In recent years, the outcomes for rheumatoid arthritis (RA) have improved dramatically, thanks to the availability of biologic disease-modifying antirheumatic drugs (bDMARDs) and treat-to-target strategies.1 Further, earlier initiation of disease-modifying therapies results in better and tighter control of disease, since prompt treatment initiation induces a deeper modulation of a less mature and more reversible inflammatory process.1 In considering the natural disease history indicating that RA develops through a series of stages, the preclinical phase is being increasingly recognized, in which genetic and environmental factors may interact in driving the break of immune tolerance; this break can be identified by the presence of blood autoantibodies.2 Thus, a population of high-risk individuals is becoming more and more delineated, thereby providing the unique opportunity to modify the inflammatory process before the development of a chronic disease. In this new context of prevention in the preclinical stage, as well as with the increasing use of predictive medicine (genetic and epigenetic), the attention of physicians may be driven to focus on modifiable risk factors through more prospective studies, taking into account the relevant exposome effects that can be further modified by lifestyle behavior. This may lead to even more timely diagnoses of up to several years earlier.3,4
A growing body of evidence has been increasingly focused on the possibility of reducing the progression from the preclinical phase to established RA.3,4 In fact, some therapeutic interventions have been proposed in clinical trials to delay or decrease the evolution toward RA, including in individuals at high risk of progression.5-7 However, the promising results of these studies could be hampered by some methodological issues, including the lack of precise disease-defined nosology, wherein there are missing standardized endpoints in these high-risk individuals, and the observed waning of the intervention effect within the relatively short-term follow-up period. In this context, the recently published Abatacept Reversing Subclinical Inflammation as Measured by Magnetic Resonance Imaging (MRI) in Anticitrullinated Protein Antibodies (ACPA) Positive Arthralgia (ARIAA) and Arthritis Prevention in the Pre-Clinical Phase of RA With Abatacept (APIPPRA) trials have provided further relevant novel insights in the clinical management of individuals at high risk for RA with abatacept (ABA).8,9
ABA is a bDMARD that binds CD80 and CD86 on antigen-presenting cells and blocks the interaction with CD28 on T lymphocytes, initiating a costimulatory signal needed for the full activation of T lymphocytes. ARIAA included a population at high risk for RA; the enrolled participants were positive for ACPAs, had joint pain but no swelling, and had MRIs suggestive of tenosynovitis, synovitis, or osteitis.8 Similarly, APIPPRA enrolled individuals at high risk for RA, including participants (1) with the presence of inflammatory joint pain with no swelling, and (2) testing positive for ACPA and rheumatoid factor (RF) or testing negative for RF but with ACPA concentrations ≥ 3 times the upper normal limit. In both studies, ABA significantly reduced the progression to RA, and the benefit seemed to persist for the 12 months following drug discontinuation.8,9
During the treatment phase, improvement in pain scores, functional well-being, and quality-of-life measurements were also observed in both trials, along with lower scores of subclinical synovitis, as assessed by MRI or ultrasound (US).8,9 Therefore, early intervention with a modulator of T cell costimulation seems to interfere with the progression from preclinical to established RA. However, it must be also pointed out that reduced rates of progression in RA development should be cautiously interpreted and viewed as a preventive strategy. In fact, the overall prevalence rate of established RA should be considered a long-term outcome that is not fully suitable in the assessment of individuals at high risk for RA in a relatively short follow-up period. In addition, although these trials represent the most optimistic data available in the context of preclinical RA, the reduced rates of progression to RA gradually decreased in the observation period.8,9 Thus, a longer follow-up is surely needed to completely assess if these clinical differences can persist in terms of prevention, or alternatively remission, thereby representing an interception (and treatment) of very early disease.
Another relevant point is the measure of outcome. The most accurate and appropriate method to measure the treatment efficacy in individuals with arthralgia has yet to be established. In both the ARIAA and APIPPRA trials,8,9 pain—as measured by the number of tender joints—was considered a valuable outcome of efficacy despite its multifactorial nature in RA, and included pain from extrainflammatory causes leading to peripheral and central sensitization.10 It is still unclear whether subclinical synovitis, as detected by MRI and ultrasound, should be used as a treatment target and outcome measure for people at high risk of developing RA. When assessing synovitis, tenosynovitis, or osteitis by imaging, it is worth considering that even if one of these conditions improves, it is still possible for the other conditions to worsen at subsequent follow-up imaging. In this context, the clinical trials investigating MRI and US did not find additional benefits from their use in conventional treat-to-target strategies.11-13 In early RA, an imaging-driven treat-to-target strategy led to more intensive treatment, but it was not associated with significantly better clinical or imaging outcomes than a clinically based disease activity–driven strategy.11-13
A separate ongoing clinical trial (ClinicalTrials.gov: NCT04909801) does not appear to confirm the findings of ARIAA and APIPPRA trials, thus suggesting the need for further works to entirely clarify these clinical issues as well as to determine the most accurate methodology for future study designs that specifically include individuals at high risk of developing RA. Specific efforts are required to establish the most appropriate clinical approach for their management, starting with properly identifying these individuals, as well as determining the best treatment options and measures of outcome over time.
Although ABA was confirmed to be a safe therapeutic option,8,9 its safety profile could have been associated with possible overtreatment. Despite being at high risk, these individuals with preclinical RA may not invariably progress toward established RA, as observed in a substantial percentage of patients randomized to receive placebo.8,9 In fact, the treatment of arthralgia in individuals at high risk of developing RA is a controversial issue. Many ACPA-positive individuals experience arthralgia without having clinical arthritis, but only a proportion will develop RA.14,15 As there is a lack of specific biomarkers to distinguish individuals who are most likely to benefit by the preventive use of drugs, the administration of any drug should be carefully evaluated after an accurate balancing of the risk-benefit ratio.
In evaluating the characteristics of participants in the ARIAA and APIPPRA trials, a substantial percentage were smokers.8,9 The amount and duration of smoking is an important feature in the development of RA16; the highest risk is observed with the highest exposure, whereas risk declines slowly back to normal with cessation.17 Smoking effects are not only toxin-dependent but may also arise by immunologic alterations in airways, promoting protein citrullination and epigenetic alterations.16,18 It may be suggested that in individuals at high risk of developing RA, lifestyle behavior corrections should be implemented at the earliest possible time, avoiding the effects of key environmental factors such as smoking and other lifestyle behaviors.19 In fact, in parallel, the role of air pollutants, including airborne particulate matter (PM) of 2.5 and 10 μm (PM2.5 and PM10, respectively), have been increasingly recognized to enhance the risk of RA development by promoting inflammation and increasing protein citrullination, oxidative stress, and immune dysregulation.20 Public policy measures and targeted preventive and therapeutic interventions are also needed to reduce the effect of pollution on RA in healthy and at-risk RA individuals, at least in certain workplaces.20
In APIPPRA participants, alcohol consumption was also recorded.9 Although moderate alcohol consumption appears to decrease the rate of RA development,14 no reliable safe threshold has been identified in high-risk individuals. In fact, the effects of alcohol consumption in altering the composition of oral and gut microbiomes could favor RA development, since this is another possible mucosal site where a loss of tolerance against self-antigens and citrullination may occur.18
Of note, dietary pattern and obesity may be further potential modifiable factors for reducing disease risk in the context of RA.21,22 In a large population-based case-control study, the Mediterranean diet score—based on a dietary pattern associated with high levels of antioxidants and antiinflammatory properties—was shown to be inversely associated with RA risk in ACPA-positive men.23 Further, findings from large population-based prospective cohorts reported that higher body fat percentage, higher waist circumference, and obesity could be associated with a higher risk of RA development, especially in women.24 Therefore, the role of a healthy lifestyle, which includes smoking and alcohol cessation, favoring an antiinflammatory dietary pattern, physical activity, and maintaining a normal body weight, needs to be more accurately investigated to evaluate its potential impact on the risk of RA development (Figure).
Our proposal is to act on modifiable risk factors by helping patients make healthier lifestyle choices, as well as by using predictive medicine in the analyses of (1) microbial DNA and (2) human DNA involved in RA to unveil genetic and epigenetic alterations in familial cases of RA.
Thus, taking together these observations, we advocate for future clinical preventive trials that control modifiable risk factors, either as the primary or secondary interventions, to manage individuals at high risk of RA. In fact, an integrated clinical nonpharmacological strategy to correct environmental RA risk factors could be safer than any drug administration, avoiding exposure to possible iatrogenic adverse events as well as unnecessary expenditures.
We would also like to emphasize the importance of genetic and epigenetic changes, as identified through a panel of gene alterations associated with RA (Figure),3,4 at least in families in which cases have been already observed in first- or second-degree relatives. The possibility of using a polygenic risk score, as indicated by Ruscitti et al,4 may help to distinguish among different types of arthritis based on patient genetics.
Finally, one-third of ARIAA participants showed RA familial history in first-degree relatives.8 The precise interplay between genetic and environmental risk factors and how this interaction leads to RA development have not yet been elucidated, and this point may suggest the idea of implementing prevention strategies in predisposed individuals.3,4,19
All the observations mentioned up to this point indicate that more tailored disease management is being increasingly advocated for, pointing toward an era of precision medicine both in individuals at high risk for RA as well as in patients with RA.3,4,25
In conclusion, more data are needed regarding the clinical profile of individuals at high risk of developing RA, as well as for which features of this preclinical condition may represent potential treatment targets. Further, it is urgent to establish whether high-risk individuals represent a very early phenotype of RA that should be appropriately treated. Moreover, before devising clinical trials using drugs, researchers should first design studies in which an integrated clinical approach is used to correct modifiable risk factors. Importantly, genetic and epigenetic analyses should be conducted specifically in individuals with a family history of RA, as they are at higher risk. All these suggestions are safe, widely available, and readily transferable to clinical practice under a wide array of circumstances.
Footnotes
CONTRIBUTIONS
FC: conceptualization, acquisition and interpretation of data, supervision, validation, visualization, and writing – original draft. RG: conceptualization, acquisition and interpretation of data, supervision, validation, visualization, writing – original draft, writing – review and editing. MN: writing – review and editing, visualization, resources. FDM: writing – review and editing, visualization, and resources. RS contributed to conceptualization, acquisition and interpretation of data, supervision, validation, visualization, writing – review and editing. PR: conceptualization, acquisition and interpretation of data, supervision, validation, visualization, writing – original draft, writing – review and editing. FS: conceptualization, acquisition and interpretation of data, supervision, validation, visualization, and writing – review and editing. All authors made substantial contributions to the conception or design of the work, and the acquisition and interpretation of data. All authors contributed to the critical review and revision of the manuscript and approved the final version. All the authors agreed to be accountable for all aspects of the work.
FUNDING
The authors declare no funding or support for this article.
COMPETING INTERESTS
The authors declare no conflicts of interest relevant to this article.
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