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How does established rheumatoid arthritis develop, and are there possibilities for prevention?
Best Practice & Research Clinical Rheumatology
Established rheumatoid arthritis (RA) is a chronic state with more or less joint damage and inflammation, which persists after a phase of early arthritis. Autoimmunity is the main determinant of persistence. Although the autoimmune response is already fully developed in the phase of early arthritis, targeted treatment within the first months produces better results than delayed treatment. Prevention of established RA currently depends on the success of remission-targeted treatment of early disease. Early recognition is aided by the new criteria for RA. Further improvement may be possible by even earlier recognition and treatment in the at-risk phase. This requires the improvement of prediction models and strategies, and more intervention studies. Such interventions should also be directed at modifiable risk factors such as smoking and obesity. The incidence of RA has declined for decades in parallel with the decrease of smoking rates; however, a recent increase has occurred that is associated with obesity.
Keywords: Preclinical, Early and established rheumatoid arthritis, Undifferentiated arthritis, Prediction, Risk factors, Prevention.
The concept of “established rheumatoid arthritis” (RA) appears to be clear for the clinician. The picture arises of a patient with a “longstanding disease” that has caused a certain amount of joint and comorbid damage, and it remains in a fixed state with more or less active disease. The counterpart is the concept of “early (rheumatoid) arthritis,” a more fluid state of recent synovitis where everything is still possible, including spontaneous or induced complete remission. Although the contrasting states are clear, the transition between them is gradual and less well defined. It is reasonable to expect that causative factors for RA also influence the course of the disease, in this case the progression from early to established RA. For example, anti-citrullinated protein antibodies (ACPAs) are associated with both the risk of developing RA and the risk of a severe, unremitting course of RA.
In this chapter, we review risk factors for the development of early RA and for the transition to established RA. The concept of undifferentiated arthritis (UA) as a separate entity in a continuum from health to RA is undergoing changes due to new definitions. Finally, we focus on efforts to prevent RA from occurring (primary prevention) or from progressing from UA to RA (secondary prevention).
Apart from the uncertainty over the transitions between the different phases of RA, there is also considerable uncertainty over the question of whether RA is a modern or an ancient disease. The name RA first appears in the medical literature in 1876
Risk factors for RA development
The risk of developing RA is determined by genetic susceptibility combined with environmental factors  and . Certain environmental factors operate already early in life, and they may help to lay the foundation for autoimmunity. In a large part of those later developing seropositive RA, there is a phase of autoimmunity and subclinical inflammation, during which another transient cause of inflammation such as an infection is thought to trigger the onset of clinically apparent disease
In the following, we present a short overview of genetic and environmental risk factors for RA, with a focus on recent publications. Due to the preclinical phase that many later patients go through, biomarkers of autoimmunity and inflammation can also be used as risk factors or predictors of disease. Recently, several prediction models have been constructed using information from various cohorts of persons at risk of RA.
Genetic risk factors
Approximately 65% of RA risk has been shown to be heritable, and >100 risk loci are now known. Most of these confer a low risk, and together they explain approximately 16% of total susceptibility
A disadvantage of the GWAS method is that the implicated SNPs are not necessarily causally linked to the development of RA itself. Moreover, until now, they cannot be used for individual prediction because of their low effect sizes. Most have odds ratios (ORs) for developing ACPA-positive RA of 1.1–1.2, with a few exceptions having an individual OR of around 2.0 (e.g., locus 1p13 on the PTPN22 gene, and 6p21 on the HLA*04 genes)
Genetic risk scores
Given the many involved genes with small effect sizes, genetic risk scores (GRS) have been developed to help individual prediction of RA by adding up multiple validated genetic risk loci. In the next step, these can be combined with environmental factors in prediction models. GRS for RA usually take both the number of alleles an individual possesses and the effect size of the alleles into account. Published GRS prediction models for RA, some including environmental factors, are presented in
Prediction models for development of rheumatoid arthritis using genetic, clinical, and behavioral (smoking) data.
Genetic loci: HLADRB1 SE alleles, 11 SNPs
Clinical parameter: smoking
Genetic loci and clinical parameter: AUC 0.89 (CI: 0.86–0.95)
Genetic loci: 1 HLA allele, 29 SNPs
African ancestry: AUC 0.63 (CI: 0.56–0.70)
East Asian ancestry: AUC 0.74 (CI: 0.59–0.89)
Hispanic ancestry: AUC 0.66 (CI: 0.56–0.76)
Genetic loci: 25 HLA alleles, 31 SNPs
Clinical parameter: smoking
UKRAGG: AUC 0.76 (CI 0.72–0.79)
HLA-SNP-smoking model WTCCC: AUC 0.84 (CI: 0.81–0.87)
UKRAGG: AUC 0.86 (CI: 0.80–0.91)
Validation in CORRONA
Genetic loci: 45 SNPs, imputed amino acids at HLA-DRB1 , , and  and HLA-DPB1 (position 9) HLA-B (position 9)
Clinical parameters: gender, smoking
OR 2.0 (CI: 2.0–2.0), AUC 0.74, sens 35%, spec 91%
Genetic loci combined – CORRONA:
OR 2.0 (CI: 1.9–2.1), AUC 0.72, sens 30%, spec 92%
Addition of smoking improved the AUC to 0.80, without improving sens and spec
Validation in EIRA, Sweden
Genetic loci: 8 HLA alleles, 31 SNPs
Clinical parameters: family history, epidemiologic factors, HLA-smoking interaction
Genetic loci and clinical parameters: AUC 0.74 (CI: 0.70–0.78)
Genetic loci combined – EIRA: AUC 0.58 (CI: 0.55–0.60)
Genetic loci and clinical parameters: AUC 0.69 (CI: 0.67–0.72)
ACPA = anti-citrullinated protein antibodies, AUC = area under the receiver operating characteristic curve, CI = confidence interval (excluding 0.50 means statistically significant predictive value), CORRONA = Consortium of Rheumatology Researchers of North America registry, EHR = Electronic Health Records, EIRA = Epidemiologic Investigation of Rheumatoid Arthritis, HLA = human leukocyte antigen, NHS = Nurses׳ Health study, RA = rheumatoid arthritis, SE = shared epitope, sens = sensitivity, SNPs = single-nucleotide polymorphisms, spec = specificity, UA = undifferentiated arthritis, UK = United Kingdom, UKRAGG = RA Genetics Group Consortium UK, USA = United States of America, WTCCC = Wellcome Trust Case–Control Consortium.
In summary, these studies show ORs of different models of around 2.0, and a wide variation of area under the curves (AUC) from a low value of 0.54 to a high value of 0.89 (with the highest values also including clinical parameters). A relatively high specificity for identifying individuals at risk (75–90%) is unfortunately accompanied by a very low sensitivity (30–45%). Therefore, apart from the disadvantage of its high cost, genetic risk prediction is thus still not precise enough to be used in current clinical practice, even though more and more genetic loci are being discovered. However, a recent study shows that a GRS plus environmental factors in family members of RA patients provides enough discrimination to enable the selection of high-risk subjects for intervention studies
Environmental and behavioral factors
Environmental risk factors for development of rheumatoid arthritis.
One controversial factor was alcohol consumption, which was shown earlier to be protective, even in small quantities
More focus has been directed lately toward different dietary components and the risk of RA development. Already in 2004, a review suggested the possible role of diet, but it could not quantify the risk
Most environmental risk factors seem to be more related to seropositive than to seronegative RA. However, obesity was shown to be related mainly to seronegative RA in most publications , , and , with only one report also showing a higher risk of ACPA-positive RA in women
Besides obesity, several other comorbidities have since long been linked to the development of RA, such as diabetes mellitus and schizophrenia. Recently, two other diseases have been investigated. Sleep disorders (without sleep apnea) had an HR of 1.45,
The exact mechanism as to how systemic autoimmunity advances into local inflammation in the joints still needs to be further investigated
Finally, de Roos et al. investigated living in the proximity to traffic, ambient air pollution, and community noise. They found a higher risk of RA when living within 50 m from the highway (OR 1.37), but they could not relate this to ambient air pollution or noise
A distinction was made between traditional risk factors, meaning generally accepted risk factors before at least 4 years ago (most already presented in previous edition of Best Practice & Research), and the ones receiving more attention over the past years and generating new insights.
Gene–environment interactions and environmental factors influencing each other
A strong interaction exists between smoking and genetic background (namely HLA-DRB1 alleles)
Autoimmunity and biomarkers
Approximately two-thirds of RA patients test positive for RF and/or ACPA at diagnosis, underlying their importance in this disease. Other antibodies preceding and predicting a diagnosis of RA, independent of RF and ACPA status, are anti-carbamylated protein antibodies and anti-peptidyl arginine deiminase type 4 antibodies
Other blood-based biomarkers such as acute phase reactants or cytokines were not found to have predictive capacity for RA
Clinical prediction models
Quantifying progression to RA with genetic modeling alone is not ready for clinical use, as we have shown earlier. Several studies have taken a different approach by using a combination of clinical characteristics, symptoms, and sometimes imaging findings. The resulting prediction rules are summarized in
Clinical prediction models for development of rheumatoid arthritis.
Prediction rule variables: alcohol nonuse, family history, several symptoms, autoantibody status
Intermediate vs. low risk group: HR 4.52 (CI: 2.42–8.77)
High vs. low risk group: HR 14.86 (CI: 8.40–28)
Predictive variables: smoking, BMI
Obesity (BMI ≥25 vs. <25) and risk of RA: HR 5.6 (CI: 1.3–25)
Prediction rule variables: alcohol use, smoking, occupation, BMI, diabetes mellitus, parity
(184 developed IP, 138 developed RA)
Seropositive in men and risk of IP: HR 1.24 (CI: 1.10–1.41)
Having DM (I or II) and risk of IP: HR 2.54 (CI: 1.26–5.09)
Alcohol and risk of IP (per unit/day): HR 0.36 (CI: 0.15–0.89)
Overweight and risk of seronegative IP: HR 2.75 (CI: 1.39–5.46)
Parity ≥2 and risk of IP: HR 2.81 (CI: 1.37–5.76)
Breastfeeding and risk of IP: HR 0.66 (CI: 0.46–0.94)
Prediction rule variables: several symptoms, high-positive ACPA, positive ultrasound power
Progression to IA:
Low risk (0 points) 0%
Moderate risk (1–2 points) 31%
High risk (≥3 points) 62%
ACPA = anti-citrullinated protein antibody, AUC = area under the receiver operating characteristic curve, BMI = body mass index, CI = confidence interval, DM = diabetes mellitus, EIRA = Epidemiological Investigation of RA, HR = hazard ratio, IA = inflammatory arthritis, IP = inflammatory polyarthritis, NHS = Nurses׳ Health Study, OR = odds ratio, RA = rheumatoid arthritis, VAS = visual analog scale. Reproduced from Turk et al., 2014
Changing incidence rates and mode of presentation of RA
In 1979, it was hypothesized that RA as a disease entity would disappear eventually
More recent studies in Denmark
Another important note about changes in incidence rates over time is that the timing of the measurement and used RA criteria can vary between studies, and it also depends on the duration of the study period, mode of presentation, awareness of the disease by general practitioners, and the delay of referral after symptom onset. In the following, we describe two of these factors in more detail. First, the new ACR/European League Against Rheumatism (EULAR) 2010 criteria for RA (see subsequent discussion) are more sensitive than the earlier criteria, which will probably lead to earlier detection (and treatment) and thereby affect the measurement of incidence rates in the coming years
In conclusion, relevant trends are a steady decrease of worldwide RA incidence during the period 1955–1995, followed by a recent increase in at least Denmark and the USA, probably explained in part by changing environmental factors. Furthermore, factors such as differences in the use of RA criteria and differences in the awareness of RA across countries can affect the incidence rates over time.
UA, past and present
The term “UA” suggests that the condition in the patient concerned is in a stage of transition from an unspecified type of arthritis toward either RA, another arthritis-associated diagnosis, or spontaneous remission. The incidence of UA ranges from 41 (in Finland) to 149 (in Sweden) per 100,000 adults, and 13–54% of these patients will eventually develop RA, according to the 1987 ACR criteria
The 2010 ACR/EULAR criteria for RA aim to increase sensitivity in early disease
Just as was the case with 1987 UA patients, a part of 2010 UA patients will remit and a part will go on to have a severe disease course. In a recent study of three early arthritis cohorts, the Leiden prediction rule (developed to predict 1987 RA in 1987 UA patients) and the ACPA status failed to predict the development of 2010 RA in 2010 UA patients
When does early RA become established RA?
This question gives rise to the suggestion that there is a difference between the pathology at the beginning of the disease and what is found later on, and that this distinction has clinical significance. In fact, this is closely related to the concept of a therapeutic “window of opportunity,” which states that treatment initiated at an early stage of the disease is more successful than when it is started later on. “Early” would mean that there is joint inflammation of recent onset, which may at this stage still resolve without further consequences or at least decrease to a barely detectable minimum, if treated adequately. “Established” on the other hand would mean the inflammation is there to stay, more or less pronounced, whatever intervention is applied. Moreover, the concept of “established” RA will generally include damage to the joints, and diverse comorbidities with their complications such as osteoporosis or cardiovascular disease, which may arise as a consequence of the ongoing inflammation.
To begin with, the pathology of RA does not suddenly start around the onset of clinical arthritis. RA-specific systemic autoimmunity as well as nonspecific subclinical inflammation occurs in concert on average 5 years before the onset of symptoms  and . During the period of presymptomatic autoimmunity, there is a maturation of the immune response to citrullinated and carbamylated antigens, which is consistent with an increasing break of tolerance
The synovial infiltrate of knee joints of RA patients that had not been clinically swollen before, nevertheless, showed chronic inflammation
Although the immunological driving processes of RA do not seem to differ between early and late RA, it is well known that better clinical results can be obtained by treating RA patients early and aggressively
Primary prevention of RA
The different stages of RA development offer opportunities for preventive interventions, varying from (primary) prevention of the development of arthritis in the at-risk phase to (secondary) prevention of progression from UA to RA or from early to established RA.
The list of risk factors for RA (
The concept of primary prevention of RA with drugs has become possible through the recognition of a prolonged at-risk phase with variable symptoms and/or autoimmunity before the outbreak of clinical RA. The first clinical trial was a post hoc analysis of the effect of vitamin E in a study designed to prevent coronary heart disease in the general population
Some clinicians confronted with seropositive arthralgia patients will try antimalarial treatment. Apart from being a relatively nontoxic RA remedy, the rationale for this treatment comes from the experience with antimalarials in the treatment of palindromic rheumatism, a rather ill-defined syndrome of intermittently occurring peripheral arthritis. A subgroup of those patients is RF or ACPA positive with a tendency to develop RA
In conclusion, no intervention has yet showed an effect in a randomized controlled trial in the primary prevention of RA. The scarcity of data gives rise to the suggestion that it is not easy to perform clinical trials in the at-risk phase of RA, and that positive outcomes are not readily obtained. A major ethical issue with intervening pharmacologically in this phase is that persons are exposed to potentially toxic drugs, whereas a part of the study subjects will never develop RA.
Secondary prevention of RA
One of the explicit goals of the 2010 ACR/EULAR criteria for RA was to facilitate the performance of trials in early RA
The results of the PROMPT study of methotrexate to prevent progression of UA to RA (1987 criteria) and its long-term follow-up showed less progression to RA, but only in ACPA-positive patients and only as long as the treatment was continued
Biologics have also been tested for this indication. Three months of infliximab did not prevent progression to 1987 RA after 1 year
In conclusion, intervening in the early phase of clinical arthritis with minimal joint involvement leads to similar remission rates as are found in early RA, and there is not much evidence supporting the halting of progression from UA to RA. This suggests that it is not easy to further enhance the benefit of treating RA patients early, by treating patients with fewer involved joints even earlier in the disease course.
The broader question to what extent the transition to established RA can be prevented in patients with early RA is answered by the relative but not yet absolute success of early targeted treatment during the window of opportunity. Secondary prevention in this case could be defined as the goal of achieving and maintaining remission by early and aggressive treatment followed by minimization of therapy
Remission in different stages of rheumatoid arthritis.
The increasingly successful management of RA now leads to more patients achieving early and sustained remission, and this will lead to less patients progressing to the classical state of established RA. A next goal in the management of RA can be the improved recognition and intervention in the early or even at-risk phase of RA.
Prediction depends on the knowledge of risk factors. Recent advances in the risk factor assessment of RA include alcohol consumption as a confirmed protective factor, whereas fish consumption could not be confirmed as a protective factor. New risk factors are coffee consumption, sugar consumption, sleep disorders, and thyroid disease, whereas exercise and recent infections have been put forward as protective factors. Increasingly, risk factors are being combined to establish prediction rules. Those containing genetic risk plus environmental factors are not yet ready for general use. However, new prediction rules for arthralgia subjects using clinical characteristics, serology, and sometimes imaging are quite simple to perform, and they can be used to inform patients of their risk of RA.
Interestingly, RA incidence seems to have been declining since 1955, when formal measurements started, at least until the end of the last century. However, recent reports suggest that the incidence is on the rise again, mainly in seronegative females, and that this can be ascribed largely to the recent increase in obesity. When comparing trends in different countries, it becomes necessary to take into account the large variation between countries in the public and physician awareness of the need to identify RA early.
The problem of assessing UA has been reduced considerably by the introduction of the 2010 RA criteria. Many former UA patients can now be classified as RA, leaving a smaller group of UA patients with more heterogeneous and milder disease. Treating UA patients early gives results similar to early treatment of RA. In line with the concept of an early “window of opportunity,” a few studies have attempted to treat patients at an even earlier stage, before clinical arthritis becomes apparent. These primary prevention studies with pharmacological interventions have not yet produced positive results. Although these efforts are continued, the identification of modifiable risk factors for RA such as smoking, obesity, and lack of exercise should incite physicians to promote healthy behavior in persons at risk of RA.
- Worldwide RA incidence showed a steady decrease during the period 1955–1995, followed by a recent increase in at least Denmark and the USA.
- New possible risk factors for the development of RA are nonalcohol use, coffee consumption, sugar-sweetened soda intake, obesity, physical inactivity, sleep disorders, and thyroid disease.
- Possible options for the primary prevention of RA include dietary changes, weight reduction, and dental care. No drug intervention has proven to be effective in the prevention of RA.
- With the advent of the 2010 ACR/EULAR criteria, the subgroup of UA in early arthritis patients is strongly reduced, and it contains mainly seronegative (oligo-) arthritis patients with a mild disease course.
- Secondary prevention of RA is becoming less of an issue due to the high sensitivity of the 2010 ACR/EULAR criteria in early disease, and the tendency to treat early arthritis rapidly.
- Improve prediction models of RA by integrating personal characteristics, symptoms, and genetic information with new biomarkers.
- Establish simple prediction aids for different situations, for example, in the general practitioner (GP) office, the rheumatology clinic, or the general public.
- Controlled intervention studies in persons at risk of RA in different stages.
- Improved identification of UA with poor prognosis.
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a Amsterdam Rheumatology and Immunology Center, Reade, Doctor Jan van Breemenstraat 2, 1056 AB Amsterdam, The Netherlands
b Amsterdam Rheumatology and Immunology Center, Reade and Academic Medical Center, Amsterdam, The Netherlands
⁎ Corresponding author. Department of Rheumatology, Jan van Breemen Research, Institute/Reade, PO Box 58271, 1040 HG Amsterdam, The Netherlands. Tel.: +31 205896222; fax: +31 20 6833498.
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