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When confronted with very early arthritis, the objective, after having excluded spondylarthritis (SpA), connective tissue disease, and a viral or microcrystal arthropathy, is to determine as rapidly as possible whether erosion(s) will develop, and if so, when and how severe. When persistent and erosive, these symptoms and signs are classically called rheumatoid arthritis (RA), which is the most frequent severe chronic inflammatory arthritis, often responsible for severe disability and deterioration of quality of life (1).
It is currently thought that to control disease activity and slow or even stop the progression of structural joint involvement, disease-modifying antirheumatic drugs (DMARDs) must be started very early (2–5). Under such treatment, prolonged benefit was obtained, particularly in preventing structural joint damage (6, 7). Several therapeutic modalities have proven efficacy: notably, the combinations of DMARDs and systemic glucocorticoids (6, 8), and more recently, biologics alone or combined with methotrexate (9–11). However, all of these treatments have side effects, sometimes severe, and the biotherapies are very expensive. Therefore, for very early arthritis, it is important to identify rapidly the factors predictive of erosion(s), thereby assuring that aggressive therapy is given only to patients requiring it, with milder treatments being prescribed to patients whose signs are considered benign, i.e., with no erosions and therefore no severe functional joint damage.
Few studies have attempted to identify factors predictive of erosion(s) in patients with early arthritis (12, 13). The authors of the Leiden study (12) constructed a model that discriminated well between patients with persistent arthritis and ≥1 erosion(s) and those with no erosions at 2 years of followup. To the best of our knowledge, no study has evaluated the value of bone and/or cartilage markers to predict erosion(s) in very early arthritis.
This study was conducted on the very early arthritis inception cohort recruited from the general population, comprised of patients with recent-onset inflammatory arthritis, untreated before inclusion, then followed and conservatively treated for 2 years. Its objectives were to identify baseline factors predictive of ≥1 erosion(s) at 2 years and to attempt to construct a simple to use prediction model for routine practice.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
The primary objective of this study was to test the ability of baseline clinical and laboratory parameters, including numerous autoantibodies and cartilage and bone markers, to predict ≥1 unequivocal erosion(s) at 2 years in patients with very early arthritis recruited for an inception community-based cohort.
Taking these factors into account makes it possible to adapt initial treatment, which markedly influences structural joint outcome (6, 7). Based on recruitment methods, this study population was representative of very early arthritis seen in the primary care setting in Northwestern France. Patients with severe disease were not excluded because short-term glucocorticoid use was tolerated for highly active disease, if necessary, and because the arthritis onset inclusion interval was very short. Therefore, all but a few patients had never taken glucocorticoids and none had ever taken DMARDs, to avoid any impact on certain initial parameters. All of the patients were subsequently treated homogeneously in a nonaggressive manner, in accordance with protocol recommendations and the therapeutic approach practiced in France at the time the protocol was written. Therefore, none of the cohort patients received a biotherapy during the first 6 months of followup and only 1.8% diagnosed with RA were administered a biologic agent during the first year.
In our experience, monarticular arthritis does not pose the same diagnostic difficulties as oligo- or polyarthritis and was excluded a priori; its progression toward chronic arthritis, such as RA, is unusual (12). We selected 2 years of followup because it represents the minimal time required to draw any conclusion about the likelihood of erosion occurrence (18, 19).
When this article was written, it was routine practice to initiate very early a systemic DMARD/glucocorticoid regimen for early active RA, considering that disease activity would be better controlled in the short term and long-lasting structural joint benefit would be obtained (6, 7, 20). Early strong inhibition of active RA, using prednisone combined with DMARD(s) or a TNFα blocker and methotrexate, has been advocated to capitalize on therapeutic impact during this critical period (5, 6, 10). However, that approach is probably not adapted to all RA and, a fortiori, to all very early arthritides, as long as we do not know whether or not erosions will develop. Therefore, to avoid overtreatment of patients not requiring such intensive therapy, it has become essential to identify markers predictive of that structural joint damage (21). Therefore, 69% of our patients diagnosed with RA and 89% of those with UA had no erosions at 2 years of followup. This finding seems even more pertinent because it was obtained for conservatively treated patients, i.e., in a setting closer to the natural history of very early arthritis. Considering the RA subgroup, the erosion frequency was lower than that usually observed in RA cohorts (19), probably reflecting our population-based recruitment.
Numerous clinical and biologic parameters were assessed as predictors for erosion(s) at 2 years, along with a panel of autoantibodies, some of which had not been tested previously in this context, i.e., serum bone and cartilage markers, genetic traits, and bone mineral density of the hands.
Many investigators have attempted to identify markers predictive of structural joint damage in RA, but only a few involved early arthritis (19, 22–29). In RA, predictive factors retained by multivariate analyses varied from one study to another. Our judgment criterion differed from those used previously, e.g., progression of either radiologic severity and/or structural joint involvement, which are prognostic and not diagnostic criteria. RF, in conjunction with initial radiologic involvement, was the early factor most frequently identified. An elevated CRP concentration is usually predictive (24, 27, 29), even more often than the initial ESR (23). Even so, no isolated criterion or composite index is able to predict, at disease onset, the severity or progression of structural joint involvement in a given RA patient (12).
Few cohort studies were devoted to structural joint involvement in patients with early arthritis recruited prospectively. Compilers of the Norfolk Arthritis Register wondered if it is indeed possible to predict the transformation of UA into RA (13). The inclusion criteria and recruitment modalities that we used are close to those applied for that Register. However, because initial radiographs were lacking, the analyses of that English cohort were based on factors associated with the severity of structural joint involvement, i.e., a prognostic criterion, not the presence of ≥1 erosion(s) at 2 years. Visser et al constructed a model for persistent erosive arthritis at 2 years (12). Some of their inclusion criteria differed from ours: monarticular arthritides were accepted and the joint symptoms could have lasted for as long as 2 years. Despite these differences, the baseline erosive arthritis rate for their cohort was comparable (15% versus 17% for ours). The Leiden model consisted of 7 variables: symptom duration, morning stiffness lasting ≥1 hour, arthritis affecting >3 joints, squeeze test, RF positivity, anti–CPP-1 positivity, and erosions. However, their model applied to our cohort, replacing the squeeze test by ≥1 painful metatarsophalangeal joint, was inoperative, whether all of the patients or only those whose arthritis persisted at 2 years were considered (data not shown). Their model's inefficacy is probably attributable to the different inclusion criteria used (e.g., exclusion of monarticular arthritis from our cohort), but also to the different therapeutic modalities prescribed to the 2 cohorts. In addition, our sole objective was to identify factors predictive of erosion(s), not arthritis persistence, at 2 years.
Based on the characteristics of our conservatively treated, community-based cohort, our multivariate analysis was able to identify a strong association between 2 independent variables, serum IgA-RF and pyridinoline concentrations, and ≥1 unequivocal erosion(s) at 2 years. Consequently, we were able to construct a simple model using 2 readily available parameters: ELISA-determined IgA-RF level and serum pyridinoline concentration. IgA-RF can be replaced by ELISA-determined IgM-RF or IgG-RF (data not shown) or latex test–detected IgM-RF level without significantly modifying the results. Obviously, the positive predictive value does not reach 100%. According to the ROC curve, the false-negative rate was approximately 25%, in which case, the patient could risk being undertreated. Indeed, this model should serve only as a guide, indicating “risk factors” of developing ≥1 unequivocal erosion(s) within 2 years. It does not eliminate the need to monitor repeatedly functional joint status during the first 2 years of followup (21).
The fact that RF is predictive of erosion was expected because it was included as the ELISA-determined IgM-RF level in the Leiden model for persistent arthritis (12). In contrast to their observations, our multivariate analysis retained the IgA-RF isotype but not autoantibodies to CCP-2 as being predictive of erosion. In our study, anti–CCP-2 was effectively linked to erosion in univariate analysis (P = 0.003). But anti–CCP-2 also being strongly linked to IgA-RF (P < 10−6) in univariate analysis did not persist in multivariate analysis. It cannot be formally excluded that this discrepancy reflects the antibody isotype detected because the Leiden group sought only IgM-RF and used the first-generation anti-CCP detection kit, whereas we looked for all RF isotypes and used a second-generation test for CCP.
We included several markers of bone, cartilage, and synovium anabolism and catabolism (15, 30): pyridinoline, a molecule bridging collagen types I and II, is a marker of bone, cartilage, and synovium degradation; deoxypyridinoline indicates bone degradation; and serum CTX-I is a marker of bone and synovium degeneration, whereas cartilage and synovium syntheses are identified by YKL-40 (glycoprotein-39). Serum pyridinoline was the only marker independently predictive of ≥1 erosion(s) that, to the best of our knowledge, has never been reported previously. Studies designed to identify relationship(s) between erosion(s) and serum bone, cartilage, and/or synovium factors have been scarce. They generally concerned patients with proven RA and the potential link between those factors and the severity of structural joint involvement. Lindqvist et al used logistic regression analysis of the characteristics of patients with RA of a duration of <2 years to show that ESR, IgA-RF, anti-CCP, and anti–interleukin-1 receptor antagonists were associated with the severity of structural damage at 5 years (31). A satellite study of the COBRA (Combinatietherapie Bij Reumatoïde Artritis) therapeutic trial on RA evolving for <2 years showed that high baseline urinary CTX-I and CTX-II levels independently predicted a higher risk of structural damage progression over 4 years (32). When patients were grouped according to the presence or absence of initial joint damage, those molecules were predictive only for those without baseline structural joint involvement.
Several other studies examined the potential relationships between certain bone, cartilage, or synovium markers and RA activity: concentrations of urinary CTX-II and, to a lesser extent, CTX-I, serum matrix metalloproteinase 3, and pyridinoline varied according to disease activity (33, 34). Jansen et al (35) studied homogeneously treated patients with peripheral arthritis affecting ≥2 joints and a duration of symptoms of <2 years, and found that higher serum CTX-I levels were associated with radiographic progression at 2 years, but less predictive of factors already being used. To our knowledge, no study has determined the abilities of bone and cartilage markers to predict erosion(s) in an early arthritis cohort.
To conclude, 2 easily obtainable parameters, serum IgA-RF and pyridinoline levels, constitute risk factors for erosion(s). When their levels were simultaneously elevated, their OR for ≥1 erosion(s) at 2 years reached 51. It is now necessary to validate this prediction model on other population cohorts.