Rheumatoid arthritis (RA) used to be viewed as an inexorably progressive disease. More recently, RA has started to be perceived as a potentially curable condition with early, aggressive use of disease-modifying antirheumatic drugs (DMARDs) [1,2,3••,4,5]. The rationale for early initiation of DMARDs is based on the ‘therapeutic window of opportunity’ paradigm, a critical period during which therapy may have a durable effect and change the natural course of the disease. A meta-analysis  found that delaying antirheumatic therapy for 9 months after symptom onset results in significantly worse long-term outcomes. Thus, identifying individuals at high risk of developing RA as soon and as precisely as possible and initiating an appropriate antirheumatic therapy has become a critical objective for the management of early inflammatory arthritis.
Pathophysiological concepts of rheumatoid arthritis development
The finding of a strong gene–environment interaction in RA has modified our concepts of its pathogenesis and opened important opportunities for potential disease prevention . RA is now believed to result from a multistep process, in which an environmental trigger (i.e. tobacco smoke) induces specific posttranslational modifications (i.e. citrullination of proteins), which in turn initiate immune reactions [i.e. anticyclic citrullinated peptide antibodies (anti-CCP Ab)] in genetically susceptible individuals (i.e. the shared epitope) [8,9]. Other environmental exposures such as breast feeding, oral contraceptives, or regular alcohol consumption may be protective against the development of RA [10–12]. The pathologic activation of the immune system, or ‘immune onset of the disease’, occurs years before the ‘clinical onset of the disease’ (Fig. 1). The immune onset is followed by an asymptomatic or preclinical phase of the disease. During the preclinical phase, auto-antibodies are present [13–16], pro-inflammatory cytokines are elevated , and synovitis can be demonstrated on histology in clinically asymptomatic joints, years before the disease becomes clinically apparent . The existence of a period of asymptomatic activation of the immune system long before the first clinical symptoms emerge suggests that clinical RA represents already a chronic phase of the disease.
In order to stop autoimmune diseases, it is widely believed that we need to treat patients as early as possible, ideally before its clinical manifestations are fully developed . In animal models of autoimmune diseases, early therapeutic interventions are capable of preventing the development of the clinical disease . To date, only indirect evidence supporting this hypothesis is available in humans, but existing data suggest that early in the disease process, the immune system might still be malleable and some immunologic reprograming achievable. Currently, antirheumatic treatment is still initiated only relatively late, commonly more than 12 months after onset of symptoms . However, markers for RA exist and imply that early diagnosis and treatment may be possible in early inflammatory arthritis.
Identification of individuals with undifferentiated arthritis who will develop rheumatoid arthritis
At an early stage, not all patients with inflammatory polyarthritis can be reliably diagnosed. Early polyarthritis may develop into RA or another definite arthropathy, may resolve spontaneously, or may remain undifferentiated [22••]. Patients with inflammatory polyarthritis consult a physician on average within 4 weeks of symptom onset, yet the diagnosis of RA is delayed on average by 36 weeks . The current gold standard for the classification of RA remains the American College of Rheumatology (ACR) criteria . Although these criteria are specifically intended as a case definition for research purposes, they are often used for clinical diagnosis. For new-onset RA, the sensitivity and specificity of the ACR criteria are notably low . The poor discriminative abilities of ACR criteria in early RA may contribute to delayed diagnosis by physicians .
Technological advances, such as new biomarkers and clinical prediction rules, have improved prediction of progression to RA in patients presenting with undifferentiated polyarthritis. A meta-analysis [25•] reviewed the diagnostic accuracy of autoantibodies against CCP and rheumatoid factor. The systematic review confirmed that anti-CCP antibodies are more specific but not more sensitive than rheumatoid factor for diagnosing RA. The pooled sensitivity for anti-CCP was 67% (65–68%) and the specificity was 95% (95–96%). The diagnostic accuracy of anti-CCP was as good in early disease as in established RA, which makes anti-CCP particularly useful to predict the development of RA in patients with early inflammatory polyarthritis. The anti-CCP2 assay appears to be a more sensitive marker than the anti-CCP1 assay. Overall, no significant diagnostic benefit could be demonstrated by combining anti-CCP with IgM-rheumatoid factor [25•]. Several authors have suggested that incorporating anti-CCP testing into the standard evaluation of patients with early inflammatory polyarthritis would improve our ability to diagnose early RA and should therefore be included in future diagnostic criteria of RA and early RA. When incorporating anti-CCP status into the 1987 ACR classification criteria of RA, the sensitivity greatly improves, in particular for patients with symptoms of less than 6 months, however at the cost of slight decrease in specificity . Further research is needed to establish the clinical usefulness of other diagnostic tests such as genotyping, C-reactive protein, cytokine and chemokine profiling, magnetic resonance imaging (MRI), or articular ultrasound imaging in early undifferentiated polyarthritis.
The clinical utility of anti-CCP or any other diagnostic tests varies with the prior probability of the disease, which is the major implication of Bayes' theorem. The anti-CCP assay is comparatively a very specific diagnostic test; however, if used as a screening tool in individuals at a low pretest probability of RA, it will produce many false positive results . Clinical rules have been developed to estimate the risk of progression to RA in individual patients presenting with undifferentiated arthritis. The best validated prediction rule was established at the Leiden early arthritis clinic in the Netherlands [22••,28•]. Among the 570 patients with recent-onset undifferentiated arthritis, 177 patients developed RA, 150 achieved remission, and 94 developed another rheumatologic disorder after 1 year of follow-up. Using regression analysis, nine independent clinical parameters could be identified that predict the risk of developing RA within 1 year (sex, age, localization of symptoms, morning stiffness, tender joint count, swollen joint count, C-reactive protein level, rheumatoid factor positivity, and anti-CCP status). These were simplified into a 14-point, easy-to-use, weighted score (Table 1). The accuracy of this prediction rule was confirmed in several independent cohorts of patients with undifferentiated arthritis [28•], and corroborated the good discriminative ability of this tool (area under the receiver operating characteristic curve between 0.83 and 0.97). Usage of this instrument should allow improving individualized treatment decisions for patients suffering from early undifferentiated arthritis. A score of 0 represents the lowest risk of developing RA, and a score of 14 represents the highest risk. The positive predicted value for patients with a prediction score of 8 or greater was 97%; the negative predictive value for patients with a score of 6 or lower was 83% and virtually none of the patients with a score of 3 or less was ultimately diagnosed with RA [28•]. On the basis of these findings, for patients with a score of at least 8, DMARD therapy should be considered, whereas for patients with a score of 6 or less, the risk of progression is low and careful clinical supervision might be enough.
Treating patients with undifferentiated inflammatory arthritis
Current treatment guidelines for the management of early arthritis recommend that ‘patients at risk of developing persistent and/or erosive arthritis should be started with DMARDs as early as possible, even if they do not fulfill established classification criteria for inflammatory rheumatological diseases yet’ . Practice guidelines suggest primarily methotrexate as the first DMARD in patients at risk of developing persistent disease and propose to consider concomitant systemic glucocorticoids – at least temporarily – to reduce pain and joint swelling [29,30]. The main goal of introducing DMARD therapy at such an early stage is to achieve remission .
Whereas there is a considerable body of literature on the therapy of early RA, only a limited number of clinical trials have been performed in the setting of early inflammatory arthritis. The Probable Rheumatoid Arthritis: methotrexate versus Placebo Treatment (PROMPT) study [3••] investigated the benefits of methotrexate in patients with undifferentiated arthritis fulfilling the 1958 ACR criteria for probable RA. The primary outcomes were the rate of progression to RA and radiographic joint damage. One hundred and ten patients were randomized to methotrexate 15 mg/week or placebo. After 12 months, the study medication was discontinued and patients were followed up for 30 months. At the end of the follow-up, 40% of patients in the methotrexate group and 53% in the placebo group had developed definite RA. Furthermore, patients in the methotrexate group developed RA at a later time point (P = 0.04) and fewer patients demonstrated radiographic joint damage (P = 0.046). One of the most interesting findings from the study was that only patients with positive anti-CCP test benefited significantly from methotrexate (Fig. 2). Overall, the results of this study suggest that a limited course of methotrexate can delay the onset of RA or even prevent progression to full-blown RA in some patients.
Another study [31••] investigated the benefits of a limited course of intramuscular (i.m.) steroids in patients with early undifferentiated arthritis. The aim of this study was also to determine whether treatment of recent onset inflammatory polyarthritis with 3 weekly injections of i.m. glucocorticoids could suppress evolution to RA. The ‘steroids in very early arthritis’ (STIVEA) trial was a double-blind, placebo-controlled multicenter trial of methylprednisolone i.m. 80 mg/week three times versus placebo in patients with more than two swollen or tender joints and 4–11 weeks of symptom duration. Patients were followed up for 12 months after randomization and assessed for the initiation of DMARD therapy. Two hundred and sixty-five patients were enrolled and baseline characteristics were balanced between the two treatment groups. At 6 months, 78% of the placebo group and 62% of the steroid group had either started or been referred for DMARD therapy [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.21, 4.30]. At 12 months, 60% of the placebo group, compared to 50% of the steroid group, reached a diagnosis of RA (OR 1.49, 95% CI 0.81, 2.75), and 20% of patients in the glucorticoid arm were arthritis-free compared with 10% in the placebo arm.
A third study [32••] examined the benefits of the biological agent abatacept in patients with early undifferentiated polyarthritis. Similar to the previous trials, the study's objective was to assess whether a limited course of active therapy is more effective than placebo in preventing the development of RA in anti-CCP-positive patients with undifferentiated inflammatory polyarthritis at high risk of developing RA. In this exploratory study, 56 patients were randomized 1: 1 to abatacept or placebo for up to 6 months, after which treatment was terminated. By 1 year, 46% (12/26) abatacept-treated patients developed RA versus 67% (16/24) placebo-treated patients (20.5% difference; 95% CI: from −7.8 to +47.4). The authors concluded that abatacept may delay progression to definite RA in some patients with undifferentiated polyarthritis, with a sustained benefit even after therapy cessation.
Taken together, these trials in undifferentiated arthritis suggest that giving potent anti-inflammatory therapy to patients at an early stage will slow the progression from undifferentiated inflammatory polyarthritis to definite RA, especially in anti-CCP-positive patients. The optimal treatment in this setting is not yet established, but one strategy could be to start a short course of systemic glucocorticoids and initiate DMARDs in those patients not responding to – or flaring after discontinuation of – glucocorticoids. Clearly, further research is warranted and longer follow-up is needed before definite therapeutic strategies can be proposed.
Early inflammatory arthritis is a critical period of the disease, during which therapy may have a durable effect and change the natural course of the condition. Thus, identifying patients at high risk of developing RA at a very early stage should be an essential objective of the clinical care of patients with undifferentiated inflammatory arthritis. Anti-CCP antibodies and prediction rules have improved our ability to estimate the risk of progression to RA in individual patients presenting with undifferentiated arthritis. Existing data suggest that treating patients with undifferentiated arthritis at high risk of developing RA with potent antirheumatic therapy slows the progression from early inflammatory polyarthritis to definite RA and inhibits the progression of joint damage.
Grant support by the Swiss National Science Foundation (grant 3200B0_120639/1).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 190–191).
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