individuals is now a realistic goal. Authors Mankia and Emery drafted the article, revised it critically for important intellectual content, and approved the final version to be published.